Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO

PURPOSE To verify whether the intensification of the upfront chemotherapy backbone with a modified schedule of modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) increases the activity of fluorouracil, leucovorin, and oxaliplatin when both regimens are combined with panitumumab as initial treatment for RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC).METHODS TRIPLETE was a prospective, open-label, phase III trial in which previously untreated patients with unresectable RAS and BRAF wt mCRC were randomly assigned 1:1 to modified FOLFOX/panitumumab (control group) or mFOLFOXIRI/panitumumab (experimental group) up to 12 cycles, followed by fluorouracil/-leucovorin/panitumumab until disease progression. The primary end point was objective response rate (ORR) according to RECIST 1.1. Hypothesizing an ORR of 60% in the control group, 432 cases provided 90% power to a two-sided chi-square test for heterogeneity with a two-sided alpha error of .05 to detect >= 15% differences between arms (ClinicalTrials.gov identifier: NCT03231722).RESULTS From September 2017 to September 2021, 435 patients were enrolled (control group/experimental group: 217/218) in 57 Italian sites. One hundred sixty (73%) patients treated with mFOLFOXIRI plus panitumumab and 165 (76%) patients treated with modified FOLFOX plus panitumumab achieved RECIST response (odds ratio 0.87, 95% CI, 0.56 to 1.34, P= .526). No differences in early tumor shrinkage rate (57%/58%, P = .878) and deepness of response (median: 48%/47%, P = .845) were reported, nor in RO resection rate (25%/29%, P = .317). No significant difference between arms was reported in terms of progression-free survival (median progression-free survival: 12.7 in the experimental group v 12.3 months in the control group, hazard ratio: 0.88, 95% CI, 0.70 to 1.11, P = .277).CONCLUSION The intensification of the upfront chemotherapy backbone in combination with panitumumab does not provide additional benefit in terms of treatment activity at the price of increased gastrointestinal toxicity in patients with RAS and BRAF wt mCRC. (C) 2022 by American Society of Clinical Oncolog

Whole Lung Irradiation after High-Dose Busulfan/Melphalan in Ewing Sarcoma with Lung Metastases: An Italian Sarcoma Group and Associazione Italiana Ematologia Oncologia Pediatrica Joint Study

SIMPLE SUMMARY: The lung is the most frequent site of metastasis in Ewing sarcoma, the second most common bone cancer affecting children, adolescents and young adults. The five-year overall survival of patients with isolated lung metastasis is approximately 50% after multimodal treatments including chemotherapy, surgery and radiotherapy. This retrospective study aimed to investigate the feasibility and the predictors of survival in 68 Ewing sarcoma patients with lung metastases who received high-dose chemotherapy with busulfan and melphalan, followed by reduced dose whole-lung irradiation, as part of two prospective and consecutive treatment protocols. This combined treatment strategy is feasible and might contribute to the disease control in lung metastatic Ewing sarcoma with responsive disease. Furthermore, the results of this study provide support to explore the treatment stratification for lung metastatic Ewing sarcoma based on the histological response of the primary tumor. ABSTRACT: Purpose: To analyze toxicity and outcome predictors in Ewing sarcoma patients with lung metastases treated with busulfan and melphalan (BU-MEL) followed by whole-lung irradiation (WLI). Methods: This retrospective study included 68 lung metastatic Ewing Sarcoma patients who underwent WLI after BU-MEL with autologous stem cell transplantation, as part of two prospective and consecutive treatment protocols. WLI 12 Gy for <14 years old and 15 Gy for ≥14 years old patients were applied at least eight weeks after BU-MEL. Toxicity, overall survival (OS), event-free survival (EFS) and pulmonary relapse-free survival (PRFS) were estimated and analyzed. Results: After WLI, grade 1–2 and grade 3 clinical toxicity was reported in 16.2% and 5.9% patients, respectively. The five-year OS, EFS and PRFS with 95% confidence interval (CI) were 69.8% (57.1–79.3), 61.2% (48.4–71.7) and 70.5% (56.3–80.8), respectively. Patients with good histological necrosis of the primary tumor after neoadjuvant chemotherapy showed a significant decreased risk of pulmonary relapse or death compared to patients with poor histological necrosis. Conclusions: WLI at recommended doses and time interval after BU-MEL is feasible and might contribute to the disease control in Ewing sarcoma with lung metastases and responsive disease. Further studies are needed to explore the treatment stratification based on the histological response of the primary tumor

Irresponsiveness of two retinoblastoma cases to conservative therapy correlates with up- regulation of hERG1 channels and of the VEGF-A pathway

<p>Abstract</p> <p>Background</p> <p>Treatment strategies for Retinoblastoma (RB), the most common primary intraocular tumor in children, have evolved over the past few decades and chemoreduction is currently the most popular treatment strategy. Despite success, systemic chemotherapeutic treatment has relevant toxicity, especially in the pediatric population. Antiangiogenic therapy has thus been proposed as a valuable alternative for pediatric malignancies, in particolar RB. Indeed, it has been shown that vessel density correlates with both local invasive growth and presence of metastases in RB, suggesting that angiogenesis could play a pivotal role for both local and systemic invasive growth in RB. We present here two cases of sporadic, bilateral RB that did not benefit from the conservative treatment and we provide evidence that the VEGF-A pathway is significantly up-regulated in both RB cases along with an over expression of hERG1 K⁺channels.</p> <p>Case presentation</p> <p>Two patients showed a sporadic, bilateral RB, classified at Stage II of the Reese-Elsworth Classification. Neither of them got benefits from conservative treatment, and the two eyes were enucleated. In samples from both RB cases we studied the VEGF-A pathway: VEGF-A showed high levels in the vitreous, the <it>vegf-a, flt-1, kdr</it>, and <it>hif1-α </it>transcripts were over-expressed. Moreover, both the transcripts and proteins of the hERG1 K⁺channels turned out to be up-regulated in the two RB cases compared to the non cancerous retinal tissue.</p> <p>Conclusions</p> <p>We provide evidence that the VEGF-A pathway is up-regulated in two particular aggressive cases of bilateral RB, which did not experience any benefit from conservative treatment, showing the overexpression of the <it>vegf-a</it>, <it>flt-1</it>, <it>kdr </it>and <it>hif1-α </it>transcripts and the high secretion of VEGF-A. Moreover we also show for the first time that the <it>herg1 </it>gene transcripts and protein are over expressed in RB, as occurs in several aggressive tumors. These results further stress the relevance of the VEGF-A pathway in RB and the correlation with hERG1, making aggressive and recurrent RB cases good candidates for antiangiogenesis therapies based on the targeting of VEGF-A.</p

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

The genetic diversity and spatial genetic structure of the Corso-Sardinian endemic Ferula arrigonii Bocchieri (Apiaceae)

Corsica and Sardinia represent major hotspots of plant diversity in the Mediterranean area and are priority regions for conservation due to their high number of endemic plant species. However, information supporting human decision-making on the conservation of these species is still scarce, especially at the genetic level. In this work, the first assessment is reported of the species-wide spatial genetic structure and diversity of Ferula arrigonii Bocchieri, a Corso-Sardinian endemic located in a few coastal sites and on small islands. Nine populations covering the entire natural range of the species were investigated by means of AFLP (amplified fragment length polymorphism) markers. Results indicate that this species is characterised by high levels of genetic polymorphism (92% polymorphic fragments) and of genetic diversity (Hw = 0.317) and by relatively low differentiation among populations (Fst = 0.057). PCoA, Bayesian analysis and neighbour-joining clustering were also employed to investigate the genetic structure of this species. Three genetically distinct groups were detected, although with considerable overlap between populations

The Role of Exercise in Pediatric and Adolescent Cancers: A Review of Assessments and Suggestions for Clinical Implementation

In the European Union, five-year survival rates for childhood cancer patients are approaching 72–80%, which is a testament to better diagnostics and improved treatment. As a result, a large proportion of childhood cancer patients go on to live productive lives well past reproductive age. While this is encouraging, childhood cancer treatment is accompanied by multiple long-term adverse effects on physical and mental wellbeing. While there are several approaches to address mental health, reproductive integrity, secondary pathologies, and recurrence, in order to optimize quality of life in childhood cancer patients, exercise and nutrition should also be considered. It is clear that physical activity plays an important role in the prevention and reduction of long-term adverse side effects associated with cancer treatment in both children and adults. However, the current exercise guidelines for cancer survivors are based on adult data and accordingly are not appropriate for children. As children and adults are markedly different, including both the pathophysiology of cancer and exercise response, treatment plans incorporating exercise for children should be age-specific and individually tailored to both reduce the development of future comorbidities and enhance physical health. The purpose of this paper is to review the predominant cancer types and effects of cancer treatment in children, describe several special considerations, and propose a framework for assessment and exercise guidelines for this population

International open ideas competition for the design of the surrounding area of the ancient theater 'A' in Larissa, Greece

The presence of archeology within contemporary urban fabrics can often arise problems of different nature, which transform the city into an obstacle course between fenced cultural heritage and "archaeological" ruins, isolated and detached from urban city life and from its relational spaces. The competition proposal seeks to integrate the requests for the enhancement of cultural and archaeological heritage with those of contemporary social life within a new free, playful and healthy public space, lived in by all social groups and all kind of citizens. The Ancient Theater 'A' will be part of a linear public path that starts from the Central Square of Larissa, where an "urban nave", obtained from the demolition of the blocks between the parallel streets Papanastasiou and Apollonos, connects to Venizelou street, towards the ancient theater 'A'. At the urban scale, our proposal intends to re-center the acropolis area, giving it a central role not only from a symbolic point of view, but also as a hub for the network of the urban pedestrian paths. Throughout a straight path, that borders the edge of the green embankment of the reconstituted cavea, the acropolis comes to be the heart of a circular environmental system that connects the green and river systems of the city. The "urban nave" is characterized by a long canopy-pergola made up of slender steel structures and shading slats, fragmented by some pre-existing architectural structures and by precious existing and newly planted trees. At the edge of the "urban nave", towards Venizelou Street, there is a ramp that leads to an underground level, an open air patio which overlooks the ticket office, the toilets, the bookshop, a cafeteria and the entrance to the technical rooms of the theater: dressing rooms, bathrooms, showers, costume warehouse and, to the left of the theater, the prop warehouse. This patio comes to be the open air foyer to the visit area of ​​the archaeological site, leading in the orchestra and the proscenium of the theater. To the right of the ‘Ancient theater A’ there is a multifunctional building that contains a cafeteria with a panoramic terrace, situated at the level of the street, while at the lower level there is a multipurpose conference room of 200 square meters. From Venizelou Street the urban path reaches the level of the Fortress hill with a climb, set to the left of the theater, which runs along the cavea on one side, along the enclosure reserved to the archeologists on the other. The enclosure reserved to the archaeologists is a courtyard building with walls and shelves for remains, that makes the archaeological finds perceptible from the public path. In the courtyard of the building, on the other hand, the warehouses, archives and offices overlook. The path between the warehouse and the theatre is divided into one that runs in the green of the Fortress Hill and another one that climbs up to the top of the slope of the theater. The park is redesigned according to landscape criteria through an abstract grid in which new plantings are arranged, integrating the existing ones, thus giving the new paths a healthy shade that mitigates the temperature and oxygenates the urban area. The main route divides the green area into a predominantly wooded area, to the west side, and into a grass one, with meadows surrounding the archaeological remains, situated at the east side, where new playgrounds are located at the edge of the garden. Thus, through interventions targeted to subtract degraded buildings, floors, green surfaces and a few new volumes, including the virtual and dematerialized one of the canopy-pergola, the BB8888 competition proposal transforms a series of isolated, underused and degraded urban places into an unitary linear public space, which links in a single path the Fortress Hill with the Central Square, providing a series of social spaces, archaeological areas, green parterre and playgrounds, giving the city a new identity grafted on its millenary tradition. The ‘Ancient theater A’, on the other hand, becomes the hinge of this public space, transforming itself into a multipurpose structure that is at the same time an archaeological site, a theatrical space, a public promenade, an urban scenography and a green area for relax. In this long path, all the activities proper of contemporary city life are arranged, according to criteria of environmental sustainability, social resilience and cultural identity: parks, services for commerce and dining, playgrounds, archaeological sites equipped with services and cultural structures, the small auditorium-multipurpose room, the theater itself with its service areas (dressing rooms, warehouses) and, finally, the Larissa Archeo LAB located in the former bakery, freed from the current function of warehouse, now located in the West enclosure. This space is a participatory archeology laboratory, to actively involve the community and raise awareness of the patrimonial value of one's territory