Publications by authors named "Gabriella Nesi"

197 Publications

Immune Checkpoint Inhibitors in Urothelial Bladder Cancer: State of the Art and Future Perspectives.

Cancers (Basel) 2021 Aug 31;13(17). Epub 2021 Aug 31.

Department of Health Sciences, University of Florence, 50139 Florence, Italy.

Bladder cancer (BC) is the most common malignancy of the genitourinary tract, with high morbidity and mortality rates. Until recently, the treatment of locally advanced or metastatic urothelial BC was based on the use of chemotherapy alone. Since 2016, five immune checkpoint inhibitors (ICIs) have been approved by the Food and Drug Administration (FDA) in different settings, i.e., first-line, maintenance and second-line treatment, while several trials are still ongoing in the perioperative context. Lately, pembrolizumab, a programmed death-1 (PD-1) inhibitor, has been approved for Bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle invasive bladder cancer (NMIBC), using immunotherapy at an early stage of the disease. This review investigates the current state and future perspectives of immunotherapy in BC, focusing on the rationale and results of combining immunotherapy with other therapeutic strategies.
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http://dx.doi.org/10.3390/cancers13174411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431680PMC
August 2021

Prostate Cancer Characteristics in Renal Transplant Recipients: A 25-Year Experience From a Single Centre.

Front Surg 2021 29;8:716861. Epub 2021 Jul 29.

Unit of Urological Robotic Surgery and Renal Transplantation, Careggi Hospital, Florence, Italy.

The incidence of prostate cancer in renal transplant recipients (RTRs) is increasing, but few data are available in the literature. In this study, we reviewed the 25-year experience in the management of prostate cancer after kidney transplantation at the Florence Transplant Centre. We retrospectively reviewed the data from 617 RTR male patients who underwent renal transplantation at our institute between July 1996 and September 2016. Data regarding demographics, renal transplantation, prostate cancer and immunosuppressive treatment were analyzed. The probability of death was estimated by using the Kaplan-Meier method and differences between patients' groups were assessed by the log-rank test. From July 1991 to September 2016, 617 kidney transplantations of male patients were performed at our institute. Among these, 20 patients were subsequently diagnosed with prostate cancer accounting for a cumulative incidence of 3.24%. After a median follow-up of 59 months, 10 patients underwent radical prostatectomy whereas 10 patients underwent primary radiotherapy. A biochemical recurrence was identified in five (25%) patients while a fatal event occurred in 11 (55%) patients. Univariate Cox regression showed that the basal value of PSA >10 ng/ml was the only significant factor negatively affecting the survival of patients. Standard treatments can be proposed to RTR with satisfactory results on both post-operative and oncological outcomes. Further studies are needed to address the issue of prostate cancer screening based on PSA levels and the optimal management of prostate cancer in RTRs.
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http://dx.doi.org/10.3389/fsurg.2021.716861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358676PMC
July 2021

Circulating Fascin 1 as a Promising Prognostic Marker in Adrenocortical Cancer.

Front Endocrinol (Lausanne) 2021 23;12:698862. Epub 2021 Jun 23.

Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.

Fascin-1 (FSCN1) is an actin-bundling protein associated with an invasive and aggressive phenotype of several solid carcinomas, as it is involved in cell cytoskeleton rearrangement and filopodia formation. Adrenocortical carcinoma (ACC) is a rare endocrine malignancy characterized by poor prognosis, particularly when metastatic at diagnosis. Radical resection is the only therapeutic option for ACC patients in addition to the adjuvant treatment with mitotane. Novel specific biomarkers suggestive of tumor progression to refine diagnosis and prognosis of patients with advanced ACC are urgently needed. ACC intratumoral FSCN1 has previously been suggested as a valid prognostic marker. In the present study, we identified FSCN1 in the bloodstream of a small cohort of ACC patients (n = 27), through a specific ELISA assay for human FSCN1. FSCN1 can be detected in the serum, and its circulating levels were evaluated in pre-surgery samples, which resulted to be significantly higher in ACC patients from stage I/II and stage III/IV compared with nontumoral healthy controls (HC, n = 4, FI: 5.5 ± 0.8, P<0.001, and 8.0 ± 0.5, < 0.001 for stage I/II and stage III/IV group HC, respectively). In particular, FSCN1 levels were significantly higher in advanced stage versus stage I/II (22.8 ± 1.1 15.8 ± 1.8 ng/ml, < 0.005, respectively). Interestingly, circulating levels of pre-surgical FSCN1 can significantly predict tumor progression/recurrence (Log rank = 0.013), but not the overall survival (Log rank=0.317), in patients stratified in high/low PreS FSCN1. In conclusion, these findings-though very preliminary-suggest that circulating FSCN1 may represent a new minimally-invasive prognostic marker in advanced ACC, in particular when measured before surgery enables histological diagnosis.
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http://dx.doi.org/10.3389/fendo.2021.698862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261281PMC
June 2021

AR-V7 in Metastatic Prostate Cancer: A Strategy beyond Redemption.

Int J Mol Sci 2021 May 24;22(11). Epub 2021 May 24.

Department of Health Sciences, University of Florence, 50139 Florence, Italy.

Metastatic prostate cancer is the most common cancer in males and the fifth cause of cancer mortality worldwide. Despite the major progress in this field, leading to the approval of novel anti-androgens, the prognosis is still poor. A significant number of patients acquire an androgen receptor splice variant 7 (AR-V7), which is constitutively activated and lacks the ligand-binding domain (LBD) while maintaining the nuclear localization signal and DNA-binding domain (DBD). This conformational change, even in the absence of the ligand, allows its retention within the nucleus, where it acts as a transcription factor repressing crucial tumor suppressor genes. AR-V7 is an important oncogenic driver and plays a role as an early diagnostic and prognostic marker, as well as a therapeutic target for antagonists such as niclosamide and TAS3681. Anti-AR-V7 drugs have shown promise in recent clinical investigations on this subset of patients. This mini-review focuses on the relevance of AR-V7 in the clinical manifestations of castration-resistant prostate cancer (CRPC) and summarizes redemptive therapeutic strategies.
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http://dx.doi.org/10.3390/ijms22115515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197232PMC
May 2021

Prognostic relevance and putative histogenetic role of cytokeratin 7 and MUC5AC expression in Crohn's disease-associated small bowel carcinoma.

Virchows Arch 2021 May 8. Epub 2021 May 8.

Unit of Anatomic Pathology, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Via Carlo Forlanini 16 -, 27100, Pavia, Italy.

Most Crohn's disease-associated small bowel carcinomas (CrD-SBCs) are diagnosed in advanced stage and have poor prognosis. To improve diagnosis and therapy, a better knowledge of tumour precancerous lesions, histotypes and prognostic factors is needed. We investigated histologically and immunohistochemically 52 CrD-SBCs and 51 small bowel carcinomas unrelated to inflammatory disease, together with their tumour-associated mucosa, looking for Crohn-selective changes. Histologic patterns and phenotypic markers potentially predictive of CrD-SBC histogenesis and prognosis were analysed. Cytokeratin 7 or MUC5AC-positive metaplastic changes were found in about half of investigated CrD-SBCs, significantly more frequently than in CrD-unrelated SBCs. They correlated with metaplastic changes of their associated mucosa, while being absent in normal ileal mucosa. Histologic patterns suggestive for progression of some cytokeratin 7 and/or MUC5AC-positive metaplastic lesions into cancer of the same phenotype were also observed. Patient survival analyses showed that tumour cytokeratin 7 or MUC5AC expression and non-cohesive histotype were adverse prognostic factors at univariable analysis, while cytokeratin 7 and non-cohesive histotype were also found to predict worse survival in stage- and age-inclusive multivariable analyses. Besides conventional dysplasia, hyperplasia-like non-conventional lesions were observed in CrD-SBC-associated mucosa, with patterns suggestive for a histogenetic link with adjacent cancer. In conclusion the cytokeratin 7 and/or MUC5AC-positive metaplastic foci and the non-conventional growths may have a role in cancer histogenesis, while tumour cytokeratin 7 and non-cohesive histotype may also predict poor patient survival. Present findings are worth being considered in future prospective histogenetic and clinical studies.
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http://dx.doi.org/10.1007/s00428-021-03109-2DOI Listing
May 2021

Angiosarcoma of the Urinary Bladder Following Radiotherapy: Report of a Case and Review of the Literature.

Medicina (Kaunas) 2021 Apr 1;57(4). Epub 2021 Apr 1.

Department of Health Sciences, Division of Pathological Anatomy, University of Florence, 50139 Florence, Italy.

: Angiosarcomas are uncommon and extremely aggressive malignancies derived from vascular endothelial cells. Although they can occur anywhere in the body and at any age, they are more frequently found in the skin of the head and neck regions and in the elderly. Few cases have been recorded in deep soft tissues and in parenchymal organs. Angiosarcomas of the urinary bladder are exceedingly rare. They usually arise in adult patients with a history of radiation therapy, cigarette smoking, or exposure to chemical agents (e.g., vinyl chloride). Despite multidisciplinary treatment approaches combining surgery, radiotherapy, and chemotherapy, prognosis is dismal. : We describe a case of a 78-year-old Caucasian man presenting with a vesical mass incidentally discovered with abdominal computerized tomography (CT). He underwent transurethral resection of the bladder (TURB), and histology was compatible with angiosarcoma. : The patient had been a heavy smoker and his medical history included therapeutic irradiation for prostate cancer eight years previously. Radical cystoprostatectomy was feasible, and pathologic examination of the surgical specimen confirmed angiosarcoma involving the urinary bladder, prostate, and seminal vesicles. Post-operative peritonitis resulted in progressive multi-organ failure and death. : Angiosarcoma primary to the urinary bladder is seldom encountered, however, it should be considered in the differential diagnosis of vesical tumors, especially in elderly men with a history of pelvic radiotherapy.
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http://dx.doi.org/10.3390/medicina57040329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066026PMC
April 2021

The feasibility of multimodal fiber optic spectroscopy analysis in bladder cancer detection, grading, and staging.

Urologia 2021 Mar 31:3915603211007018. Epub 2021 Mar 31.

Unit of Minimally Invasive and Robotic Urologic Surgery and Kidney Transplantation, Careggi University Hospital, Florence, Italy.

Objective: To prove the feasibility of Multimodal Fiber Optic Spectroscopy (MFOS) analysis in bladder cancer (BCa) detection, grading, and staging.

Materials And Methods: Bladder specimens from patients underwent TURBT or TURP were recorded and analyzed with MFOS within 30 min from excision. In detail, our MFOS combined fluorescence, Raman spectroscopy, and diffuse reflectance. We used these optical techniques to collect spectra from bladder biopsies, then we compared the obtained results to gold standard pathological analysis. Finally, we developed a classification algorithm based on principal component analysis-linear discriminant analysis.

Results: A total of 169 specimens were collected and analyzed from 114 patients, 40 (23.7%) healthy (from TURP), and 129 (76.3%) with BCa. BCa specimens were divided according to their grade-34 (26.4%) low grade (LG) and 95 (73.6%) high grade (HG) BCa-and stage-64 (49.6%) Ta, 45 (34.9%) T1, and 20 (15.5%) T2. MFOS-based classification algorithm correctly discriminated healthy versus BCa with 90% accuracy, HG versus LG with 83% accuracy. Furthermore, it assessed tumor stage with 75% accuracy for Ta versus T1, 85% for T1 versus T2, and 86% for Ta versus T2.

Conclusions: Our preliminary results suggest that MFOS could be a reliable, fast, and label-free tool for BCa assessment, providing also grading and staging information. This technique could be applied in future for in vivo inspection as well as of ex vivo tissue biopsies. Thus, MFOS might improve urothelial cancer management. Further studies are required.
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http://dx.doi.org/10.1177/03915603211007018DOI Listing
March 2021

Sperm retrieval by conventional testicular sperm extraction for assisted reproduction in patients with Zinner syndrome.

Clin Exp Reprod Med 2021 Mar 25;48(1):85-90. Epub 2021 Jan 25.

Department of Urology, Careggi Hospital, Florence, Italy.

We present data from three Caucasian men with Zinner syndrome who attended our center for the treatment of primary couple's infertility. Each patient was scheduled for conventional testicular sperm extraction (cTESE) and cryopreservation. Sperm analysis confirmed absolute azoospermia. Patient 1 had right and left testis volumes of 24 mL and 23 mL, respectively; left seminal vesicle (SV) agenesis, severe right SV hypotrophy with right renal agenesis. Follicle-stimulating hormone (FSH) was 3.2 IU/L. Patient 2 exhibited right and left testis volumes of 18 mL and 16 mL, respectively; a left SV cyst of 32 × 28 mm, ipsilateral kidney absence, and right SV agenesis. FSH was 2.8 IU/L. Patient 3 showed a testicular volume of 10 mL bilaterally, a 65 × 46 mm left SV cyst, right SV enlargement, and left kidney agenesis. FSH was 32.0 IU/L. Sperm retrieval was successful in all patients. Nevertheless, cTESE should be performed on the day of oocyte retrieval.
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http://dx.doi.org/10.5653/cerm.2020.03769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943355PMC
March 2021

Prognostic and Monitoring Value of Circulating Tumor Cells in Adrenocortical Carcinoma: A Preliminary Monocentric Study.

Cancers (Basel) 2020 Oct 29;12(11). Epub 2020 Oct 29.

Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50139 Florence, Italy.

Adrenocortical carcinoma (ACC), a rare and aggressive neoplasia, presents poor prognosis when metastatic at diagnosis and limited therapies are available. Specific and sensitive markers for early diagnosis and a monitoring system of therapy and tumor evolution are urgently needed. The liquid biopsy represents a source of tumor material within a minimally invasive blood draw that allows the recovery of circulating tumor cells (CTCs). CTCs have been recently shown to be detectable in ACC. In the present paper, we evaluated the prognostic value of CTCs obtained by size-filtration in a small pilot cohort of 19 ACC patients. We found CTCs in 68% of pre-surgery and in 38% of post-surgery blood samples. In addition, CTC clusters (CTMs) and cancer associated macrophages (CAMLs) were detectable in some ACC patients. The median number of CTCs significantly decreased after the mass removal. Finally, stratifying patients in high and low pre-surgery CTC number groups, assuming the 75th percentile CTC value as cut-off, CTCs significantly predicted patients' overall survival (log rank = 0.005), also in a multivariate analysis adjusted for age and tumor stage. In conclusion, though preliminary and performed in a small cohort of patients, our study suggests that CTC number may represent a promising marker for prognosis and disease monitoring in ACC.
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http://dx.doi.org/10.3390/cancers12113176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693770PMC
October 2020

Cardiac Metastasis of Sacral Chordoma.

Ann Thorac Surg 2021 05 29;111(5):e319-e321. Epub 2020 Oct 29.

Department of Diagnostic Cardiology, Careggi University Hospital, Florence, Italy.

Chordoma is a rare tumor, usually diagnosed when the disease is advanced. Despite its slow growth, it is locally aggressive and has a poor long-term prognosis. Surgery is the mainstay treatment. Although cardiac metastases are very rare, the heart is frequently involved in systemic neoplastic diseases. This report describes a typical case of metastatic chordoma: the age at first diagnosis, the site of the primary tumor, and the slow growth of the cardiac metastasis were all typical features. Surgical excision of the mass from the right ventricular outflow tract is described together with echocardiographic, radiologic, and histopathologic characteristics of the metastatic chordoma.
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http://dx.doi.org/10.1016/j.athoracsur.2020.07.093DOI Listing
May 2021

Focus on Biochemical and Clinical Predictors of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma: Where Do We Stand?

Int J Mol Sci 2020 Oct 26;21(21). Epub 2020 Oct 26.

Department of Health Sciences, University of Florence, Section of Pathological Anatomy, University Hospital of Florence, 50139 Florence, Italy.

Urothelial bladder cancer is one of the most lethal cancers worldwide with barely 5% five-year survival in patients with metastatic disease. Intravesical immunotherapy with and platinum-based chemotherapy are currently the standard of care for non-muscle invasive and advanced or metastatic urothelial cancer (mUC), respectively. Recently, a subset of patients with locally advanced or mUC has shown to be responsive to immune checkpoint inhibitors (ICIs), e.g., the anti-cytotoxic T-lymphocyte-associated protein 4 and programmed cell death -1/programmed death-ligand1 (PD-1/PD-L1) antibodies. Due to the relevant clinical benefit of immunotherapy for mUC, in 2016, the United States Food and Drug Administration (FDA) approved five immunotherapeutic agents as second-line or first-line treatments for patients with advanced bladder cancer who did not profit from or were ineligible for standard therapy. In this review, we discuss the role of immunotherapy in bladder cancer and recent clinical applications of PD-1/PD-L1 blockade in mUC. Furthermore, we evaluate a variable response rate to ICIs treatment and outline potential biomarkers predictive of immunotherapy response.
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http://dx.doi.org/10.3390/ijms21217935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662285PMC
October 2020

and Non-Chromaffin Tumors: A Mediastinal Germ Cell Tumor Occurring in a Young Man with Germline Mutation.

Medicina (Kaunas) 2020 Oct 25;56(11). Epub 2020 Oct 25.

Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50139 Florence, Italy.

Mutations in genes encoding one of the subunits of succinate dehydrogenase (SDH) are involved in pheochromocytoma (PHEO) and paraganglioma (PGL) development. Over the last few years, such mutations have also been associated with non-chromaffin tumors. However, immunohistochemistry (IHC) on the tumor tissue and a study on the loss of heterozygosity (LOH) aimed at demonstrating the pathogenic role of genes have only been employed in a few cases. We describe the case of a 19-year-old Caucasian man with a germline mutation, who presented with acne resistant to medical treatment. His follow-up for chromaffin tumors was negative, while hormonal tests revealed suppressed gonadotropins with testosterone in the upper range of normality and elevated β-human chorionic gonadotropin (β-hCG). At the whole-body enhanced CT scan, a mediastinal lesion suggestive of a germ cell tumor (GCT) was detected. FDG-PET (fluorodeoxyglucose-positron emission tomography) imaging showed low glucose metabolism at the mediastinal site. Surgical removal of the mass was uneventful. Pathology confirmed the diagnosis of GCT consisting of cystic teratoma (95%) and seminoma (5%). IHC for SDHB showed normal protein expression, and genetic analysis of the tumor tissue revealed the absence of LOH. Normalization of the hormonal tests and acne attenuation were achieved after surgery. We report an incidental association of a germinal mutation and mediastinal GCT in a young Caucasian man. Our paper highlights the importance of IHC and genetic analysis in confirming the etiologic role of genes in nonchromaffin tumors, thus excluding incidental associations.
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http://dx.doi.org/10.3390/medicina56110561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693473PMC
October 2020

An unexpected intraoperative finding of cystic adventitial degeneration of the common femoral artery.

J Surg Case Rep 2020 Aug 14;2020(8):rjaa200. Epub 2020 Aug 14.

Vascular Surgery Department, Careggi University Hospital, 50134, Florence, Italy.

Herein we present a rare case of cystic adventitial degeneration involving the common femoral artery (CFA) of a 71-year-old patient, an unusual site of presentation of the disease. The most commonly affected district is the popliteal artery, and only a few cases of CFA involvement are described in literature. The history and comorbidities of the patient oriented us initially towards the diagnosis of an atherosclerotic obstructive disease. It was only intraoperatively indeed that a diagnosis of cystic adventitial arterial degeneration was made, subsequently confirmed by microscopic examination. Our case shows how both clinical and instrumental diagnosis of cystic adventitial disease can be challenging, given its non-specific presentation and low incidence. Suspicion of cystic adventitial degeneration is recommended in patients with sudden appearance of symptoms and with an isolated lesion of the affected artery without other involvement of the vascular tree.
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http://dx.doi.org/10.1093/jscr/rjaa200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427030PMC
August 2020

ETV4 promotes late development of prostatic intraepithelial neoplasia and cell proliferation through direct and p53-mediated downregulation of p21.

J Hematol Oncol 2020 08 13;13(1):112. Epub 2020 Aug 13.

Laboratory of Cancer Genetics, Core Research Laboratory, Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Florence, 50139, Italy.

Background: ETV4 is one of the ETS proteins overexpressed in prostate cancer (PC) as a result of recurrent chromosomal translocations. In human prostate cell lines, ETV4 promotes migration, invasion, and proliferation; however, its role in PC has been unclear. In this study, we have explored the effects of ETV4 expression in the prostate in a novel transgenic mouse model.

Methods: We have created a mouse model with prostate-specific expression of ETV4 (ETV4 mice). By histochemical and molecular analysis, we have investigated in these engineered mice the expression of p21, p27, and p53. The implications of our in vivo findings have been further investigated in human cells lines by chromatin-immunoprecipitation (ChIP) and luciferase assays.

Results: ETV4 mice, from two independent transgenic lines, have increased cell proliferation in their prostate and two-thirds of them, by the age of 10 months, developed mouse prostatic intraepithelial neoplasia (mPIN). In these mice, cdkn1a and its p21 protein product were reduced compared to controls; p27 protein was also reduced. By ChIP assay in human prostate cell lines, we show that ETV4 binds to a specific site (-704/-696 bp upstream of the transcription start) in the CDKN1A promoter that was proven, by luciferase assay, to be functionally competent. ETV4 further controls CDKN1A expression by downregulating p53 protein: this reduction of p53 was confirmed in vivo in ETV4 mice.

Conclusions: ETV4 overexpression results in the development of mPIN but not in progression to cancer. ETV4 increases prostate cell proliferation through multiple mechanisms, including downregulation of CDKN1A and its p21 protein product: this in turn is mediated through direct binding of ETV4 to the CDKN1A promoter and through the ETV4-mediated decrease of p53. This multi-faceted role of ETV4 in prostate cancer makes it a potential target for novel therapeutic approaches that could be explored in this ETV4 transgenic model.
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http://dx.doi.org/10.1186/s13045-020-00943-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427297PMC
August 2020

Prognostic Role of Mismatch Repair Status, Histotype and High-Risk Pathologic Features in Stage II Small Bowel Adenocarcinomas.

Ann Surg Oncol 2021 Feb 5;28(2):1167-1177. Epub 2020 Aug 5.

Unit of Pathology, Cervello Hospital, Palermo, Italy.

Background: Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer.

Patients And Methods: In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability.

Results: We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status.

Conclusions: Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy.
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http://dx.doi.org/10.1245/s10434-020-08926-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801310PMC
February 2021

Myointimoma of the penis.

Int J Impot Res 2021 Sep 2;33(6):583-586. Epub 2020 Jun 2.

Pathology Section, Department of Health Sciences, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy.

Myointimoma is an uncommon, benign soft-tissue tumor derived from the intimal cells of blood vessels. Since little is known about this rare tumor entity, our aim is to describe an additional case and to perform the first literature review on this topic. A 49-year-old Caucasian man presented with a 12-month history of a palpable, firm, solitary lesion involving the glans penis. On physical examination, there was a 1 cm palpable, endophytic well-circumscribed nodule located to the left side of glans penis, close to the coronal sulcus, with disease-free external urethral orifice. The patient was submitted to complete excisional biopsy. A skin rhombus measuring 1.1 × 0.8 × 0.3 cm was removed and the biopsy sample, fixed in 10% formaldehyde, sent to Pathology. At the 18-month follow-up visit, the patient was clinically disease free. Histopathology revealed a multinodular intravascular proliferation of the corpus spongiosum. This myointimal proliferation comprised bland predominantly spindle cells in an abundant fibromyxoid stroma. Immunostains for smooth muscle actin (1A4), cytokeratins (AE1/AE3, CAM5.2), and CD34 were carried out using the avidin-biotin complex (ABC) immunoperoxidase method. Lesional cells displayed positivity for smooth muscle actin and negativity for cytokeratins and CD34. Myointimoma is confirmed to be a penile benign lesion that may be adequately treated with excisional biopsy. Even after incomplete or marginal removal, the penile lesion has been shown to remain stable overtime or regress. Differential diagnosis is essential to exclude similar histologic entities that could be more aggressive or have possible systemic implications.
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http://dx.doi.org/10.1038/s41443-020-0316-7DOI Listing
September 2021

Cancer-testis Antigen FATE1 Expression in Adrenocortical Tumors Is Associated with A Pervasive Autoimmune Response and Is A Marker of Malignancy in Adult, but Not Children, ACC.

Cancers (Basel) 2020 Mar 14;12(3). Epub 2020 Mar 14.

NEOGENEX-CANCER CNRS International Associated Laboratory, 660 route des Lucioles, Sophia Antipolis, 06560 Valbonne, France; 1532 Av. Silva Jardim, Curitiba PR 80250-200, Brazil.

The SF-1 transcription factor target gene encodes a cancer-testis antigen that has an important role in regulating apoptosis and response to chemotherapy in adrenocortical carcinoma (ACC) cells. Autoantibodies directed against FATE1 were previously detected in patients with hepatocellular carcinoma. In this study, we investigated the prevalence of circulating anti-FATE1 antibodies in pediatric and adult patients with adrenocortical tumors using three different methods (immunofluorescence, ELISA and Western blot). Our results show that a pervasive anti-FATE1 immune response is present in those patients. Furthermore, expression is a robust prognostic indicator in adult patients with ACC and is associated with increased steroidogenic and decreased immune response gene expression. These data can open perspectives for novel strategies in ACC immunotherapy.
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http://dx.doi.org/10.3390/cancers12030689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140037PMC
March 2020

PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability.

Mod Pathol 2020 07 17;33(7):1398-1409. Epub 2020 Feb 17.

Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy.

Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn's disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1 immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1 cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1 microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.
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http://dx.doi.org/10.1038/s41379-020-0497-0DOI Listing
July 2020

The Adipose Stem Cell as a Novel Metabolic Actor in Adrenocortical Carcinoma Progression: Evidence from an In Vitro Tumor Microenvironment Crosstalk Model.

Cancers (Basel) 2019 Dec 4;11(12). Epub 2019 Dec 4.

Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50139 Florence, Italy.

Metabolic interplay between the tumor microenvironment and cancer cells is a potential target for novel anti-cancer approaches. Among stromal components, adipocytes and adipose precursors have been shown to actively participate in tumor progression in several solid malignancies. In adrenocortical carcinoma (ACC), a rare endocrine neoplasia with a poor prognosis, cancer cells often infiltrate the fat mass surrounding the adrenal organ, enabling possible crosstalk with the adipose cells. Here, by using an in vitro co-culture system, we show that the interaction between adipose-derived stem cells (ASCs) and the adrenocortical cancer cell line H295R leads to metabolic and functional reprogramming of both cell types: cancer cells limit differentiation and increase proliferation of ASCs, which in turn support tumor growth and invasion. This effect associates with a shift from the paracrine cancer-promoting IGF2 axis towards an ASC-associated leptin axis, along with a shift in the SDF-1 axis towards CXCR7 expression in H295R cells. In conclusion, our findings suggest that adipose precursors, as pivotal components of the ACC microenvironment, promote cancer cell reprogramming and invasion, opening new perspectives for the development of more effective therapeutic approaches.
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http://dx.doi.org/10.3390/cancers11121931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966501PMC
December 2019

Environment and urinary bladder cancer. A historical perspective.

Pol J Pathol 2019 ;70(1):21-25

Careggi University Hospital, Florence, Italy.

Our understanding of aetiological factors associated with urinary bladder cancer has radically improved over the last decades. Cigarette smoking is considered the most important risk factor, even in the industrialised world, while various occupational and environmental exposures to chemicals are also held responsible. The link between bladder cancer and schistosomiasis, highly prevalent in sub-Saharan Africa, Sudan, Egypt, and Yemen, provides input for investigating and potentially preventing bladder carcinogenesis. Growing concern regarding environmental diseases prompts investigation into the historical milestones that have helped disentangle the relationships between health and environment.
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http://dx.doi.org/10.5114/pjp.2019.84458DOI Listing
October 2019

Results from a meta-analysis of immune checkpoint inhibitors in first-line renal cancer patients: does PD-L1 matter?

Ther Adv Med Oncol 2019 5;11:1758835919861905. Epub 2019 Aug 5.

Department of Health Sciences, University of Florence, Italy.

Background: The aim of this study was to perform a literature-based meta-analysis to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in first-line metastatic renal cell carcinoma (RCC), focusing on the predictive role of PD-L1 expression.

Methods: The primary outcome was overall survival, and secondary outcomes were progression-free survival (PFS) and objective response. We planned a subgroup analysis for overall survival according to PD-L1 status.

Results: Five studies were included in the analysis for a total of 4063 cases. Overall survival was greater in PD-L1 positive tumours (HR = 0.49, 95% CI: 0.36-0.67;  < 0.001). The pooled analysis of the unselected cases showed a statistically significative improvement in PFS with the use of ICIs (HR = 0.85, 95% CI: 0.72-0.99;  = 0.04) and we found a greater PFS benefit (HR = 0.65, 95% CI: 0.57-0.74;  < 0.001) in patients with PD-L1 positive tumours.

Conclusions: This study supports the efficacy of ICIs and, although a significant clinical benefit has been reported in PD-L1 negative patients, a greater efficacy of ICIs was observed in PD-L1 positive patients. More prospective randomized studies are needed to clarify the role of PDL-1 status in metastatic RCC treated with ICIs.
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http://dx.doi.org/10.1177/1758835919861905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683319PMC
August 2019

Separation of Low- Versus High-grade Crohn's Disease-associated Small Bowel Carcinomas is Improved by Invasive Front Prognostic Marker Analysis.

J Crohns Colitis 2020 Mar;14(3):295-302

IBD, San Filippo Neri Hospital, Rome, Italy.

Background And Aims: Crohn's disease-associated small bowel carcinoma is a rare event, usually reported to have a severe prognosis. However, in previous investigations we have found a minority of cases displaying a relatively favourable behaviour, thus outlining the need to improve the histopathological prediction of Crohn's disease-associated small bowel carcinoma prognosis.

Methods: As in recent studies on colorectal cancer, a substantial improvement in prognostic evaluations has been provided by the histological analysis of the tumour invasive front; we therefore systematically analysed the tumour budding and poorly differentiated clusters in the invasive front of 47 Crohn's disease-associated small bowel carcinomas collected through the Small Bowel Cancer Italian Consortium.

Results: Both tumour budding and poorly differentiated cluster analyses proved highly effective in prognostic evaluation of Crohn's disease-associated small bowel carcinomas. In addition, they retained prognostic value when combined with two other parameters, i.e. glandular histology and stage I/II, both known to predict a relatively favourable small bowel carcinoma behaviour. In particular, association of tumour budding and poorly differentiated clusters in a combined invasive front score allowed identification of a minor subset of cancers [12/47, 25%] characterised by combined invasive front low grade coupled with a glandular histology and a low stage [I or II] and showing no cancer-related death during a median follow-up of 73.5 months.

Conclusions: The improved distinction of lower- from higher-grade Crohn's disease-associated small bowel carcinomas provided by invasive front analysis should be of potential help in choosing appropriate therapy for these rare and frequently ominous neoplasms.
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http://dx.doi.org/10.1093/ecco-jcc/jjz140DOI Listing
March 2020

Current Knowledge of the Potential Links between Inflammation and Prostate Cancer.

Int J Mol Sci 2019 Aug 6;20(15). Epub 2019 Aug 6.

Department of Health Sciences, University of Florence, 50139 Florence, Italy.

Inflammation is inherent in prostatic diseases and it is now accepted that it may facilitate cellular proliferation in both benign and malignant conditions. The strong relationship between prostatic inflammation and pathogenesis of benign prostatic hyperplasia (BPH) is supported by epidemiologic, histopathologic and molecular evidence. Contrariwise, the role of inflammation in prostate carcinogenesis is still controversial, although current data indicate that the inflammatory microenvironment can regulate prostate cancer (PCa) growth and progression. Knowledge of the complex molecular landscape associated with chronic inflammation in the context of PCa may lead to the introduction and optimization of novel targeted therapies. In this perspective, evaluation of the inflammatory component in prostate specimens could be included in routine pathology reports.
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http://dx.doi.org/10.3390/ijms20153833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696519PMC
August 2019

Common and uncommon features of nephrogenic adenoma revisited.

Pathol Res Pract 2019 Oct 25;215(10):152561. Epub 2019 Jul 25.

Department of Pathology, Cruces University Hospital, Biocruces-Bizkaia Institute, Barakaldo, University of the Basque Country (UPV/EHU), Barakaldo, Bizkaia, Spain. Electronic address:

Nephrogenic adenoma is a common diagnosis in urological pathology that may be challenging for general pathologists. Due to its polymorphic appearance under the microscope, some cases can be misdiagnosed as malignancy and then unnecessarily overtreated. Aside from the typical tubules, cysts and papillae, nephrogenic adenoma may display a broad spectrum of histologic appearances and locations, some of them atypical or unexpected. These unusual and concerning features will have special consideration in this description. The goal of the review is to increase awareness of general pathologists of the varied histology of nephrogenic adenoma.
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http://dx.doi.org/10.1016/j.prp.2019.152561DOI Listing
October 2019

Label-free grading and staging of urothelial carcinoma through multimodal fibre-probe spectroscopy.

J Biophotonics 2019 11 13;12(11):e201900087. Epub 2019 Aug 13.

National Institute of Optics, National Research Council, Sesto Fiorentino, Italy.

Urothelial carcinoma (UC) is the most common bladder tumour. Proper treatment requires tumour resection for diagnosing its grade (aggressiveness) and stage (invasiveness). White-light cystoscopy and histopathological examination are the gold standard procedures for clinical and histopathological diagnostics, respectively. However, cystoscopy is limited in terms of specificity, histology requires long tissue processing, both procedures rely on operator's experience. Multimodal optical spectroscopy can provide a powerful tool for detecting, staging and grading bladder tumours in a fast, reliable and label-free modality. In this study, we collected fluorescence, Raman and reflectance spectra from 50 biopsies obtained from 32 patients undergoing transurethral resection of bladder tumour using a multimodal fibre-probe. Principal component analysis allowed distinguishing normal from pathological tissues, as well as discriminating tumour stages and grades. Each individual spectroscopic technique provided high specificity and sensitivity in classifying all tissues; however, a multimodal approach resulted in a considerable increase in diagnostic accuracy (≥95%), which is of paramount importance for tumour grading and staging. The presented method offers the potential for being applied in cystoscopy and for providing an automated diagnosis of UC at the clinical level, with an improvement with respect to current state-of-the-art procedures.
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http://dx.doi.org/10.1002/jbio.201900087DOI Listing
November 2019

State of the art in post-mortem computed tomography: a review of current literature.

Virchows Arch 2019 Aug 1;475(2):139-150. Epub 2019 Apr 1.

Department of Experimental and Clinical Biomedical Sciences, Radiodiagnostic Unit No. 2, University of Florence, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy.

Computed tomography (CT) and other advanced diagnostic imaging techniques are gaining popularity in forensic pathology. This paper aims to define and offer complete and easily accessible "state of the art" for post-mortem computed tomography (PMCT), by reviewing the latest international literature. The proposed format answers the "five Ws" that follows: (1) What: We report the different kinds of CT scan and settings generally used in post-mortem imaging. The machine most employed is a 8/16-slice spiral CT, usually without contrast enhancement. The introduction of some variables, such as CT-guided biopsies, post-mortem ventilation, and PMCT angiography is becoming increasingly useful. (2) Why: Literature highlights the many advantages of PMCT. Limitations can be partly overcome by modern imaging techniques and combined evaluation with traditional autopsy. (3) Who: Most authors agree that collaboration between different specialists, i.e., radiologists and pathologists, is the best scenario, since radiologic, anatomic, and forensic skills are needed simultaneously. The most important human factor is "teamwork". (4) When: Literature provides no absolute limits for performing PMCT. Some authors have tested PMCT as a replacement for conventional autopsy but found some limitations. Others evaluated PMCT as a guide or screening tool for traditional autopsy. (5) Where: Many research groups around the world have performed studies on the use of PMCT. Although few countries adopt PMCT in routine practice, its use is rapidly spreading.
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http://dx.doi.org/10.1007/s00428-019-02562-4DOI Listing
August 2019
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