Publications by authors named "Emanuela Scarpi"

178 Publications

Prognostic Value of NLRP3 Inflammasome and TLR4 Expression in Breast Cancer Patients.

Front Oncol 2021 2;11:705331. Epub 2021 Sep 2.

Functional Biomorphology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy.

Inflammasome complexes play a pivotal role in different cancer types. NOD-like receptor protein 3 (NLRP3) inflammasome is one of the most well-studied inflammasomes. Activation of the NLRP3 inflammasome induces abnormal secretion of soluble cytokines, generating advantageous inflammatory surroundings that support tumor growth. The expression levels of the NLRP3, PYCARD and TLR4 were determined by immunohistochemistry in a cohort of primary invasive breast carcinomas (BCs). We observed different NLRP3 and PYCARD expressions in non-tumor tumor areas (p<0.0001). All the proteins were associated to more aggressive clinicopathological characteristics (tumor size, grade, tumor proliferative activity etc.). Univariate analyses were carried out and related Kaplan-Meier curves plotted for NLRP3, PYCARD and TLR4 expression. Patients with higher NLRP3 and TLR4 expression had worse 5-year disease-free survival (DFS) compared to patients with lower NLRP3 and TLR4 expression (p =0.021 and p = 0.009, respectively). In multivariate analysis, TLR4 was confirmed as independent prognostic factors for DFS (HR = 2.03, 95% CI 1.16-3.57, p = 0.014), and high NLRP3 expression showed a slight association with DFS (HR = 1.75, 95% CI 0.98-3.15, p = 0.06). In conclusion, we showed TLR4 expression as independent prognostic factors and we highlighted for the first time that high expression of NLRP3 is linked to a poor prognosis in BC patients. These results suggest that NLRP3 and TLR4 could be two new good prognostic factor for BC patients.
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http://dx.doi.org/10.3389/fonc.2021.705331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443770PMC
September 2021

Multimodal Treatment with GEMOX Plus Helical Tomotherapy in Unresectable Locally Advanced Pancreatic Cancer: A Pooled Analysis of Two Phase 2 Studies.

Biomolecules 2021 08 12;11(8). Epub 2021 Aug 12.

Radiotherapy Unit, IRCCS Istituto Romagnolo Per lo Studio dei Tumori "Dino Amadori"-IRST, 47014 Meldola, Italy.

In locally advanced pancreatic cancer (LAPC), the combination of chemotherapy and radiotherapy is a widely used treatment option. We performed a pooled analysis, including an exploratory analysis for prognostic and predictive factors, of two phase 2 trials including 73 patients with LAPC, treated with gemcitabine and oxaliplatin (GEMOX) and hypofractionated tomotherapy. With a median follow-up of 36 months (range 1-65), median progression-free (PFS) and overall survival (OS) were 10.2 (95% confidence interval [CI] 7.8-13.2) and 14.3 (95% CI 12.0-18.1) months, respectively. The overall resectability rate was 23.3% (95% CI 13.6-33.0), and the R0 resection rate was 13.7% (95% CI 5.8-21.6). In the multivariate analysis, ECOG performance status (PS) 0 and low levels of CA 19-9 were associated with improved OS and PFS. Concerning OS, log(CA19-9) resulted in a hazard ratio (HR) of 1.20 (95% CI 1.02-1.42), = 0.027. For ECOG PS 0, HR was 1.00; for PS 1, HR was 2.69 (95% CI 1.46-4.96); for PS 2, HR was 4.18 (95% CI 0.90-19.46); = 0.003. Low CA19-9 levels were also predictive for resection, with an odds ratio of 0.71 (95% CI 0.52-0.97), = 0.034. In conclusion, GEMOX and hypofractionated radiotherapy is a treatment option in LAPC. Further studies are needed to identify differences in tumor biology, which may help to predict resectability and prognosis.
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http://dx.doi.org/10.3390/biom11081200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393939PMC
August 2021

Melphalan as a Promising Treatment for BRCA-Related Ovarian Carcinoma.

Front Oncol 2021 21;11:716467. Epub 2021 Jul 21.

Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.

Introduction: Melphalan, as a bifunctional alkylating agent has been shown to be selectively efficient in BRCA-deficient case reports of epithelial ovarian cancer (EOC). The clinical benefit of melphalan on unselected platinum-resistant EOC population and stratified by BRCA status has not been clearly elucidated. We aimed to determine the response to melphalan in patients with recurrent EOC after platinum-based therapy.

Material And Methods: This retrospective observational study included patients with recurrent EOC treated with melphalan between February 2007 to July 2020. Eligibility criteria included having a histological confirmation of EOC, previous treatment with carboplatin plus paclitaxel regimens, and disease recurrence during treatment with or within 6 months of the end of the platinum-based chemotherapy.

Results: A total of 75 platinum-resistant EOC patients were enrolled. Median age was 69 years (range 41-82). Median of previous therapies before melphalan was 4 (range 1-7). We observed a median follow-up of 32 months (range 1-62), progression-free survival (PFS) and overall survival (OS) of 3.6 months (range 2.9-4.7) and 9.5 months (range 8.0-14.1), respectively. In the whole population, 1 complete response, 6 partial responses and 37 stable diseases were registered with an overall clinical benefit rate of 58.7%. In BRCA1/2 mutant patients, we showed a significant longer PFS compared to BRCA1/2 wild type patients (6.2 2.6 months; hazard ratio (HR) 0.25, 95% confidence interval (CI) 0.10-0.61; =0.002). Moreover, a trend was seen for BRCA1/2 mutants to have a better OS (25.9 8.0 months; HR 0.38; 95% CI 0.12-1.19; =0.097).

Conclusions: Our study represents the largest cohort of heavily-pretreated EOC patients receiving melphalan treatment. Here, we report a considerable clinical activity of melphalan chemotherapy, more evident in a subset of BRCA1/2 mutated patients. Prospective studies to validate these findings are warranted.
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http://dx.doi.org/10.3389/fonc.2021.716467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336462PMC
July 2021

Neonatal Nav1.5 Protein Expression in Human Colorectal Cancer: Immunohistochemical Characterization and Clinical Evaluation.

Cancers (Basel) 2021 Jul 30;13(15). Epub 2021 Jul 30.

Department of Experimental and Clinical Medicine, University of Florence, viale GB Morgagni 50, 50134 Florence, Italy.

Voltage-gated Na channels (VGSCs) are expressed widely in human carcinomas and play a significant role in promoting cellular invasiveness and metastasis. However, human tissue-based studies and clinical characterization are lacking. In several carcinomas, including colorectal cancer (CRCa), the predominant VGSC is the neonatal splice variant of Nav1.5 (nNav1.5). The present study was designed to determine the expression patterns and clinical relevance of nNav1.5 protein in human CRCa tissues from patients with available clinicopathological history. The immunohistochemistry was made possible by the use of a polyclonal antibody (NESOpAb) specific for nNav1.5. The analysis showed that, compared with normal mucosa, nNav1.5 expression occurred in CRCa samples (i) at levels that were significantly higher and (ii) with a pattern that was more delineated (i.e., apical/basal or mixed). A surprisingly high level of nNav1.5 protein expression also occurred in adenomas, but this was mainly intracellular and diffuse. nNav1.5 showed a statistically significant association with TNM stage, highest expression being associated with TNM IV and metastatic status. Interestingly, nNav1.5 expression co-occurred with other biomarkers associated with metastasis, including hERG1, KCa3.1, VEGF-A, Glut1, and EGFR. Finally, univariate analysis showed that nNav1.5 expression had an impact on progression-free survival. We conclude (i) that nNav1.5 could represent a novel clinical biomarker ('companion diagnostic') useful to better stratify CRCa patients and (ii) that since nNav1.5 expression is functional, it could form the basis of anti-metastatic therapies including in combination with standard treatments.
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http://dx.doi.org/10.3390/cancers13153832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345135PMC
July 2021

Special Issue on Molecular and Translational Research on Colorectal Cancer 2.0.

Int J Mol Sci 2021 Jul 13;22(14). Epub 2021 Jul 13.

Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Via P. Maroncelli 40, 47014 Meldola, Italy.

The present editorial aims to summarise the six scientific papers that have contributed to this Special Issue, focusing on different aspects of molecular and translational research on colorectal cancer. We believe that the present Special Issue might contribute to the expansion of the current knowledge concerning potential molecular predictive and/or prognostic biomarkers in CRC, as well as new targets for anticancer treatment. This may help in identifying new strategies to improve diagnostic and therapeutic approaches.
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http://dx.doi.org/10.3390/ijms22147479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307826PMC
July 2021

Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations.

Leukemia 2021 Jun 30. Epub 2021 Jun 30.

MLL Munich Leukemia Laboratory, Munich, Germany.

Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis. At intracellular level, AML displayed dysregulated amino acid, nucleotide, lipid, and bioenergetic metabolism. The integration of intracellular and biofluid metabolomics provided a map of alterations in the metabolism of polyamine, purine, keton bodies and polyunsaturated fatty acids and tricarboxylic acid cycle. The intracellular metabolome distinguished three AML clusters, correlating with distinct genomic profiles: NPM1-mutated(mut), chromatin/spliceosome-mut and TP53-mut/aneuploid AML that were confirmed by biofluid analysis. Interestingly, integrated genomic-metabolic profiles defined two subgroups of NPM1-mut AML. One was enriched for mutations in cohesin/DNA damage-related genes (NPM1/cohesin-mut AML) and showed increased serum choline + trimethylamine-N-oxide and leucine, higher mutation load, transcriptomic signatures of reduced inflammatory status and better ex-vivo response to EGFR and MET inhibition. The transcriptional differences of enzyme-encoding genes between NPM1/cohesin-mut and NPM1-mut allowed in silico modeling of intracellular metabolic perturbations. This approach predicted alterations in NAD and purine metabolism in NPM1/cohesin-mut AML that suggest potential vulnerabilities, worthy of being therapeutically explored.
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http://dx.doi.org/10.1038/s41375-021-01318-xDOI Listing
June 2021

Plasma androgen receptor and response to adapted and standard docetaxel regimen in castration-resistant prostate cancer: A multicenter biomarker study.

Eur J Cancer 2021 Jul 30;152:49-59. Epub 2021 May 30.

IRCCS Istituto Romagnolo per Lo Studio Dei Tumori (IRST) "Dino Amadori", Meldola, Italy.

Background: Plasma AR status has been identified as a potential biomarker of response in metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel or AR-targeted therapies. However, the relevance of plasma AR in the overall management of CRPC patients receiving different docetaxel doses is unknown.

Patients And Methods: This was a multi-institution study of associations between baseline plasma AR copy number status, assessed by droplet digital PCR, and outcome in 325 mCRPC patients receiving docetaxel at standard or adapted regimen at the discretion of the treating physician. Upon analysis, patients were assigned randomly to either a training (n = 217) or validation (n = 108) cohort.

Results: In the training cohort, AR-gained patients treated with adapted docetaxel regimen had a significantly worse median progression-free survival (PFS) (3.8 vs 6.3 months, hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.34-4.95, p < 0.0001), median overall survival (10.8 vs 20.6 months, HR 1.98, 95% CI 1.09-3.62, p = 0.0064) and PSA response (PSA > -50%: odds ratio 4.88 95%CI 1.55-14.32, p = 0.013) as compared to plasma AR normal patients. These findings were all confirmed in the validation cohort. However, in patients treated with standard docetaxel regimen, these differences were not seen. The interaction between AR CN status and dose reduction of docetaxel was considered as independent factor for PFS in both the training and validation cohort (HR 2.84, 95% CI 1.41-5.73, p = 0.003, and HR 4.79, 95% CI 1.79-12.82, p = 0.002).

Conclusion: Despite the retrospective non-randomised design of this study, our hypothesis-generating findings could suggest plasma AR as a potential biomarker for optimal docetaxel timing and dose in mCRPC patients. Prospective trials are warranted.
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http://dx.doi.org/10.1016/j.ejca.2021.04.025DOI Listing
July 2021

Detection and Investigation of Extracellular Vesicles in Serum and Urine Supernatant of Prostate Cancer Patients.

Diagnostics (Basel) 2021 Mar 8;11(3). Epub 2021 Mar 8.

Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014 Meldola, Italy.

Prostate Cancer (PCa) is one of the most frequently identified urological cancers. PCa patients are often over-diagnosed due to still not highly specific diagnostic methods. The need for more accurate diagnostic tools to prevent overestimated diagnosis and unnecessary treatment of patients with non-malignant conditions is clear, and new markers and methods are strongly desirable. Extracellular vesicles (EVs) hold great promises as liquid biopsy-based markers. Despite the biological and technical issues present in their detection and study, these particles can be found highly abundantly in the biofluid and encompass a wealth of macromolecules that have been reported to be related to many physiological and pathological processes, including cancer onset, metastasis spreading, and treatment resistance. The present study aims to perform a technical feasibility study to develop a new workflow for investigating EVs from several biological sources. Serum and urinary supernatant EVs of PCa, benign prostatic hyperplasia (BPH) patients, and healthy donors were isolated and investigated by a fast, easily performable, and cost-effective cytofluorimetric approach for a multiplex detection of 37 EV-antigens. We also observed significant alterations in serum and urinary supernatant EVs potentially related to BPH and PCa, suggesting a potential clinical application of this workflow.
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http://dx.doi.org/10.3390/diagnostics11030466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998238PMC
March 2021

The potential role of MR based radiomic biomarkers in the characterization of focal testicular lesions.

Sci Rep 2021 Feb 10;11(1):3456. Epub 2021 Feb 10.

Department of Morphology Surgery and Experimental Medicine, University of Ferrara, Via L. Ariosto 34, 44121, Ferrara, Italy.

How to differentiate with MRI-based techniques testicular germ (TGCTs) and testicular non-germ cell tumors (TNGCTs) is still under debate and Radiomics may be the turning key. Our purpose is to investigate the performance of MRI-based Radiomics signatures for the preoperative prediction of testicular neoplasm histology. The aim is twofold: (i), differentiating TGCTs and TNGCTs status and (ii) differentiating seminomas (SGCTs) from non-seminomatous (NSGCTs). Forty-two patients with pathology-proven testicular neoplasms and referred for pre-treatment MRI, were retrospectively enrolled. Thirty-two out of 44 lesions were TGCTs. Twelve out of 44 were TNGCTs or other histologies. Two radiologists segmented the volume of interest on T2-weighted images. Approximately 500 imaging features were extracted. Least Absolute Shrinkage and Selection Operator (LASSO) was applied as method for variable selection. A linear model and a linear support vector machine (SVM) were trained with selected features to assess discrimination scores for the two endpoints. LASSO identified 3 features that were employed to build fivefold validated linear discriminant and linear SVM classifiers for the TGCT-TNGCT endpoint giving an overall accuracy of 89%. Four features were employed to build another SVM for the SGCT-SNGCT endpoint with an overall accuracy of 86%. The data obtained proved that T2-weighted-based Radiomics is a promising tool in the diagnostic workup of testicular neoplasms by discriminating germ cell from non-gem cell tumors, and seminomas from non-seminomas.
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http://dx.doi.org/10.1038/s41598-021-83023-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875983PMC
February 2021

Neoadjuvant treatment (FOLFOX4 plus hypofractionated tomotherapy) for patients with locally advanced rectal cancer: a multicenter phase II trial.

Ther Adv Med Oncol 2020 8;12:1758835920977139. Epub 2020 Dec 8.

Radiotherapy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Aims: This study aims to evaluate the safety and efficacy of a new neoadjuvant regimen (FOLFOX4 plus hypofractionated tomotherapy) in patients with locally advanced rectal cancer.

Methods: Patients with stage II-III rectal cancer were treated with the pre-operative chemoradiotherapy regimen comprising FOLFOX4 (two cycles), TomoTherapy (25 Gy in five consecutive fractions, one fraction per day in 5 days on the clinical target volume at the isodose of 95% of the total dose), FOLFOX4 (two cycles), followed by surgery with total mesorectal excision and adjuvant chemotherapy with FOLFOX4 (eight cycles). The primary endpoint was pathological complete response (pCR).

Results: Fifty-two patients were enrolled and 50 patients were evaluable. A total of 46 (92%) patients completed chemoradiotherapy according to the study protocol and 49 patients underwent surgery. Overall, 12 patients achieved a pCR (24.5%, 95% CI 12.5-36.5). The most common grade 3 or more adverse events were neutropenia and alteration of the alvus. Adverse reactions due to radiotherapy, mainly grade 1-2 dermatitis, tenesmus, urinary dysfunction and pain, were tolerable and fully reversible. The most important surgical complications included infection, anastomotic leakage and fistula, all resolved with conservative treatment.

Conclusion: FOLFOX and hypofractionated TomoTherapy is effective and safe in patients with locally advanced rectal cancer. Long-term efficacy needs to be further evaluated.

Trial Registration: ClinicalTrials.gov identifier: NCT02000050 (registration date: 26 November 2013) https://clinicaltrials.gov/ct2/show/NCT02000050.
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http://dx.doi.org/10.1177/1758835920977139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727058PMC
December 2020

Ga-PSMA-11 PET/CT-Guided Stereotactic Body Radiation Therapy Retreatment in Prostate Cancer Patients with PSA Failure after Salvage Radiotherapy.

Biomedicines 2020 Nov 25;8(12). Epub 2020 Nov 25.

Department of Radiotherapy, Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.

(1) Purpose: To investigate the role of Ga-PSMA-11 PET/CT in guiding retreatment stereotactic body radiation therapy (SBRT) in prostate cancer (PCa) patients in biochemical recurrence (BCR) after salvage radiotherapy (S-RT). (2) Methods: We retrospectively evaluated PCa patients previously treated with S-RT on the prostate bed and with proven serum prostate antigen (PSA) failure after S-RT. In all patients (pts), Ga-PSMA-11 PET/CT was positive in the prostate bed only and guided retreatment SBRT. All retreatments were performed by applying the same radiotherapy protocol (median dose of 18 Gy/3 fractions; IQR 18-21 Gy). The median follow-up was 27 months (range 4-35 months). (3) Results: 38 consecutive patients were considered in this analysis. The overall median PSA level before RT was 1.10 ng/mL (IQR 0.82-2.59). PSA decreased at 3 and 6 months after treatment, with a median value of 0.60 ng/mL (IQR 0.31-0.96; < 0.001) and 0.51 ng/mL (IQR 0.29-1.17; < 0.001), respectively. Overall, biochemical recurrence-free survival (b-RFS) was 15.0 months (95% CI 13-23). Grade-1 toxicity was reported in 31.6% of patients (12/38). (4) Conclusion: These results confirm that Ga-PSMA-11-PET/CT is able to identify the site of recurrence in patients who have failed S-RT, thus supporting the use of metastases-directed radiotherapy as a safe and effective treatment.
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http://dx.doi.org/10.3390/biomedicines8120536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761444PMC
November 2020

Early Gastric Cancer: identification of molecular markers able to distinguish submucosa-penetrating lesions with different prognosis.

Gastric Cancer 2021 Mar 6;24(2):392-401. Epub 2020 Nov 6.

Pathology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy.

Background: Early Gastric Cancer (EGC) reaches 25% of the gastric cancers surgically treated in some areas of Northeastern Italy and is usually characterized by a good prognosis. However, among EGCs classified according to Kodama's criteria, Pen A subgroup is characterized by extensive submucosal invasion, lymph node metastases and worse prognosis, whereas Pen B subgroup by better prognosis. The aim of the study was to characterize the differences between Pen A, Pen B and locally advanced gastric cancer (T3N0) in order to identify biomarkers involved in aggressiveness and clinical outcome.

Methods: We selected 33 Pen A, 34 Pen B and 20 T3N0 tumors and performed immunohistochemistry of mucins, copy number variation analysis of a gene panel, microsatellite instability (MSI), TP53 mutation and loss of heterozygosity (LOH) analyses.

Results: Pen A subgroup was characterized by MUC6 overexpression (p = 0.021). Otherwise, the Pen B subgroup was significantly associated with the amplification of GATA6 gene (p = 0.002). The higher percentage of MSI tumors was observed in T3N0 group (p = 0.002), but no significant differences between EGC types were found. Finally, TP53 gene analysis showed that 32.8% of Pen tumors have a mutation in exons 5-8 and 50.0% presented LOH. Co-occurrence of TP53 mutation and LOH mainly characterized Pen A tumors (p = 0.022).

Conclusions: Our analyses revealed that clinico-pathological parameters, microsatellite status and frequency of TP53 mutations do not seem to distinguish Pen subgroups. Conversely, the amplification of GATA6 was associated with Pen B, as well as the overexpression of MUC6 and the TP53 significantly characterized Pen A.
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http://dx.doi.org/10.1007/s10120-020-01135-8DOI Listing
March 2021

Inflammatory indexes as predictive factors for platinum sensitivity and as prognostic factors in recurrent epithelial ovarian cancer patients: a MITO24 retrospective study.

Sci Rep 2020 10 23;10(1):18190. Epub 2020 Oct 23.

Medical Oncology Department, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Neutrophil-to-lymphocyte ratio (NLR) and systemic inflammatory index (SII) are prognostic factors in epithelial ovarian cancer (EOC). Their predictive value for platinum-sensitivity and their role in recurrent EOC are unknown. A total of 375 EOC patients were retrospectively analyzed. The correlation between baseline NLR and SII, and platinum-free interval (PFI) according to first line bevacizumab treatment were analyzed using logistic regression analyses adjusted for baseline patient characteristics. Subsequently NLR and SII calculated before second line treatment initiation were evaluated to identify a potential correlation with progression-free survival (PFS) and overall survival (OS) in platinum-sensitive and in platinum-resistant population. In multivariate analysis, NLR ≥ 3 is an independent predictive factor for PFI at 6 months in the chemotherapy group (OR = 2.77, 95% CI 1.38-5.56, p = 0.004), not in bevacizumab treated patients. After having adjusted for ECOG performance status, histology, ascites, bevacizumab treatment at second line and BRCA status, NLR ≥ 3 and SII ≥ 730 are significantly associated with worse OS in platinum-sensitive (HR = 2.69, 95% CI 1.60-4.53, p = 0.002; HR = 2.11, 95% CI 1.29-3.43, p = 0.003, respectively), not in platinum-resistant EOC patients. Low NLR is an independent predictive factor for platinum-sensitivity in patients treated without bevacizumab. NLR and SII are prognostic factors in recurrent platinum-sensitive EOC patients.
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http://dx.doi.org/10.1038/s41598-020-75316-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585431PMC
October 2020

Plasma Copy Number Changes and Outcome to Abiraterone and Enzalutamide.

Front Oncol 2020 24;10:567809. Epub 2020 Sep 24.

Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Plasma androgen receptor () copy number (CN) status identifies castration-resistant prostate cancer (CRPC) patients with worse outcome on abiraterone/enzalutamide. However, the impact of CN changes on clinical outcome in CRPC is unknown. Plasma samples from 73 patients treated with abiraterone or enzalutamide were collected at baseline and at the time of progression disease (PD). Droplet digital polymerase chain reaction was used to assess CN status. We showed that 11 patients (15.1%) changed CN status from baseline to PD (9 patients from normal to gain, 2 from gain to normal). Patients changing CN status from normal at baseline to gain at PD had intermediate median overall survival (OS) of 20.5 months (95% CI = 8.0-44.2) between those who remained CN normal from baseline to PD (27.3 months [95% CI = 21.9-34.4]) and those who remained CN gain from baseline to PD (9.1 months [95% CI = 3.8-14.5], < 0.0001). Patients changing CN from normal at baseline to gain at PD had a median progression-free survival (PFS) of 9.2 months (95% CI = 2.0-14.7), patients who remained CN normal had a median PFS of 9.1 months (95% CI = 7.2-10.1), and patients who remained CN gain had a median PFS of 5.4 (95% CI = 3.6-6.5, = 0.0005). Both OS and PFS were not significantly different between patients with CN that changes from normal to gain and patients with stable CN normal. We showed that CRPC patients changing CN status from baseline to progression time point had intermediate OS and we suggested that CN evaluation at baseline could be the most informative for clinical outcome of CRPC patients treated with abiraterone or enzalutamide. Larger prospective studies are warranted.
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http://dx.doi.org/10.3389/fonc.2020.567809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542981PMC
September 2020

Prognostic role of a new index (multi inflammatory index) in patients with metastatic colorectal cancer: results from the randomized ITACa trial.

Ther Adv Med Oncol 2020 28;12:1758835920958363. Epub 2020 Sep 28.

Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Aims: We created a new index (Multi Inflammatory Index, MII) composed of an inflammatory index [neutrophil-to lymphocyte-ratio (NLR): MII-1; platelet-to-lymphocyte ratio (PLR): MII-2; or systemic immune-inflammation index (SII): MII-3] and C-reactive protein (CRP). Our aim was to evaluate the prognostic and/or predictive capacity of the MII in the randomized ITACa (Italian Trial in Advanced Colorectal Cancer) study on patients with metastatic colorectal cancer undergoing first-line chemotherapy.

Methods: Between November 2007 and March 2012, baseline NLR, PLR; SII and CRP were available for 131 patients, 66 receiving chemotherapy plus bevacizumab and 65 receiving chemotherapy alone.

Results: Patients with low (<25) MII-1 levels had a better outcome than those with high (⩾25) levels: median progression-free survival (PFS) was 12.4 8.9 months [hazard ratio (HR) = 1.74, 95% confidence interval (CI) 1.21-2.51,  = 0.003] and median overall survival (OS) was 30.9 months 15.0 months (HR = 2.05, 95% CI 1.40-3.02,  = 0.0002), respectively. Similar results were obtained for patients with low (<1424) MII-2 levels compared with those with high (⩾1424) levels: median PFS was 12.6 8.9 months (HR = 1.95, 95% CI 1.35-2.82,  = 0.0004) and median OS was 32.4 14.6 months, respectively (HR = 2.42, 95% CI 1.64-3.57,  < 0.0001). Patients with low (<6068) MII-3 levels had a longer median PFS and OS than those with high (⩾6068) levels: 12.6 8.9 months (HR = 1.91, 95% CI 1.33-2.76,  = 0.005) and 30.9 15.0 months (HR = 2.10, 95% CI 1.43-3.09,  = 0.0002), respectively. Following adjustment for clinical covariates, multivariate analysis confirmed all MII indexes as independent prognostic factors for predicting PFS and OS.

Conclusion: All MII indexes appear to be useful as prognostic markers.

Trial Registration: ClinicalTrials.gov identifier: NCT01878422 (registration date: 07/06/2013) https://clinicaltrials.gov/ct2/show/NCT01878422.
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http://dx.doi.org/10.1177/1758835920958363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534088PMC
September 2020

Body mass index (BMI) and benefit from adjuvant chemotherapy in breast cancer: is it enough?

Breast Cancer Res Treat 2021 01 14;185(1):255-256. Epub 2020 Sep 14.

Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori (IRST) IRCCS, via Piero Maroncelli 40, 47014, Meldola, Italy.

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http://dx.doi.org/10.1007/s10549-020-05923-9DOI Listing
January 2021

Prognostic Role of Systemic Inflammatory Indexes in Germ Cell Tumors Treated With High-Dose Chemotherapy.

Front Oncol 2020 14;10:1325. Epub 2020 Aug 14.

Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

High-dose chemotherapy (HDCT) has curative potential in relapsed/refractory germ cell tumors (GCT). Due to the complexity of this population and the toxicity of HDCT, we evaluated the association between blood-based systemic inflammatory indexes and the outcome of GCT patients undergoing salvage treatment with HDCT in order to define additional prognostic factors able to orient clinical decision. Baseline characteristics, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and the systemic immune-inflammation index (SII) of 62 patients undergoing HDCT for GCT were retrospectively collected. The aim is to evaluate the correlation between each inflammatory marker (NLR, PLR, and SII) and response to HDCT, overall survival (OS), and progression-free survival (PFS). Using the receiver operating curve to identify the best cutoff values, it was found that patients with GCT with NLR ≥3.3 and SII ≥844,000 had shorter PFS and inferior OS. In the multivariable analysis including inflammatory markers, the International Prognostic Factor Study Group (IPFSG) risk group, age, and previous line of treatment, NLR ≥3.3 and SII ≥844,000 were identified to be independently associated with shorter PFS and OS. Moreover, NLR, PLR, and SII significantly correlate with overall response to HDCT. Associating IPFSG prognostic score to inflammatory markers at baseline of HDCT may improve prognostic information and could help physicians to make more personalized treatment decisions.
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http://dx.doi.org/10.3389/fonc.2020.01325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457022PMC
August 2020

Effectiveness of bevacizumab in first- and second-line treatment for metastatic colorectal cancer: ITACa randomized trial.

Ther Adv Med Oncol 2020 23;12:1758835920937427. Epub 2020 Jul 23.

Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Background: Cancer trials involving multiple treatment lines substantially increase our understanding of therapeutic strategies. However, even when the primary end-point of these studies is progression-free survival (PFS), their statistical analysis usually focuses on each line separately, or does not consider repeated events, thus missing potentially relevant information. Consequently, the evaluation of the effectiveness of treatment strategies is highly impaired.

Methods: We evaluated the potentially different effect of bevacizumab (B) administered for the first- or second-line treatment of metastatic colorectal cancer (mCRC) in the ITACa (Italian Trial in Advanced Colorectal Cancer) randomized trial. The ITACa trial consisted of two arms: first-line chemotherapy (CT)+B followed by second-line CT alone first-line CT alone followed by second-line CT+B or CT+B+cetuximab according to KRAS status. Cox models for repeated disease progression were performed, and potential selection bias was adjusted using the inverse probability of censoring weighting method. Hazard ratios (HR) [95% confidence interval (CI)] for PFS (primary endpoint) were reported.

Results: The overall effect of B across the two lines resulted in a HR = 0.80 (95% CI 0.68-0.95,  = 0.008). Evaluating the differential effect of B in first- and second-line, the addition of B to first-line chemotherapy (CT) produced a 10% risk reduction (HR = 0.90, 95% CI 0.72-1.12,  = 0.340) CT alone; B added to second-line CT produced a 36% risk reduction (HR = 0.64, 95% CI 0.49-0.84,  = 0.0011) CT alone.

Conclusion: Our results seem to suggest that B confers a PFS advantage when administered in combination with second-line chemotherapy, which could help to improve current international guidelines on optimal sequential treatment strategies.
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http://dx.doi.org/10.1177/1758835920937427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378711PMC
July 2020

PROTECT Trial: A cluster-randomized study with hydroxychloroquine versus observational support for prevention or early-phase treatment of Coronavirus disease (COVID-19): A structured summary of a study protocol for a randomized controlled trial.

Trials 2020 Jul 31;21(1):689. Epub 2020 Jul 31.

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Objectives: Hydroxychloroquine has shown to have antiviral activity in vitro against coronaviruses, specifically SARS-CoV-2. It is believed to block virus infection by increasing endosomal pH required for virus cell fusion and glycosylation of viral surface proteins. In addition to its antiviral activity, hydroxychloroquine has an immune-modulating activity that may synergistically enhance its antiviral effect in vivo, making it a potentially promising drug for the prevention and the cure of SARS-CoV-19. However, randomized controlled trials are needed to assess whether it can be used safely to treat COVID-19 patients or to prevent infection. The main objective of the present study is to evaluate the efficacy of hydroxychloroquine for (I) the prevention of COVID-19 or related symptoms in SARS-CoV-2-exposed subjects, such as as household members/contacts of COVID-19 patients and (II) the treatment of early-phase asymptomatic or paucisymptomatic COVID-19 patients.

Trial Design: This is a controlled, open label, cluster-randomized, superiority trial with parallel group design. Subjects will be randomized either to receive hydroxychloroquine or to observation (2:1).

Participants: SARS-CoV-2-exposed subjects, including household members and/or contacts of COVID-19 patients and healthcare professionals (Group 1) or patients with COVID-19 (positive PCR test on a rhinopharyngeal or oropharyngeal swab for SARS-CoV-2), asymptomatic or paucisymptomatic in home situations who are not undergoing treatment with any anti COVID-19 medication (Group 2), will be enrolled. Paucisymptomatic patients are defined as patients with a low number of mild symptoms. All subjects must be aged ≥18 years, male or female, must be willing and able to give informed consent and must not have any contraindications to take hydroxychloroquine (intolerance or previous toxicity for hydroxychloroquine/chloroquine, bradycardia or reduction in heart rhythm with arrhythmia, ischemic heart disease, retinopathy, congestive heart failure with use of diuretics, favism or glucose-6-phosphate dehydrogenase (G6PD) deficiency, diabetes type 1, major comorbidities such as advanced chronic kidney disease or dialysis therapy, known history of ventricular arrhythmia, any oncologic/hematologic malignancy, severe neurological and mental illness, current use of medications with known significant drug-drug interactions, and known prolonged QT syndrome or current use of drugs with known QT prolongation). The study is monocentric and will be conducted at Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS. Subjects will be enrolled from a large epidemic region (North-Central Italy). The Public Health Departments of several Italian regions will collaborate by identifying potentially eligible subjects.

Intervention And Comparator: The participants will be randomized (2:1 randomization) to receive either hydroxychloroquine (Arm A) or to Observation (Arm B). Hydroxychloroquine will be administered with the following schedule: Group1: A loading dose hydroxychloroquine 400 mg twice daily on day 1, followed by a weekly dose of hydroxychloroquine 200 mg twice daily on days 8, 15 and 22, for a total of one month of treatment. Group 2: A loading dose hydroxychloroquine 400 mg twice daily on day 1 followed by 200 mg twice daily for a total of 5-7 days. The comparator in this trial is observation given that currently neither treatment is administered to asymptomatic or paucisymptomatic subjects, nor prophylaxis is available for contacts. Hydroxychloroquine will be shipped to subjects within 24 hours of randomization. Given the extraordinary nature of the COVID-19 pandemic, only telephonic interviews will be carried out and electronic Patient Reported Outcomes (ePRO) completed. During treatment, each subject will be contacted every other day for the first week and weekly thereafter (Group 2) or weekly (Group 1) by a study physician to assess early onset of any COVID-19 symptom or any adverse reaction to hydroxychloroquine and to check subject compliance. Furthermore, all subjects will receive periodic ePROs which may be completed through smartphone or tablets to record drug self-administration and onset of any symptom or adverse event. All subjects will be followed up for a total of 6 months by periodic telephonic interviews and ePROs.

Main Outcomes: The primary endpoint/outcome measure for this trial is: for Group 1, the proportion of subjects who become symptomatic and/or swab-positive in each arm within one month of randomization; for Group 2, the proportion of subjects who become swab-negative in each arm within 14 days of randomization.

Randomization: All household members and/or contacts of each COVID-19 index case, and the COVID-19 patient himself/herself, fulfilling all inclusion criteria will be grouped into a single cluster and this cluster will be randomized (2:1) to either arm A or arm B. Information on each subject will be recorded in specific data records. Randomization lists will be stratified according to the following factors regarding COVID-19 index cases: 1. COVID-19 risk level on the basis of province of residence (high vs. low/intermediate); 2. Index case is a healthcare professional (yes vs.no) 3. Index case with COVID-19 treatment (yes vs. no) An independent statistician not otherwise involved in the trial will generate the allocation sequence, and COVID-19 response teams will be unaware of the allocation of clusters. Randomization will be performed through an interactive web-based electronic data-capturing database. An Independent Data Monitoring Committee has been established.

Blinding (masking): This study is open label.

Numbers To Be Randomized (sample Size): For Group 1, a sample size of about 2000 SARS-CoV-2-exposed subjects such as household members and/or contacts of COVID-19 patients will take part in the study. Assuming around 1.5-2.0 asymptomatic household members and/or contacts for each COVID-19 patient, we expect to identify approximately 1000-1300 COVID-19 index cases to be randomized. An interim analysis on efficacy is planned using standard alpha-spending function. For Group 2, sufficient power for primary objective (negative swab within 14 days of randomization) will be reached given a sample size of 300 asymptomatic or paucisymptomatic COVID-19 subjects in home situations not treated for COVID-19 (25%-30% of about 1000-1300 expected index cases). Since up to date reduced evidence about COVID-19 infection epidemiology, the continuous update of diagnostic and therapeutic approaches, the sample size estimation could be updated after a one third of population will be recruited and eventually modified according to a substantial protocol amendment. An interim analysis at 100 enrolled COVID-19 patients is planned. We have planned a Generalized Estimating Equation analysis, which is more efficient than a cluster level analysis, to take advantage of subject-specific covariates. The above reported sample size analysis is therefore to be considered conservative.

Trial Status: The current version of the PROTECT trial protocol is 'Final version, 15 April 2020'. The study started on 9 May 2020. The first patient was enrolled on 14 May 2020. Recruitment is expected to last through September 2020.

Trial Registration: The PROTECT trial is registered in the EudraCT database (no. 2020-001501-24) and in ClinicalTrials.gov ( NCT04363827 ), date of registration 24 April 2020.

Full Protocol: The full PROTECT protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interests of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol (Protocol final version, 15 April 2020). The study protocol has been reported in accordance with Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
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http://dx.doi.org/10.1186/s13063-020-04527-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393246PMC
July 2020

Plasma tumour DNA as an early indicator of treatment response in metastatic castration-resistant prostate cancer.

Br J Cancer 2020 09 16;123(6):982-987. Epub 2020 Jul 16.

University College London Cancer Institute, London, WC1E 6DD, UK.

Background: Plasma tumour DNA (ptDNA) levels on treatment are associated with response in a variety of cancers. However, the role of ptDNA in prostate cancer monitoring remains largely unexplored. Here we characterised on-treatment ptDNA dynamics and evaluated its potential for early assessment of therapy efficacy for metastatic castration-resistant prostate cancer (mCRPC).

Methods: Between 2011 and 2016, 114 sequential plasma samples from 43 mCRPC abiraterone-treated patients were collected. Targeted next-generation sequencing was performed to determine ptDNA fraction. ptDNA progressive disease was defined as a rise in the fraction compared to the pre-treatment.

Results: A ptDNA rise in the first on-treatment sample (interquartile range (IQR) 2.6-3.7 months) was significantly associated with increased risk of early radiographic or any prostate-specific antigen (PSA) rise (odds ratio (OR) = 15.8, 95% confidence interval (CI) 3.5-60.2, p = 0.0002 and OR = 6.0, 95% CI 1.6-20.0, p = 0.01, respectively). We also identified exemplar cases that had a rise in PSA or pseudoprogression secondary to bone flare but no rise in ptDNA. In an exploratory analysis, initial ptDNA change was found to associate with the duration of response to prior androgen deprivation therapy (p < 0.0001) but not to prior taxanes (p = 0.32).

Conclusions: We found that ptDNA assessment for therapy monitoring in mCRPC is feasible and provides data relevant to the clinical setting. Prospective evaluation of these findings is now merited.
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http://dx.doi.org/10.1038/s41416-020-0969-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492429PMC
September 2020

Immune Modulation in Prostate Cancer Patients Treated with Androgen Receptor (AR)-Targeted Therapy.

J Clin Med 2020 Jun 22;9(6). Epub 2020 Jun 22.

Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Piero Maroncelli 40, 47014 Meldola, Italy.

Androgen deprivation therapy (ADT) is a cornerstone of treatment for prostate cancer and, in recent years, androgen receptor (AR)-targeted therapies (abiraterone and enzalutamide) have both been used for the treatment of castration-resistant prostate cancer (CRPC). In our study, we sought to investigate the association between ADT and immune disorders, considering a potential role of androgens in the immune modulation. We retrospectively evaluated CRPC patients treated with abiraterone/enzalutamide between July 2011 and December 2018. We assessed the risk of developing immune alterations and their impact on outcome. We included 844 CRPC patients receiving AR-directed therapies, of whom 36 (4.3%) had autoimmune diseases and 47 (5.6%) second tumors as comorbidities. Median age was 70 years [interquartile range (IQR) = 63-75)]. We showed higher significant incidence of autoimmune diseases during their hormone sensitive status ( = 0.021) and the presence of autoimmune comorbidities before starting treatment with abiraterone/enzalutamide was significantly associated with worse overall survival (OS) (10.1 vs. 13.7 months, HR = 1.59, 95% CI 1.03-2.27, = 0.038). In a multivariate analysis, the presence of autoimmune disorders was an independent predictor of OS (HR = 1.65, 95% CI 1.05-2.60, = 0.031). In conclusion, CRPC patients with autoimmune alterations before starting AR-directed therapies may have worse prognosis. Further prospective studies are warranted to assess the role of immune modulation in the management of prostate cancer patients.
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http://dx.doi.org/10.3390/jcm9061950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356925PMC
June 2020

Molecular and Translational Research on Colorectal Cancer.

Int J Mol Sci 2020 Jun 9;21(11). Epub 2020 Jun 9.

Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014 Meldola (FC), Italy.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer in the world [...].
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http://dx.doi.org/10.3390/ijms21114105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312519PMC
June 2020

Lu-PRRT in advanced gastrointestinal neuroendocrine tumors: 10-year follow-up of the IRST phase II prospective study.

Eur J Nucl Med Mol Imaging 2021 01 29;48(1):152-160. Epub 2020 May 29.

Nuclear Medicine and Radiometabolic Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola, Italy.

Purpose: In March 2014, we reported the activity and safety of Lu-DOTA-octreotate peptide receptor radionuclide therapy (Lu-PRRT) at two different dosages (18.5 GBq and 27.5 GBq in 5 cycles) in patients with progressive metastatic gastrointestinal neuroendocrine tumors (GI-NETs). Disease control rate (DCR) and toxicity were addressed. Herein, we report the late toxicity, progression-free survival (PFS), and overall survival (OS) in the same cohort after a 10-year follow-up.

Methods: We conducted an open-label, disease-oriented prospective phase II trial. From March 2008 to June 2011, 43 patients received 3.7 GBq or 5.5 GBq of Lu-PRRT every 6 to 8 weeks, each cycle repeated 5 times. All patients showed Gallium-DOTA-peptide PET/Octreoscan® positivity (score 3-4 Rotterdam scale) in known lesions. Tumor burden was estimated radiologically. Time-to-event data (PFS and OS) were described using Kaplan-Meier curves and compared with the log-rank test.

Results: Forty-three patients (28 males and 15 females) were evaluable and were monitored for a median period of 118 months (range 12.6-139.6). Median PFS in patients receiving 18.5 GBq was 59.8 months (95% confidence interval [95% CI] 14.3-79.6), identical to that of patients treated with 27.5 GBq (59.8 months, 95% CI 23.4-82.0). Median OS was 71.0 months (95% CI 46.1-107.3) in the group who received 18.5 GBq and 97.6 months (95% CI 64.3-not reached) in the group treated with 27.5 GBq (P = 0.22). Patients with progression limited to lymph nodes showed significantly longer median PFS and OS than those with hepatic lesions (P = 0.02 for PFS and P = 0.04 for OS). Age over 65 years at the time of PRRT was also significant for OS. Of note, no late hematological or renal toxicity was observed in either group.

Conclusions: The long-term follow-up of the IRST phase II study shows that Lu-PRRT is a safe and effective therapy for patients with advanced GI-NET, the most important prognostic factor being tumor burden, hepatic lesions, and age. We believe that Lu-PRRT should be offered to patients with early-stage disease.
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http://dx.doi.org/10.1007/s00259-020-04873-0DOI Listing
January 2021

Instability of Non-Standard Microsatellites in Relation to Prognosis in Metastatic Colorectal Cancer Patients.

Int J Mol Sci 2020 May 16;21(10). Epub 2020 May 16.

Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.

Very few data are reported in the literature on the association between elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) and prognosis in advanced colorectal cancer. Moreover, there is no information available in relation to the response to antiangiogenic treatment. We analyzed EMAST and vascular endothelial growth factor-B (VEGF-B) microsatellite status, together with standard microsatellite instability (MSI), in relation to prognosis in 141 patients with metastatic colorectal cancer (mCRC) treated with chemotherapy (CT) alone ( = 51) or chemotherapy with bevacizumab (B) (CT + B; = 90). High MSI (MSI-H) was detected in 3% of patients and was associated with progression-free survival (PFS; = 0.005) and overall survival (OS; < 0.0001). A total of 8% of cases showed EMAST instability, which was associated with worse PFS ( = 0.0006) and OS ( < 0.0001) in patients treated with CT + B. A total of 24.2% of patients showed VEGF-B instability associated with poorer outcome in ( = 0.005) in the CT arm. In conclusion, our analysis indicated that EMAST instability is associated with worse prognosis, particularly evident in patients receiving CT + B.
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http://dx.doi.org/10.3390/ijms21103532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279028PMC
May 2020

The impact of progesterone receptor expression on prognosis of patients with rapidly proliferating, hormone receptor-positive early breast cancer: a analysis of the IBIS 3 trial.

Ther Adv Med Oncol 2020 27;12:1758835919888999. Epub 2020 Feb 27.

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy.

Background: In the Italian Breast Cancer Intergroup Studies (IBIS) 3 phase III trial, we compared cyclophosphamide, methotrexate, 5-fluorouracil (CMF) alone to sequential epirubicin/CMF regimens in patients with rapidly proliferating early breast cancer (RPEBC). We performed a analysis in the subgroup of patients with hormone-receptor-positive RPEBC on the prognostic role of progesterone receptor (PgR) status.

Methods: RPEBC was defined by thymidine labeling index (TLI) >3% or grade 3 or S-phase >10% or Ki67 >20%. We analyzed 466 patients with hormone-receptor-positive RPEBC receiving sequential epirubicin/CMF regimens followed by tamoxifen, and for whom the status of ER and PgR was available.

Results: Considering both cut-off values of 10% and 20%, PgR expression was significantly associated with age, menopausal status, and ER expression; HER2 status was associated with PgR status only at a cutoff value of 20% PgR. Upon univariate analysis, tumor size, nodal status, and PgR were significantly associated with disease-free survival (DFS) and overall survival (OS), while age class and local treatment type were associated only with DFS. Patients with PgR <20% showed lower 5- and 10-year DFS [hazard ratio (HR) = 1.48; 95%CI: 1.01-2.18;  = 0.044] and OS (HR = 1.85; 95%CI: 1.08-3.19,  = 0.025) rates compared with patients with PgR ⩾20%. Upon multivariate analysis, only tumor size, nodal status, and PgR were independent prognostic factors.

Conclusions: Our results highlight the independent prognostic relevance of PgR expression in patients with hormone-receptor-positive RPEBC treated with adjuvant chemotherapy and endocrine therapy, where the definition of prognostic subgroups is still a major need.
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http://dx.doi.org/10.1177/1758835919888999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047424PMC
February 2020

Erratum: Passardi, A. et al Chemoradiotherapy (Gemox Plus Helical Tomotherapy) for Unresectable Locally Advanced Pancreatic Cancer: A Phase II Study. 2019, , 663.

Cancers (Basel) 2020 Jan 10;12(1). Epub 2020 Jan 10.

Radiotherapy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli n. 40, 47014 Meldola, Italy.

The authors wish to make the following corrections to this paper [...].
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http://dx.doi.org/10.3390/cancers12010178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016811PMC
January 2020

Tumor Infiltrating Lymphocytes and NHERF1 Impact on Prognosis of Breast Cancer Patients.

Transl Oncol 2020 Feb 19;13(2):186-192. Epub 2019 Dec 19.

Functional Biomorphology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II" di Bari, 70124, Italy. Electronic address:

Background: Breast cancer (BC) is a heterogeneous disease, and patients with apparently similar clinicopathological characteristics in clinical practice show different outcome. This study evaluated in primary BCs and in the subgroup of the triple-negative breast cancers (TNBCs) the level of tumor infiltrating lymphocytes (TILs), Na/H exchanger regulatory factor 1 (NHERF1) expression, and their association respect to the clinical outcome of patients.

Material And Methods: NHERF1 expression was assessed by immunohistochemistry in 338 BC samples; the analysis of TILs was examined using hematoxylin and eosin stained slides, according to International TILs Working Group 2014.

Results: Multivariate analysis identified TILs as an independent prognostic factor for DFS in the entire cohort and in the TNBC subgroup (HR, 0.32; 95% CI, 0.12-0.87; P = 0.026; and HR, 0.22; 95% CI, 0.06-0.80; P = 0.022, respectively). Univariate and survival analysis by Kaplan-Meier method revealed that patients with cytoplasmic (c) NHERF1/TILs expression had better DFS than other patients (P = 0.049), and this result was also found in the TNBC subgroup (P = 0.031). Moreover, TNBC patients with cNHERF1/TILs expression had a worse DFS and OS than other patients (P = 0.057 and P = 0.002, respectively).

Conclusions: In the complex scenario of BC and in the era of tumor immunogenicity and immunotherapy, we found an association of TIL levels and cNHERF1 expression that could be useful to identify BCs and particularly TNBC patients with different prognosis and clinical outcome.
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http://dx.doi.org/10.1016/j.tranon.2019.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931214PMC
February 2020

The challenge of prognostication in palliative radiotherapy: the way forward is shared decision-making.

Support Care Cancer 2020 04 22;28(4):1545-1546. Epub 2019 Nov 22.

Palliative Care Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, via P. Maroncelli 40, Meldola, Italy.

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http://dx.doi.org/10.1007/s00520-019-05157-6DOI Listing
April 2020

Association between circulating tumor cells and peripheral blood monocytes in metastatic breast cancer.

Ther Adv Med Oncol 2019 14;11:1758835919866065. Epub 2019 Aug 14.

Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

Background: We retrospectively evaluated the correlation between a baseline measurement of circulating tumor cells (CTCs) and inflammation-based scores in patients with metastatic breast cancer (MBC).

Methods: The optimal value of inflammation-based scores as the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR) and systemic immune-inflammation index (SII) to predict survival was determined and compared with CTC <5 or ⩾5 per 7.5 ml of blood.

Results: In the overall population of 516 women with MBC, CTCs correlated with peripheral blood monocytes ( = 0.008) and neutrophils ( = 0.038). In triple-negative tumors, CTCs correlated with monocyte count ( = 0.009); in HER2+ tumors, CTCs correlated with neutrophil count ( = 0.009), with a trend monocyte count ( = 0.061), whereas no correlation was found in HER2- estrogen receptor-positive (ER+) tumors. In multivariate analysis only monocytes were associated with ⩾5 CTCs (OR = 2.72, 95% CI 1.09-6.80,  = 0.033). In multivariable analysis for predictors of overall survival, CTC (⩾5 <5), number of metastatic sites (>1 1), tumor subtypes (triple-negative HER2- ER+ tumors) and MLR only remained significant.

Conclusions: CTC and MLR are predictors of overall survival in MBC. CTC correlates with monocytes, in particular in triple-negative tumors.
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http://dx.doi.org/10.1177/1758835919866065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696837PMC
August 2019

Independent Negative Prognostic Role of TCF1 Expression within the Wnt/β-Catenin Signaling Pathway in Primary Breast Cancer Patients.

Cancers (Basel) 2019 Jul 22;11(7). Epub 2019 Jul 22.

Functional Biomorphology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, 70124 Bari, Italy.

The Wnt pathway is involved in the progression of breast cancer (BC). We aimed to evaluate the expression of some components of the Wnt pathway (β-catenin, FZD4 (frizzled receptor 4), LRP5 (low-density lipoprotein receptor-related protein 5), LRP6, and TCF1 (T-cell factor 1)) to detect potential associations with NHERF1 (Na+/H+ exchanger regulatory factor 1) protein. Besides, we assessed their impact on patients' clinical outcome. We evaluated 220 primary BC samples by immunohistochemistry (IHC) and protein localization by immunofluorescence. We found a significant correlation between NHERF1 and FZD4, LRP5, LRP6, and TCF1. Univariate analysis showed that the overexpression of β-catenin ( < 0.0001), FZD4 ( = 0.0001), LRP5, LRP6, and TCF1 ( < 0.0001 respectively) was related to poor disease-free survival (DFS). A Kaplan-Meier analysis confirmed univariate data and showed a poor DFS for cNHERF1+/FZD4+ ( = 0.0007), cNHERF1+/LRP5+ ( = 0.0002), cNHERF1+/LRP6+ ( < 0.0001), and cNHERF1+/TCF1+ phenotypes ( = 0.0034). In multivariate analysis, the expression of TCF1 and β-catenin was an independent prognostic variable of worse DFS ( = 0.009 and = 0.027, respectively). In conclusion, we found that the overexpression of β-catenin, FZD4, LRP5, LRP6, and TCF1 was associated with poor prognosis. Furthermore, we first identified TCF1 as an independent prognostic factor of poor outcome, indicating it as a new potential biomarker for the management of BC patients. Also, the expression of Wnt pathway proteins, both alone and in association with NHERF1, suggests original associations of biological significance for new studies.
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http://dx.doi.org/10.3390/cancers11071035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678184PMC
July 2019
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