Duodenal tumors: four case reports

We report 4 cases of neuroendocrine tumors of the duodenum. Signs and symptoms were non-specific. The choice of surgery depended on the site and stage of the tumor and any concomitant diseases.

Unilateral synchronous breast tumors. Rare association of myofibroblastoma and osteosarcoma

The authors describe the case of a patient with two particularly rare contiguous tumors, myofibroblastoma and osteosarcoma, in the same breast. Rare does not mean untreatable, and the chance of recovery is no less than with more common tumors. However, rare tumors do present a significant problem for pathologists due to diagnostic difficulties, and so an exact prognosis is not always possible.

Twenty years experience in oncologic surgery for primary cardiac tumors

Introduction. Primary cardiac tumors are uncommon in cardiac surgery. To investigate the clinical presentation, surgical results and long-term follow-up we retrospectively analyzed our experience in the treatment of primary cardiac tumors. Patients and methods. Ninety-one patients with primary cardiac tumors underwent surgery in our department in the last 20 years. Fifthy-one patients were female, the mean age was 62,2 years. Sixty-three had myxomas, 22 had papillary fibroelastoma, 4 had malignant neoformations and 2 had other benign tumors. Results. All myxomas, fibroelastomas and angiomyolipoma were radically removed. Only a palliative treatment was possible in malignant disease. In-hospital mortality was 1.2%. The mean follow-up time was 78.5 months. Three patients had recurrence of myxoma, all patients with malignant disease dead during the follow-up. Discussion. Primary benign cardiac tumors can be treated with low morbidity and mortality. The follow-up demonstrates that radical surgery is curative in case of benign tumors. The prognosis of malignant tumors is still poor. Palliative procedures have small impact on survival in these patients.

Successful management of evisceration occurred after exploratory laparotomy for bilateral ovarian micropapillary serous borderline tumors

Micropapillary serous borderline tumor of the ovary is characterized by a more frequent association with extraovarian, especially invasive, implants. The aim of this study was to report the clinicopathological findings of a rare case of micropapillary serous borderline tumor of the ovary since there are less than 100 similar cases in the published literature. Additionally, the successful management of evisceration that complicated the postoperative stay of the patient is analyzed. The incidence of this severe complication is estimated between 0.29-2.3%. There are four main causes: suture tearing through the fascia, knot failure, suture failure, and extrusion of abdominal contents between sutures placed too far apart. At least 50% of the cases are due to technical error with a potentially lethal result.

Brooke-Spiegler Syndrome - an underrecognized cause of multiple familial scalp tumors: report of a new germline mutation

BACKGROUND: Brooke-Spiegler syndrome (BSS) is probably an underdiagnosed genodermatosis that predisposes for the development of cylindromas, spiradenomas and trichoepitheliomas mainly of the head and neck. Wide phenotypic variability regarding the number and type of lesions can be observed within a family. Mutations of the CYLD gene are identified in the vast majority of cases and play a key role in BSS pathogenesis. MAIN OBSERVATIONS: Two first degree relatives with numerous erythematous telangiectatic nodules of the scalp present for decades, with recurring tendency regardless the multiple previous excisions. Histopathological review of the lesions revealed predominantly "spiradenocylindromas" in the proband and cylindromas in her sister. The suspicion of BSS was confirmed after detection of a new nonsense germline mutation of CYLD (c.1783C>T pGln 595*) in the proband. CONCLUSIONS: BSS diagnosis can be challenging and is based on clinical-pathological correlation, positive familial association and identification of CYLD mutations. CYLD exerts antineoplastic effects by downregulating intracellular NF-κB signalling pathways. The reported mutation affecting the ubiquitin-specific protease domain leads to a truncated and catalytically inactive enzyme. Despite the expanding list of CYLD mutations no firm genotype-phenotype correlation is known so far. Early recognition and treatment of BSS avoid disfiguring changes like "turban tumor".

Metabolic tug-of-war in tumors results in diminished T cell antitumor immunity.

NlmCategory="UNASSIGNED">Glycolytic activity in T cells governs T cell responses by controlling various cellular processes, including proliferation, survival, and effector functions. We recently showed that the tumor microenvironment diminishes T cell antitumor responses by depriving glucose to infiltrating T cells. Moreover, metabolic rewiring tumor-reactive T cells sustain T cell metabolic fitness and antitumor responses.

Evaluation of Adoptive T Cell Therapy and Oncolytic Virotherapy for Treatment of Brain Tumors

Adoptive immunotherapy and oncolytic virotherapy are two promising strategies for treating primary and metastatic malignant brain tumors. We demonstrate the ability of adoptively transferred tumor-specific T cells to rapidly mediate the clearance of established brain tumors in several mouse models. Similar to the clinical situation, tumor recurrences are frequent and result from immune editing of tumors. T cells can eliminate antigen-expressing tumor cells but are not effective against antigen loss variant (ALV) cancer cells that multiply and repopulate a tumor. We show that the level of tumor antigen present affects the success of adoptive T cell therapy. When high levels of antigen are present, tumor stromal cells such as microglia and macrophages present tumor peptide on their surface. As a result, T cells directly eliminate cancer cells and cross-presenting stromal cells and indirectly eliminate ALV cells. We were able to show the first direct evidence of tumor antigen cross-presentation by CD11b+ stromal cells in the brain using soluble, high-affinity T cell receptor monomers. Strategies that target brain tumor stroma or increase antigen shedding from tumor cells leading to increased crosspresentation by stromal cells may improve the clinical success of T cell adoptive therapies. We evaluated one potential strategy to complement adoptive T cell therapy by characterizing the oncolytic effects of myxoma virus (MYXV) in a syngeneic mouse brain tumor model of metastatic melanoma. MYXV is a rabbit poxvirus with strict species tropism for European rabbits. MYXV can also infect mouse and human cancer cell lines due to signaling defects in innate antiviral mechanisms and hyperphosphorylation of Akt. MYXV kills B16.SIY melanoma cells in vitro, and intratumoral injection of virus leads to robust, selective and transient infection of the tumor. We observed that virus treatment recruits innate immune cells iii to the tumor, induces TNFα and IFNβ production in the brain, and results in limited oncolytic effects in vivo. To overcome this, we evaluated the safety and efficacy of co-administering 2C T cells, MYXV, and neutralizing antibodies against IFNβ. Mice that received the triple combination therapy survived significantly longer with no apparent side effects, but eventually relapsed. Based on these findings, methods to enhance viral replication in the tumor and limit immune clearance of the virus will be pursued. We conclude that myxoma virus should be further explored as a vector for transient delivery of therapeutic genes to a tumor to enhance T cell responses.

Fluorine-18-labeled estrogens, progestins and corticosteroids for receptor-based imaging of breast tumors and target areas of the brain

Estrogens can be labeled with the positron-emitting radionuclide fluorine-18 (t$\sb{1/2}$ = 110 min) by fluoride ion (n-Bu$\sb4$N$\sp{18}$F) displacement of a 16$\beta$-trifluoromethanesulfonate (triflate) derivative of the corresponding estrone 3-triflate, and purification by HPLC. That sequence has been used to synthesize the 11$\beta$-methoxy 1 and 11$\beta$-ethyl 2 analogues of the breast tumor imaging agent, 16$\alpha$-($\sp{18}$F) fluoro-17$\beta$-estradiol (FES). Tissue distribution studies of 1 and 2 in immature female rats show high selectivity for target tissue (T, uterus) vs non-target (NT, muscle and lung), with T/NT ratios being 43 and 17 at one hour after injection for 1 and 2, respectively. The parent estrogen FES has previously been shown to display an intermediate value for tissue selectivity.

Superparamagnetic Liposomes for MRI Monitoring and External Magnetic Field-Induced Selective Targeting of Malignant Brain Tumors

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Exercise intervention in pediatric patients with solid tumors: The PAPEC trial

The randomized controlled trial ‘Physical Activity in Pediatric Cancer’ (PAPEC) determined the effects of an in-hospital exercise intervention combining aerobic and muscle strength training on pediatric cancer patients with solid tumors undergoing neoadjuvant chemotherapy. Methods. Participants were allocated to an exercise (n=24, 17 boys; mean±SEM age 10±1y) or control group (n=25, 18 boys; 11±1y). Training included three sessions/week for 19±2 weeks. Participants were assessed at treatment initiation, termination, and two months after end-treatment. The primary endpoint was muscle strength (as assessed by upper and lower-body five-repetition-maximum (5RM) tests). Secondary endpoints included cardiorespiratory fitness, functional capacity during daily life activities, physical activity, body mass and body mass index, and quality of life. Results. Most sessions were performed in the hospital’s gymnasium. Adherence to the program averaged 68±4% and no major adverse events or health issues were noted. A significant interaction (group*time) effect was found for all 5RM tests. Performance significantly increased after training (leg press: 40% (95% CI=15–41 kg); bench press: 24% (95% CI=6–14 kg); lateral row 25% (95%CI=6–15 kg)), whereas an opposite trend was found in controls. Two-month post values tended to be higher than baseline for leg (P=0.017) and bench press (P=0.014). In contrast, no significant interaction effect was found for any of the secondary endpoints. Conclusion. An in-hospital exercise program for pediatric cancer patients with solid tumors undergoing neoadjuvant treatment increases muscle strength despite the aggressiveness of such therapy. Key words: Cancer, exercise, muscle strength, fitness, quality of life.

Microenvironment and prognostic factors in bone tumors: IDH mutations in chondrosarcoma

Microenvironment in bone tumors is a dynamic entity composed of cells from different origins (immune cells, stromal cells, mesenchymal stem cells, endothelial cells, pericytes) and vascular structures surrounded by a matrix of different nature (bone, cartilage, myxoid). Interactions between cancer cells and tumor microenvironment (TME) are complex and can change as tumor progress, but are also crucial in determining response to cancer therapies. Chondrosarcoma is the second most frequent bone cancer in adult age, but its treatment still represents a challenge, for the intrinsic resistance to conventional chemotherapy and radiation therapy. This resistance is mainly due to pathological features, as dense matrix, scarce mitoses and poor vascularization, sustained by biological mechanisms only partially delucidated. Somatic mutation in the Krebs cycle enzyme isocytrate dehydrogenase (IDH) have been described in gliomas, acute myeloid leukemia, cholangiocarcinoma, melanoma, colorectal, prostate cancer, thyroid carcinoma and other cancers. In mesenchymal tumors IDH mutations are present in about 50% of central chondrosarcoma. IDH mutations are an early event in chondrosarcoma-genesis, and contribute to the acquisition of malignancy through the block of cellular differentiation, hypoxia induction through HIF stabilization, DNA methylation and alteration of cellular red-ox balance. While in gliomas IDH mutations confers a good prognosis, in chondrosarcoma IDH prognostic role is controversial in different reported series. First aim of this project is to define the prevalence and the prognostic role of IDH mutation in high grade central conventional chondrosarcoma patients treated at Istituto Ortopedico Rizzoli. Second aim is the critical revision of scientific literature to understand better how a genomic event in cancer cell can trigger alteration in the TME, through immune infiltrate reshaping, angiogenesis induction, metabolic and methylation rewiring. Third aim is to screen other sarcoma histotypes for the presence of IDH mutation.

Molecular target therapy and immunotherapy of rare lung tumors

Lung cancer is an heterogeneous disease, with 1-2% of rare histology. New molecular profiling technologies, such as next generation sequencing (NGS), haverevolutionized the assessment of molecular alteration in clinical practice. We analyzed a cohort of 1408 NSCLC-A patients treated at the Sant'Orsola- Malpighi University Hospital from 2019 to 2021. This analysis was performed using the oncomine focus thermo fischer panel. Of them, 410 (29%) had rare alteration (RET 3%, NTRK 0,2%,FGFR1 2%, MET exon14 skipping 3%, BRAF V600 4%, ALK fusion EGFR exon 20 2%) and 36 (2%)had a uncommon mutation. We enrolled 7 RET- rearranged patients in CRETA and J2G-MC-JZJC clinical trials assessing respectively unselective and selective RET-inhibitors , another 7 patients tested positive for the BRAF V6006 mutation and have been enrolled in the Array clinical trial assessing a novel combination of anti-BRAF and anti-mek agents . Other molecular alterations found are KRAS (Gly12Cys), FGFR1-4 mutation, MET skipping ex14 mutations, respectively eligible for other ongoing open studies such as Amgen 20190009 comparing efficacy of sotorasib vs docetaxel, Fight-207 assessing activity of pemigatinib and CINC280J12201 assessing activity of the novel met inhibitor capmatinib. In 2018 we joined the CHANCE clinical trial,a multicenter study evaluating the efficacy and safety of atezolizumab in patients withrare lung cancer histologies where and 14 patients have been so far enrolled in the Bologna site. Our studies underline the need of tailored approach to NSCLC patients and our results showed that precision medicine is feasible and is an effective approach to cancer treatment.

Molecular analysis of Papillomavirus-induced cutaneous tumors in equids

Papillomavirus associated tumors are well recognized entities in humans as well as in animals. Here is reviewed the current understanding of human papillomavirus (HPV) associated cancers to better understand the oncogenic mechanisms of Equine papillomavirus (EcPV) and Bovine Papillomavirus (BPV) in horses. In the first part of this study the interactions between Equine papillomavirus 2 (EcPV-2) and cell cycle proteins are discussed. EcPV-2 has been recognized as the cause of genital squamous cell carcinomas (SCCs) in horses, but the exact mechanism of carcinogenesis is not fully understood. The aim of the first part of this study is to assess the expression of cell cycle proteins p53, p16, pRB and Cyclin D1 in a series of equine SCCs and papillomas. Results confirm the role of EcPV-2 in the pathogenesis of genital SCCs. Moreover, in a small subset of ocular SCCs, EcPV-2 was detected for the first time. By immunohistochemistry, p53 was mostly expressed in ocular SCCs with a suprabasal localization. Regarding p16, overexpression was associated with increased mitotic index but not with viral infection. Investigation on pRB and Cyclin D1 proteins did not show significant correlation with other variables. The second part of this study is focused on the carcinogenetic mechanisms of BPV in equine sarcoids. The aim of the second part of this study was to characterize the typical histomorphological features of equine sarcoids, assess the expression of cell cycle proteins and Ki-67 proliferation index. Our results confirm that the typical histological features of sarcoids cannot be used to correctly classify the clinical types. Moreover, in a subset of sarcoids low pRB-Cyclin D1 scores were associated with simultaneous high p16 expression. The Ki-67 proliferation index confirm the low proliferative activity of sarcoids, except for tumors displaying a fascicular pattern. Finally, a subset of sarcoids recurred after excision.

Gastrointestinal stromal tumors: Arbutus unedo L. as a source of novel chemotherapeutics & mechanisms behind metastasis

Gastrointestinal stromal tumors (GIST) are mesenchymal neoplasms frequently caused by a gain of function mutation in KIT or PDGFRα, two tyrosine kinase receptors (TKR). For this reason, they are successfully treated with imatinib, a tyrosine kinase inhibitor (TKI). However, the therapy is typically long-term ineffective due to imatinib resistance, which represents the main issue in the clinic of GISTs. Although numerous efforts have been made in the last two decades to develop novel therapies for imatinib-resistant GISTs, the approvals of multi-target TKIs have only improved the clinical outcomes modestly. Emblematic is the recent failure of ripretinib in the phase III INTRIGUE trial, decisively marking the end of the paradigm only based on the central role of KIT secondary mutations in imatinib resistance, and the consequent seeking of multi-target TKIs as the solution. Consistent with this clinical result, preclinical studies have revealed numerous mechanisms of resistance that are not targetable with multi-target TKIs, indicating that imatinib resistance is more multifaceted than initially hypothesized and explaining the modest efficacy of these latter. In this scenario, the absence of drugs capable of long-term counteracting the rise of imatinib-resistant subclones unavoidably leads to progressive disease and metastasis. In particular, the onset of metastases remarkably impacts the median overall survival and determines the most GIST-related deaths. Therefore, new therapy proposals are needed. Here, we present two project lines investigating novel strategies to counteract imatinib-resistant GISTs.