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Lorenzo Belluzzi,1,2,* Giulio Martinelli,1,2,* Bianca Medici,1,2 Alessandro Farina,1 Enrica Martinelli,1 Fabio Canino,1,2 Federica Caggia,2,3 Alessia Molinaro,1 Monica Barbolini,2,4 Fabio Tamburrano,1 Luca Moscetti,2,4 Federico Piacentini,1,2 Massimo Dominici,1 Claudia Omarini2,4 1Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy; 2GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), Parma, Italy; 3Department of Training, Research and Innovation, University Hospital of Modena, Modena, Italy; 4Department of Medical Oncology, University Hospital of Modena, Modena, Italy*These authors contributed equally to this workCorrespondence: Claudia Omarini, Division of Medical Oncology, University Hospital of Modena, Via del Pozzo 71, 41122, Modena, Italy, Tel +39 059 4222845, Email claudia.omarini@gmail.comAbstract: In recent years, new anticancer drugs have been investigated and approved for the treatment of breast cancer based on improved survival outcomes. However, these new treatments have specific class-related side effects. Pulmonary toxicity has been identified as an adverse event of special interest with everolimus, and is becoming an increasingly significant clinical challenge with the recent approval of trastuzumab deruxtecan. Overall, the risk of pulmonary toxicity is quite low but in some cases lung damage can be fatal. We conducted an update including the available published data regarding the incidence, mechanisms of pathogenesis, clinical presentations, and treatment of lung toxicity induced by new anticancer drugs. A literature search was performed between January and June 2024, considering papers, clinical trials, case reports, case series, meta-analyses, and systematic reviews published from January 2014 to June 2024. We also provide an algorithm for diagnosis and treatment, along with real-life cases managed at the Modena Cancer Center. Data provided here show that pulmonary toxicity is a quite frequent side effect and underline that early recognition and prompt treatment are crucial for the best outcome of patients, whose overall prognosis is being improved by the availability of these new anticancer agents.Keywords: breast cancer, lung toxicity, Pulmonary toxicity, interstitial lung disease, pneumonia, trastuzumab deruxtecan, CDK4/6i

Massimiliano Salati,1,2 Luigi Marcheselli,1 Carlo Messina,3 Valeria Merz,3,4 Marco Messina,5 Pietro Carotenuto,6 Francesco Caputo,1 Fabio Gelsomino,1 Andrea Spallanzani,1 Luca Reggiani Bonetti,7 Stefania Caramaschi,7 Gabriele Luppi,1 Massimo Dominici,1 Michele Ghidini8 1Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy; 2PhD Program Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy; 3Department of Medical Oncology, Santa Chiara Hospital, Trento, Italy; 4Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy; 5Oncology Unit, Fondazione San Raffaele-Giglio, Cefalu’, Palermo, Italy; 6Telethon Institute of Genetics and Medicine, Pozzuoli, 80078, Napoli, Italy; 7Pathology Section, University Hospital of Modena, Modena, Italy; 8Medical Oncology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, ItalyCorrespondence: Massimiliano Salati, PhD Program Clinical and Experimental Medicine, University Hospital of Modena, Modena Cancer Centre, via del Pozzo 71, Modena, 41125, Italy, Tel +39/0594223808, Fax +39/0594222647, Email massimiliano.salati@unimore.itBackground: The role of second-line chemotherapy in advanced biliary cancers (ABCs) has only recently been established in phase III randomized trial and the optimal selection of patients most likely to benefit from it remains challenging.Methods: A cohort of 98 ABC treated second-line chemotherapy was used as a developmental dataset to identify covariates independently associated with overall survival (OS). Kaplan–Meier analysis was used to investigate the association between variables and OS and those retaining statistically significance were combined in a multiplexed score.Results: The following pretreatment variables were independently associated with OS: ECOG PS > 0, peritoneal disease, LDH > 430 UI/L, albumin < 3.5 gr/dL, gamma-GT > 100 UI/L, sodium < 140 mEq/L, absolute lymphocyte count < 1000/mmc, and PFS to first-line < 6 months. Based on these results, a scoring system was developed that identified three subgroups with statistically different OS: low-risk (mOS 18 months), intermediate-risk (mOS 9.4 months) and high-risk (mOS 2.9 months) (p < 0.001). The prognostic model was both internally and externally validated in a multicentre cohort of 120 ABCs.Conclusion: The Modena score is a multiplexed scoring system capable of accurately risk-stratified ABCs treated with second-line chemotherapy. Based on its reproducibility, usability and generalizability, it has the potential for assisting therapeutic decision-making in the clinic and risk-stratification in future trials.Graphical Abstract: Keywords: biliary tract cancer, chemotherapy, second-line, prognostic score, survival

Massimiliano Salati,1,2 Francesco Caputo,1 Cinzia Baldessari,1 Pietro Carotenuto,3 Marco Messina,4 Stefania Caramaschi,5 Massimo Dominici,1 Luca Reggiani Bonetti5 1Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy; 2PhD Program Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy; 3Department of Genomics, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; 4Department of Oncology, Fondazione Istituto G. Giglio, Cefalu, Italy; 5Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia – AOU Policlinico of Modena, Modena, ItalyCorrespondence: Massimiliano SalatiDepartment of Oncology and Hematology, University Hospital of Modena, Via del Pozzo 71, Modena, 41125, ItalyTel +390594223808Fax +390594222647Email massimiliano.salati@unimore.itAbstract: Intrahepatic cholangiocarcinoma (iCCA) is an anatomically and biologically distinct entity with a rising incidence and a poor prognosis on conventional treatments. Surgery followed by adjuvant chemotherapy is a potentially curative option in resectable cases, while palliative-intent chemotherapy is the standard-of-care in the advanced setting. Technological advances through massive parallel sequencing have enabled a deeper understanding of disease biology with the identification of several druggable molecular vulnerabilities in nearly 50% of cases. Among them, gene fusions involving the fibroblast growth factor receptor 2 (FGFR2) are the most therapeutically exploited so far with a number of Phase II clinical trials investigating FGFR2 inhibitors showing unprecedented efficacy results in this molecular subgroup. Over the last year, these efforts have culminated in the US FDA-approval of pemigatinib and infigratinib, the first two oral selective FGFR2 targeted agents for previously treated, locally advanced or metastatic iCCA driven by FGFR2 fusion or rearrangements. While first-line Phase III trials are currently underway to test these targeted approach against standard-of-care chemotherapy, translational studies are trying to better understand primary and secondary resistance mechanisms in order to optimize FGFR2 blockade in iCCA. In this article, we extensively reviewed the current evidence on the biological rationale, as well as preclinical and clinical development of FGFR inhibitors in iCCA.Keywords: biliary cancer, cholangiocarcinoma, intrahepatic, FGFR2, targeted therapy, precision medicine

L’articolo parte dalla problematica legata alla complessità dei flussi migratori, che vengono esaminati da diversi punti di vista: da un lato, viene evidenziato il tentativo di sottrarsi, da parte di molte persone, a situazioni ambientali di difficoltà, di sofferenza e di miseria ; dall’altro lato, si sottolinea come tale fenomeno possa essere collegato strettamente alla criminalità transnazionale.In entrambe le prospettive, si generano situazioni e rischi di vittimizzazione.Successivamente, prendendo a prestito vecchie favole, vi si costruiscono attorno le esperienze di situazioni reali che riguardano un bambino, il senso e la perdità di identità.Cet article aborde le problème de la complexité des flux migratoires. Ces derniers sont observés selon différents points de vue : d’une part, l’auter met en évidence que de nombreuses personnes essaient d’échapper à des situations éprouvantes, de souffrance et de misère ; d’autre part, l’auter souligne que ce phénomène peut être strictement lié à la criminalité transnationale.Dans les deux cas, des risques de victimisation se créent.Ensuite, en empruntant de vieilles fables, l’auter construit autour d’elles les expériences de vie réelle qui incluent un enfant, le sens et la perte d’identité. This article discusses the problem related to the complexity of migration from different points of view : on the one hand, the author underlines that a large number of people seeks to escape from difficult situations of poverty ; on the other hand, the author highlights that this phenomenon can be strictly related to transnational crime. In both cases, these situations increase the risks of victimization. Then, borrowing old fables, the author builds around them some experiences of real life including the ones of a child and of the sense and the loss of identity.

Background The optimal time interval between the end of neoadjuvant systemic therapy (NST) and breast surgery is still unclear. It is not known if a delay in surgery might influence the benefit of primary chemotherapy. The aim of this study is to evaluate the relationship between time to surgery (TTS) and survival outcomes. Patients and methods According to TTS, women with diagnosis of BC treated with NST were divided into two cohorts: group A = 21 days or fewer and group B = longer than 21 days. OS and RFS were estimated and compared according to TTS and known prognostic factors. Results A total of 319 patients were included in the study: 61 in group A and 258 in group B. Median TTS was 34 days. No association between clinical stage, nuclear grade, type of chemotherapy, type of surgery and TTS was detected. OS and RFS were significantly worse for group B compared with group A, with a hazard ratio of 3.1 (95% CI, 1.1–8.6 p = 0.03) and 3.1 (95% CI, 1.3–7.1 p = 0.008) respectively. Multivariate analysis confirmed that TTS was an independent prognostic factor in term of OS (p = 0.03) and RFS (p = 0.01). Even in the subgroup of patients with pCR, TTS continued to be an independent prognostic factor for both OS and RFS (p = 0.05 and p = 0.03). Conclusions TTS after NST seems to influence survival outcomes. BC patients underwent surgery within 21 days experienced maximal benefit from previous treatment: this advantage is consistent and maintained over time. [ABSTRACT FROM AUTHOR]

From 4 to 5 April 2008, international experts met for the second time in Tubingen, Germany, to present and discuss the latest proceedings in research on non-hematopoietic stem cells (NHSC). This report presents issues of basic research including characterization, isolation, good manufacturing practice (GMP)-like production and imaging as well as clinical applications focusing on the regenerative and immunomodulatory capacities of NHSC. [ABSTRACT FROM AUTHOR]

In recent years mesenchymal stromal cells (MSC) have emerged as a major new form of cell therapy. While the original perception was that MSC were stem/progenitor cells with the potential to contribute to the regeneration of tissue, more recent data suggest that the principal mechanism of MSC activity is through the release of soluble mediators that elicit the observed biologic response. Future studies are needed to identify more completely the spectrum of therapeutic applications and delineate better the associated molecular and cellular mechanisms. [ABSTRACT FROM AUTHOR]

Information about several reports discussed at a meeting on progress in characterization, preparation and clinical applications of non-hematopoietic stem cells is presented. These reports includes hematopoiesis and osteopoiesis by marrow-derived progenitors, complex interactions of serum content, culture conditions and source of cells, and emerging markers and new fishing tools for mesenchymal stromal cells/endothelial progenitor cells (MSC/EPC).

Background In vitro cultures of BM cells from newly diagnosed patients with AML displayed a defective BM stromal compartment, with a reduced number of fibroblast-colony-forming unit (CFU-F: 1±1.25 SD) and a decreased proliferative ability. The purposes of our study were: 1) to select BM mesenchymal stem cells (MSC) and BM-derived stromal cells (BMDSCs) from AML patients at diagnosis and from healthy subjects, using an immunomagnetic system and either anti-CD105 or anti-fibroblast MAbs; 2) to study the immunophenotypic and functional properties of freshly isolated and cultured mesenchymal cells; 3) to test the in vitro plasticity of the selected cells to differentiate towards an endothelial phenotype. Methods Fresh mononuclear cells obtained from BM of 20 patients newly diagnosed with AML and from eight healthy subjects were selected by using anti-fibroblast and anti-CD105 MAbs. Freshly isolated cells were analyzed, characterized by flow cytometry using a wide panel of MAbs and seeded in long-term culture medium to assess CFU-F formation. The level of confluence after 30 days and functional capacity in a long-term colony-forming cell culture (LTC-CFC) were tested. Furthermore, the cultured selected cell populations were assayed for their ability to differentiate into an endothelial-like cell phenotype with the addition of vascular endothelial growth factor (VEGF) and endothelial cell growth supplement (ECGS). Results In normal subjects the selection produced an increase of the CFU-F number of 2.6-fold with anti-fibroblast MAb and 2.7-fold with the anti-CD105 MAb. Anti-fibroblast and anti-CD105 MAb selection from AML BM cells resulted in a statistically significant greater count of CFU-F that was respectively 10.6-fold (P=0.04) and 14.4-fold (P=0.00001) higher in comparison with the unselected AML samples. Interestingly, in 80% of AML samples immunoselection was also able to restore the capacity of the CFU-F to proliferate and form confluent stromal layers. The isolation of those layers sustained the proliferation and differentiation of hematopoietic stem cells in the LTC-CFC. The phenotypic profile of cultured BMDSCs was different from that of the freshly isolated cells, and changed in relation to the culture conditions: CD105 + selected cells cultured with VEGF and ECGS expressed endothelial markers, a finding that suggests that this cell subpopulation may have the potential to differentiate toward an endothelial-like phenotype. Discussion We report that immunomagnetic selection represents a valid tool for the selection of BM mesenchymal cells in samples obtained from both healthy subjects and patients with AML. This technique was able to rescue two functional and immunophenotypic compartments related to two different selected populations. In particular, the CD105 + cells isolated in AML displayed, after stimulation with VEGF and ECGS, the ability to change towards an endothelial-like cell phenotype, thus revealing an unexpected plasticity. Both CD105 + and fibroblast + cells once successfully isolated might represent sources of mesenchymal cells populations useful for in vitro investigations and, above all, as therapeutic devices. [ABSTRACT FROM AUTHOR]

The life-cycle of T. ampelophaga has been observed in 3 vineyards in Umbria (Central Italy) for 9 years (1976-1984) in the field and in the laboratory in order to compare the results of both. A summary is also given on world distribution, of this insect and in particular have been studied natural enemies and abiotic factors (meteorological and summer spraying), which are supposed to be dangerous to this insect. The results show the following: - the insect has only one generation per year and overwintering takes place in the bark of the vine and in stubs as larvae of second instar; - six species of parasites were found, that is 2 Chalcididae ( Brachymeria intermedia Nees and Hocheria unicolor Walk.), 1 Braconidae ( Apanteles ultor Reinh.), 2 Tachinidae ( Zenillia libatrix [Panzer] and Exorista sp.) and 1 Trichogrammatidae ( Trichogramma evanescens Westw.). The percentage of parasites is not very high so that they are not able to control the infestation of T. ampelophaga; - rainfalls, winds and high temperatures kill the pre-adult instar of T. ampelophaga but fungicide and insecticide commonly sprayed in summer are more dangerous for the insect than the previous ones. Zusammenfassung Beiträge zur Biologie und zum Massenwechsel von Theresimima ampelophaga Bayle-Barelle (Lep., Zygaenidae) Es wurden Biologie und Ethologie von T. ampelophaga sowie die klimatischen Faktoren hinsicht-lich der Sterblichkeit der larvalen Stadien dieser Art in 3 verschiedenen Weinbergen (Mittelitalien) von 1976-1984 untersucht. Es konnte gezeigt werden, daß T. ampelophaga jährlich eine Generation bildete, deren Larven im 2. Stadium unter der Baumrinde und am Sporn der Schnittstellen des vergangenen Jahres überwinterte. Die Forschungen über T. ampelophaga ergaben 6 Arten von natürlichen Feinden der Eier, Larven und Puppen, die wegen ihrer geringen Dichte jedoch kein wesentliches Element zur Reduktion von T. ampelophaga bildeten. Die 6 Arten sind: Tricho-gramma evanescens Westw. (Hym., Trichogrammatidae), Brachymeria intermedia Nees und Hocheria unicolor Walk. (Hym., Chalcididae), Apanteles ultor Reinh. (Hym., Braconidae). Zenillia libatrix (Panzer) und Exorista sp. (Dipt., Tachinidae). Die wichtigsten Faktoren, die den Befall durch T. ampelophaga verminderten, waren hohe Temperaturen, Regen und Wind sowie Fungizid- und Insektizid-Ausbringungen in den Weinbergen. [ABSTRACT FROM AUTHOR]

This study speaks about the relationship between olive fly (D. oleae) ovipositing and certain physical parameters of drupes. During the first period of observation weight was the most important parameter statistically. Subsequently, this relationship became less important because of the remarcable increase in the density of population and because of the presence in the olives of particular substances which induce the female to select the smaller drupes for ovipositing. Zusammenfassung Verteilung des Befalls mit Dacus oleae (Gmel.) (Diptera, Tephrytidae) bei Oliven In dieser Studie sind die Ergebnisse eines Experiments zusammengefaßt, das in einem Jahr hohen Befalls von D. oleae (1983) und in 2 verschiedenen Olivenhainen Mittelitaliens die Beziehung zwischen der Anzahl der Eiablagen in einer Steinfrucht und einigen ihrer physikalischen Parameter untersuchte. Die Ergebnisse zeigten sehr deutlich, daß von alien betrachteten Variablen der Steinfrucht (Gewicht, Länge der gröml;ßen und der kleinsten Achse, Sorte sowie Lage und Zeitpunkt der Pflanzung) das Gewicht die Veränderlichkeit der Eiablagen in den Steinfrüchten statistisch am besten erklärt. Diese Abhängigkeit schwächt sich mit der Zeit ab, nicht nur auf Grund der Erhöml;hung des Befalls, sondern vor allem auf Grund der Zusammensetzung der anziehenden und abstoßenden Substanzen, die während des Reifungsprozesses von den Oliven produziert werden. Ein weiteres Resultat ist, daß schwerere Steinfrüchte, obwohl sie im Durchschnitt mehr als eine Eiablage aufweisen, die vollständige Entwicklung des Nachwuchses besser garantieren als leich-tere. [ABSTRACT FROM AUTHOR]

The considerable therapeutic potential of human multipotent mesenchymal stromal cells (MSC) has generated markedly increasing interest in a wide variety of biomedical disciplines. However, investigators report studies of MSC using different methods of isolation and expansion, and different approaches to characterizing the cells. Thus it is increasingly difficult to compare and contrast study outcomes, which hinders progress in the field. To begin to address this issue, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposes minimal criteria to define human MSC. First, MSC must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79α or CD19 and HLA-DR surface molecules. Third, MSC must differentiate to osteoblasts, adipocytes and chondroblasts in vitro . While these criteria will probably require modification as new knowledge unfolds, we believe this minimal set of standard criteria will foster a more uniform characterization of MSC and facilitate the exchange of data among investigators. [ABSTRACT FROM AUTHOR]