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Papers by Alessandro Testori

Journal of Translational Medicine, Jun 30, 2021

Advances in immune checkpoint therapy and targeted therapy have led to improvement in overall sur... more Advances in immune checkpoint therapy and targeted therapy have led to improvement in overall survival for patients with advanced melanoma. Single agent checkpoint PD-1 blockade and combination with BRAF/MEK targeted therapy demonstrated benefit in overall survival (OS). Superior response rates have been demonstrated with combined PD-1/CTLA-4 blockade, with a significant OS benefit compared with single-agent PD-1 blockade. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to therapy remain real challenges in melanoma. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers but they have yet to be fully characterized and implemented clinically. Overall, the progress in melanoma therapeutics and translational research will help to optimize treatment regimens to overcome resistance and develop robust biomarkers to guide clinical decision-making. During the Melanoma Bridge meeting (December 3rd-5th, 2020, Italy) we reviewed the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine.

Ecancermedicalscience, 2010

Journal of Translational Medicine, May 3, 2012

BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About ... more BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naïve patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors.

Value in Health, Nov 1, 2011

using an algorithm utilizing enrolment records and ICD-9 codes. A patient flow algorithm was cons... more using an algorithm utilizing enrolment records and ICD-9 codes. A patient flow algorithm was constructed to define treatment cohorts. Patients were stratified based on the lung cancer drug treatment received following diagnosis and first line therapy. Total costs are report for the 1 year follow up period after initiation of drug treatment. RESULTS: A total of 2739 lung cancer patients were included in the analysis; 53% Ͼ65 yr. Paclitaxel or docetaxel plus platinum were the most commonly utilized 1st line regimens. Pemetrexed plus docetaxel was the most common 2nd line treatment. Among patients receiving 1st line treatment and remaining enrolled in the health plan, only 16.7% received 2nd line treatment. Total costs (average ϩ/Ϫ SD) in the year following chemotherapy initiation was $70,205 Ϯ 66,956

Journal of Clinical Oncology, Aug 1, 2020

PURPOSE Three new therapies have been approved recently for the adjuvant treatment of stage III m... more PURPOSE Three new therapies have been approved recently for the adjuvant treatment of stage III melanoma, substantially reducing the risk of tumor recurrences. This study evaluates 3 independent data sets to clarify the survival probabilities of patients with stage III melanoma. PATIENTS AND METHODS The Central Malignant Melanoma Registry (CMMR) evaluated 1,553 patients with a primary diagnosis of stage III melanoma from 2000 to 2012. Studies from the European Organisation for Research and Treatment of Cancer (EORTC), of 573 patients in the observation arm of the 18991 study and 445 patients in the placebo arm of the 18071 study, were evaluated as reference cohorts. The survival outcomes were compared with the published American Joint Committee on Cancer version 8 (AJCCv8) stage III survival data. RESULTS For the CMMR stage III cohort versus the AJCCv8 cohort, the melanoma-specific survival (MSS) rates at 5 years were 67% versus 77%, and at 10 years were 56% versus 69%, respectively. For stage IIIA, the MSS rates at 5 years were 80% versus 93%, and at 10 years were 71% versus 88%; for stage IIIB, the MSS rates at 5 years were 75% versus 83%, and at 10 years were 61% versus 77%. The MSS rates of the EORTC studies either overlapped with or were lower than, the CMMR data. CONCLUSION The MSS rates in the CMMR and EORTC cohorts over the entire stage III are less favorable than those published in AJCCv8. This is particularly true for substages IIIA and IIIB.

Journal of Translational Medicine, 2014

Frontiers in Oncology

BackgroundCutaneous melanoma (CM) is one of the most aggressive types of skin cancer. Currently, ... more BackgroundCutaneous melanoma (CM) is one of the most aggressive types of skin cancer. Currently, innovative approaches such as target therapies and immunotherapies have been introduced in clinical practice. Data of clinical trials and real life studies that evaluate the outcomes of these therapeutic associations are necessary to establish their clinical utility. The aim of this study is to investigate the types of oncological treatments employed in the real-life clinical management of patients with advanced CM in several Italian centers, which are part of the Clinical National Melanoma Registry (CNMR).MethodsMelanoma-specific survival and overall survival were calculated. Multivariate Cox regression models were used to estimate the hazard ratios adjusting for confounders and other prognostic factors.ResultsThe median follow-up time was 36 months (range 1.2-185.1). 787 CM were included in the analysis with completed information about therapies. All types of immunotherapy showed a sig...

Purpose: KRAS mutations confer adverse prognosis to colorectal cancer, and no targeted therapies ... more Purpose: KRAS mutations confer adverse prognosis to colorectal cancer, and no targeted therapies have shown efficacy in this patient subset. Paracrine, nongenetic events induced by KRAS-mutant tumor cells are expected to result in specific deregulation and/or relocation of tumor microenvironment (TME) proteins, which in principle can be exploited as alternative therapeutic targets.Experimental Design: A multimodal strategy combining ex vivo/in vitro phage display screens with deep-sequencing and bioinformatics was applied to uncover TME-specific targets in KRAS-mutant hepatic metastasis from colorectal cancer. Expression and localization of BCAM and LAMA5 were validated by immunohistochemistry in preclinical models of human hepatic metastasis and in a panel of human specimens (n = 71). The antimetastatic efficacy of two BCAM-mimic peptides was evaluated in mouse models. The role of BCAM in the interaction of KRAS-mutant colorectal cancer cells with TME cells was investigated by adhe...

JAMA Surgery

Take-down policy If you believe that this document breaches copyright please contact us providing... more Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Sentinel node biopsy (SNB) is the standard of care for staging of patients with clinical stage I ... more Sentinel node biopsy (SNB) is the standard of care for staging of patients with clinical stage I and II cutaneous melanoma. No literature exists in performing SNB in patients with pelvic hot-spots at the dynamic lymphoscintigraphy in presence of concomitant inguinofemoral SNs. Nowadays, it is common practice to perform superficial inguinal SNB, followed by ilioobturatory and inguinal dissection in case of sentinel node (SN) positivity. The aim of the current study is to investigate the role of the pelvic sentinel node in the natural history of melanoma.

Dermatology Practical & Conceptual, 2015

Background: In vivo confocal microscopy is an imaging technique that has been applied to the stud... more Background: In vivo confocal microscopy is an imaging technique that has been applied to the study of the ocular surface. However, confocal microscopes dedicated to eye examination are routinely adopted only in ophthalmology reference centres and do not allow an examination of periocular tissue, nor a fluorescence examination. Methods: We applied for the first time the two in vivo confocal microscopes commonly used in dermatology (VivaScope ® 1500 and 3000, CALIBER, distributed in Europe by Mavig GmbH, Munich, Germany) to observe the cornea, the bulbar and tarsal conjunctiva, the eyelid margin, the lacrimal punctum and the palpebral skin of healthy volunteers. Tumoral, inflammatory and infectious diseases of the ocular mucosa and periocular skin from more than 200 patients were observed under the same microscopes. Both microscopes have a reflectance mode. VivaScope ® 1500 allows an additional fluorescent examination and its placement on the ocular surface was made possible by the creation of a special interface between the microscope and the ocular apparatus. Results: Thanks to its compact and flexible configuration, the handheld camera VivaScope ® 3000 allowed to access more easily to the ocular and periocular tissues. Diagnosis of benign and malignant tumors (melanoma, squamous cell carcinoma and basal cell carcinoma), as well as infectious and genetic disease (storage diseases), could be evocated. The detection of parasites (Demodex folliculorum) on eyelids was possible. Confocal images correlated well with conventional histopathology. The fluorescence examination of corneal squamous cell carcinoma by VivaScope 1500 was characterized by extravasation of fluorescein after intravenous injection. Conclusions: Confocal microscopes dedicated to the skin offer new perspectives for the diagnosis, optimization of treatments, and follow-up of the ocular diseases. They will allow dermatologists to examine conjunctival and eyelid tumors, as it is for skin or genital mucosa. In addition, thanks to some adaptations of the dermatological device VivaScope ® 1500, it is possible for the first time to perform a fluorsecnte examination of the ocular and peri-ocular tissue, opening a new era in the clinical imaging of the ocular surface. A new semiology remains to be learned.

Carcinogenesis, 2019

Neuroblastoma (NB) and malignant cutaneous melanoma (CMM) are neural crest cells (NCC)-derived tu... more Neuroblastoma (NB) and malignant cutaneous melanoma (CMM) are neural crest cells (NCC)-derived tumors and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association studies (GWAS). We took a three-staged approach to conduct cross-disease meta-analysis of GWAS for NB and CMM (2101 NB cases and 4202 controls; 12 874 CMM cases and 23 203 controls) to identify shared loci. Findings were replicated in 1403 NB cases and 1403 controls of European ancestry and in 636 NB, 508 CMM cases and 2066 controls of Italian origin. We found a cross-association at locus 1p13.2 (rs2153977, odds ratio = 0.91, P = 5.36 × 10−8). We also detected a suggestive (P < 10−7) NB-CMM cross-association at 2q37.1 with opposite effect on cancer risk. Pathway analysis of 110 NB-CMM risk loci with P < 10−4 demonstrated enrichment of biological processes such as cell migration, cell cycle, metabolism and immune response, which are essential of human NCC developmen...

Annals of Surgery, 2019

Objective: To assess whether preoperative ultrasound (US) assessment of regional lymph nodes in p... more Objective: To assess whether preoperative ultrasound (US) assessment of regional lymph nodes in patients who present with primary cutaneous melanoma provides accurate staging. Background: It has been suggested that preoperative US could avoid the need for sentinel node (SN) biopsy, but in most single-institution reports, the sensitivity of preoperative US has been low. Methods: Preoperative US data and SNB results were analyzed for patients enrolled at 20 centers participating in the screening phase of the second Multicenter Selective Lymphadenectomy Trial. Excised SNs were histopathologically assessed and considered positive if any melanoma was seen. Results: SNs were identified and removed from 2859 patients who had preoperative US evaluation. Among those patients, 548 had SN metastases. US was positive (abnormal) in 87 patients (3.0%). Among SN-positive patients, 39 (7.1%) had an abnormal US. When analyzed by lymph node basin, 3302 basins were evaluated, and 38 were true positive...

Annals of Oncology, 2017

Background. The single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated... more Background. The single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT-mutated advanced melanoma without prior KIT inhibitor treatment. Patients and Methods. Forty-two patients with KIT-mutated advanced melanoma were enrolled and treated with nilotinib 400 mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT-mutated melanomas. Thirteen patients were randomized to DTIC prior to the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors. Results. ORR was 26.2% (n=11/42; 95% CI, 13.9%-42.0%), sufficient to reject the null hypothesis (ORR ≤10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease, 10 (23.8%) had progressive disease, and 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, 4 with an L576P mutation. The median progression-free survival and overall survival were 4.2 months and 18.0 months, respectively. Three of 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib. Conclusion. Nilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an 4 exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations.

The Journal of Clinical Endocrinology & Metabolism, 2016

Context: Tumor angiogenesis is determined by host genetic background rather than environment. Ger... more Context: Tumor angiogenesis is determined by host genetic background rather than environment. Germline single nucleotide polymorphisms (SNPs) of the vascular endothelial growth factor (VEGF) pathway have demonstrated prognostic value in different tumors. Objectives: Our main objective was to test the prognostic value of germline SNPs of the VEGF pathway in nonadvanced differentiated thyroid cancer (DTC). Secondarily, we sought to correlate analyzed SNPs with microvessel density (MVD).

Dermatology (Basel, Switzerland), Jan 5, 2017

How to deal with melanoma of unknown primary (MUP) origin is a debated topic in the literature. W... more How to deal with melanoma of unknown primary (MUP) origin is a debated topic in the literature. We performed a worldwide survey to inquire what clinical and investigational workup is performed as well as the physicians' perception of this disease. A questionnaire was sent via mail to clinicians involved in melanoma care from December 2015 to April 2016 using the International Dermoscopy Society website. 119 physicians from 47 different countries answered the questionnaire. The most reported examination was skin examination followed by CT and/or PET scans. All the participants declared asking about previous excisions of skin lesions with 81% of them asking for a histopathological slide review of previous biopsies. Half of the participants checked for a possible vitiligo phenomenon that may explain regression of the primary lesion. BRAF, cKIT, and GNAQ mutations were screened by 32% of participants. The majority of participants (76%) applied the same treatment protocols for MUP as...

Annals of Oncology, 2016

HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Cancer discovery, Jun 13, 2016

Identification of genes maintaining cancer growth is critical to our understanding of tumorigenes... more Identification of genes maintaining cancer growth is critical to our understanding of tumorigenesis. We report the first in vivo genetic screen of patient-derived tumors, using metastatic melanomas and targeting 236 chromatin genes by expression of specific shRNA libraries. Our screens revealed unprecedented numerosity of genes indispensable for tumor growth (~50% of tested genes) and unexpected functional heterogeneity among patients (<15% in common). Notably, these genes were not activated by somatic mutations in the same patients and are therefore distinguished from mutated cancer driver genes. We analysed underlying molecular mechanisms of one of the identified genes, the Histone-lysine N-methyltransferase KMT2D, and showed that it promotes tumorigenesis by dysregulating a subset of transcriptional enhancers and target genes involved in cell migration. Assembly of enhancer genomic-patterns by activated KMT2D was highly patient-specific, regardless of the identity of transcrip...

Clinical Cancer Research, 2016

Purpose: KRAS mutations confer adverse prognosis to colorectal cancer, and no targeted therapies ... more Purpose: KRAS mutations confer adverse prognosis to colorectal cancer, and no targeted therapies have shown efficacy in this patient subset. Paracrine, nongenetic events induced by KRAS-mutant tumor cells are expected to result in specific deregulation and/or relocation of tumor microenvironment (TME) proteins, which in principle can be exploited as alternative therapeutic targets. Experimental Design: A multimodal strategy combining ex vivo/in vitro phage display screens with deep-sequencing and bioinformatics was applied to uncover TME-specific targets in KRAS-mutant hepatic metastasis from colorectal cancer. Expression and localization of BCAM and LAMA5 were validated by immunohistochemistry in preclinical models of human hepatic metastasis and in a panel of human specimens (n = 71). The antimetastatic efficacy of two BCAM-mimic peptides was evaluated in mouse models. The role of BCAM in the interaction of KRAS-mutant colorectal cancer cells with TME cells was investigated by adh...

Journal of Translational Medicine, Jun 30, 2021

Advances in immune checkpoint therapy and targeted therapy have led to improvement in overall sur... more Advances in immune checkpoint therapy and targeted therapy have led to improvement in overall survival for patients with advanced melanoma. Single agent checkpoint PD-1 blockade and combination with BRAF/MEK targeted therapy demonstrated benefit in overall survival (OS). Superior response rates have been demonstrated with combined PD-1/CTLA-4 blockade, with a significant OS benefit compared with single-agent PD-1 blockade. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to therapy remain real challenges in melanoma. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers but they have yet to be fully characterized and implemented clinically. Overall, the progress in melanoma therapeutics and translational research will help to optimize treatment regimens to overcome resistance and develop robust biomarkers to guide clinical decision-making. During the Melanoma Bridge meeting (December 3rd-5th, 2020, Italy) we reviewed the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine.

Ecancermedicalscience, 2010

Journal of Translational Medicine, May 3, 2012

BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About ... more BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naïve patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors.

Value in Health, Nov 1, 2011

using an algorithm utilizing enrolment records and ICD-9 codes. A patient flow algorithm was cons... more using an algorithm utilizing enrolment records and ICD-9 codes. A patient flow algorithm was constructed to define treatment cohorts. Patients were stratified based on the lung cancer drug treatment received following diagnosis and first line therapy. Total costs are report for the 1 year follow up period after initiation of drug treatment. RESULTS: A total of 2739 lung cancer patients were included in the analysis; 53% Ͼ65 yr. Paclitaxel or docetaxel plus platinum were the most commonly utilized 1st line regimens. Pemetrexed plus docetaxel was the most common 2nd line treatment. Among patients receiving 1st line treatment and remaining enrolled in the health plan, only 16.7% received 2nd line treatment. Total costs (average ϩ/Ϫ SD) in the year following chemotherapy initiation was $70,205 Ϯ 66,956

Journal of Clinical Oncology, Aug 1, 2020

PURPOSE Three new therapies have been approved recently for the adjuvant treatment of stage III m... more PURPOSE Three new therapies have been approved recently for the adjuvant treatment of stage III melanoma, substantially reducing the risk of tumor recurrences. This study evaluates 3 independent data sets to clarify the survival probabilities of patients with stage III melanoma. PATIENTS AND METHODS The Central Malignant Melanoma Registry (CMMR) evaluated 1,553 patients with a primary diagnosis of stage III melanoma from 2000 to 2012. Studies from the European Organisation for Research and Treatment of Cancer (EORTC), of 573 patients in the observation arm of the 18991 study and 445 patients in the placebo arm of the 18071 study, were evaluated as reference cohorts. The survival outcomes were compared with the published American Joint Committee on Cancer version 8 (AJCCv8) stage III survival data. RESULTS For the CMMR stage III cohort versus the AJCCv8 cohort, the melanoma-specific survival (MSS) rates at 5 years were 67% versus 77%, and at 10 years were 56% versus 69%, respectively. For stage IIIA, the MSS rates at 5 years were 80% versus 93%, and at 10 years were 71% versus 88%; for stage IIIB, the MSS rates at 5 years were 75% versus 83%, and at 10 years were 61% versus 77%. The MSS rates of the EORTC studies either overlapped with or were lower than, the CMMR data. CONCLUSION The MSS rates in the CMMR and EORTC cohorts over the entire stage III are less favorable than those published in AJCCv8. This is particularly true for substages IIIA and IIIB.

Journal of Translational Medicine, 2014

Frontiers in Oncology

BackgroundCutaneous melanoma (CM) is one of the most aggressive types of skin cancer. Currently, ... more BackgroundCutaneous melanoma (CM) is one of the most aggressive types of skin cancer. Currently, innovative approaches such as target therapies and immunotherapies have been introduced in clinical practice. Data of clinical trials and real life studies that evaluate the outcomes of these therapeutic associations are necessary to establish their clinical utility. The aim of this study is to investigate the types of oncological treatments employed in the real-life clinical management of patients with advanced CM in several Italian centers, which are part of the Clinical National Melanoma Registry (CNMR).MethodsMelanoma-specific survival and overall survival were calculated. Multivariate Cox regression models were used to estimate the hazard ratios adjusting for confounders and other prognostic factors.ResultsThe median follow-up time was 36 months (range 1.2-185.1). 787 CM were included in the analysis with completed information about therapies. All types of immunotherapy showed a sig...

Purpose: KRAS mutations confer adverse prognosis to colorectal cancer, and no targeted therapies ... more Purpose: KRAS mutations confer adverse prognosis to colorectal cancer, and no targeted therapies have shown efficacy in this patient subset. Paracrine, nongenetic events induced by KRAS-mutant tumor cells are expected to result in specific deregulation and/or relocation of tumor microenvironment (TME) proteins, which in principle can be exploited as alternative therapeutic targets.Experimental Design: A multimodal strategy combining ex vivo/in vitro phage display screens with deep-sequencing and bioinformatics was applied to uncover TME-specific targets in KRAS-mutant hepatic metastasis from colorectal cancer. Expression and localization of BCAM and LAMA5 were validated by immunohistochemistry in preclinical models of human hepatic metastasis and in a panel of human specimens (n = 71). The antimetastatic efficacy of two BCAM-mimic peptides was evaluated in mouse models. The role of BCAM in the interaction of KRAS-mutant colorectal cancer cells with TME cells was investigated by adhe...

JAMA Surgery

Take-down policy If you believe that this document breaches copyright please contact us providing... more Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Sentinel node biopsy (SNB) is the standard of care for staging of patients with clinical stage I ... more Sentinel node biopsy (SNB) is the standard of care for staging of patients with clinical stage I and II cutaneous melanoma. No literature exists in performing SNB in patients with pelvic hot-spots at the dynamic lymphoscintigraphy in presence of concomitant inguinofemoral SNs. Nowadays, it is common practice to perform superficial inguinal SNB, followed by ilioobturatory and inguinal dissection in case of sentinel node (SN) positivity. The aim of the current study is to investigate the role of the pelvic sentinel node in the natural history of melanoma.

Dermatology Practical & Conceptual, 2015

Background: In vivo confocal microscopy is an imaging technique that has been applied to the stud... more Background: In vivo confocal microscopy is an imaging technique that has been applied to the study of the ocular surface. However, confocal microscopes dedicated to eye examination are routinely adopted only in ophthalmology reference centres and do not allow an examination of periocular tissue, nor a fluorescence examination. Methods: We applied for the first time the two in vivo confocal microscopes commonly used in dermatology (VivaScope ® 1500 and 3000, CALIBER, distributed in Europe by Mavig GmbH, Munich, Germany) to observe the cornea, the bulbar and tarsal conjunctiva, the eyelid margin, the lacrimal punctum and the palpebral skin of healthy volunteers. Tumoral, inflammatory and infectious diseases of the ocular mucosa and periocular skin from more than 200 patients were observed under the same microscopes. Both microscopes have a reflectance mode. VivaScope ® 1500 allows an additional fluorescent examination and its placement on the ocular surface was made possible by the creation of a special interface between the microscope and the ocular apparatus. Results: Thanks to its compact and flexible configuration, the handheld camera VivaScope ® 3000 allowed to access more easily to the ocular and periocular tissues. Diagnosis of benign and malignant tumors (melanoma, squamous cell carcinoma and basal cell carcinoma), as well as infectious and genetic disease (storage diseases), could be evocated. The detection of parasites (Demodex folliculorum) on eyelids was possible. Confocal images correlated well with conventional histopathology. The fluorescence examination of corneal squamous cell carcinoma by VivaScope 1500 was characterized by extravasation of fluorescein after intravenous injection. Conclusions: Confocal microscopes dedicated to the skin offer new perspectives for the diagnosis, optimization of treatments, and follow-up of the ocular diseases. They will allow dermatologists to examine conjunctival and eyelid tumors, as it is for skin or genital mucosa. In addition, thanks to some adaptations of the dermatological device VivaScope ® 1500, it is possible for the first time to perform a fluorsecnte examination of the ocular and peri-ocular tissue, opening a new era in the clinical imaging of the ocular surface. A new semiology remains to be learned.

Carcinogenesis, 2019

Neuroblastoma (NB) and malignant cutaneous melanoma (CMM) are neural crest cells (NCC)-derived tu... more Neuroblastoma (NB) and malignant cutaneous melanoma (CMM) are neural crest cells (NCC)-derived tumors and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association studies (GWAS). We took a three-staged approach to conduct cross-disease meta-analysis of GWAS for NB and CMM (2101 NB cases and 4202 controls; 12 874 CMM cases and 23 203 controls) to identify shared loci. Findings were replicated in 1403 NB cases and 1403 controls of European ancestry and in 636 NB, 508 CMM cases and 2066 controls of Italian origin. We found a cross-association at locus 1p13.2 (rs2153977, odds ratio = 0.91, P = 5.36 × 10−8). We also detected a suggestive (P < 10−7) NB-CMM cross-association at 2q37.1 with opposite effect on cancer risk. Pathway analysis of 110 NB-CMM risk loci with P < 10−4 demonstrated enrichment of biological processes such as cell migration, cell cycle, metabolism and immune response, which are essential of human NCC developmen...

Annals of Surgery, 2019

Objective: To assess whether preoperative ultrasound (US) assessment of regional lymph nodes in p... more Objective: To assess whether preoperative ultrasound (US) assessment of regional lymph nodes in patients who present with primary cutaneous melanoma provides accurate staging. Background: It has been suggested that preoperative US could avoid the need for sentinel node (SN) biopsy, but in most single-institution reports, the sensitivity of preoperative US has been low. Methods: Preoperative US data and SNB results were analyzed for patients enrolled at 20 centers participating in the screening phase of the second Multicenter Selective Lymphadenectomy Trial. Excised SNs were histopathologically assessed and considered positive if any melanoma was seen. Results: SNs were identified and removed from 2859 patients who had preoperative US evaluation. Among those patients, 548 had SN metastases. US was positive (abnormal) in 87 patients (3.0%). Among SN-positive patients, 39 (7.1%) had an abnormal US. When analyzed by lymph node basin, 3302 basins were evaluated, and 38 were true positive...

Annals of Oncology, 2017

Background. The single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated... more Background. The single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT-mutated advanced melanoma without prior KIT inhibitor treatment. Patients and Methods. Forty-two patients with KIT-mutated advanced melanoma were enrolled and treated with nilotinib 400 mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT-mutated melanomas. Thirteen patients were randomized to DTIC prior to the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors. Results. ORR was 26.2% (n=11/42; 95% CI, 13.9%-42.0%), sufficient to reject the null hypothesis (ORR ≤10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease, 10 (23.8%) had progressive disease, and 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, 4 with an L576P mutation. The median progression-free survival and overall survival were 4.2 months and 18.0 months, respectively. Three of 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib. Conclusion. Nilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an 4 exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations.

The Journal of Clinical Endocrinology & Metabolism, 2016

Context: Tumor angiogenesis is determined by host genetic background rather than environment. Ger... more Context: Tumor angiogenesis is determined by host genetic background rather than environment. Germline single nucleotide polymorphisms (SNPs) of the vascular endothelial growth factor (VEGF) pathway have demonstrated prognostic value in different tumors. Objectives: Our main objective was to test the prognostic value of germline SNPs of the VEGF pathway in nonadvanced differentiated thyroid cancer (DTC). Secondarily, we sought to correlate analyzed SNPs with microvessel density (MVD).

Dermatology (Basel, Switzerland), Jan 5, 2017

How to deal with melanoma of unknown primary (MUP) origin is a debated topic in the literature. W... more How to deal with melanoma of unknown primary (MUP) origin is a debated topic in the literature. We performed a worldwide survey to inquire what clinical and investigational workup is performed as well as the physicians' perception of this disease. A questionnaire was sent via mail to clinicians involved in melanoma care from December 2015 to April 2016 using the International Dermoscopy Society website. 119 physicians from 47 different countries answered the questionnaire. The most reported examination was skin examination followed by CT and/or PET scans. All the participants declared asking about previous excisions of skin lesions with 81% of them asking for a histopathological slide review of previous biopsies. Half of the participants checked for a possible vitiligo phenomenon that may explain regression of the primary lesion. BRAF, cKIT, and GNAQ mutations were screened by 32% of participants. The majority of participants (76%) applied the same treatment protocols for MUP as...

Annals of Oncology, 2016

HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Cancer discovery, Jun 13, 2016

Identification of genes maintaining cancer growth is critical to our understanding of tumorigenes... more Identification of genes maintaining cancer growth is critical to our understanding of tumorigenesis. We report the first in vivo genetic screen of patient-derived tumors, using metastatic melanomas and targeting 236 chromatin genes by expression of specific shRNA libraries. Our screens revealed unprecedented numerosity of genes indispensable for tumor growth (~50% of tested genes) and unexpected functional heterogeneity among patients (<15% in common). Notably, these genes were not activated by somatic mutations in the same patients and are therefore distinguished from mutated cancer driver genes. We analysed underlying molecular mechanisms of one of the identified genes, the Histone-lysine N-methyltransferase KMT2D, and showed that it promotes tumorigenesis by dysregulating a subset of transcriptional enhancers and target genes involved in cell migration. Assembly of enhancer genomic-patterns by activated KMT2D was highly patient-specific, regardless of the identity of transcrip...

Clinical Cancer Research, 2016

Purpose: KRAS mutations confer adverse prognosis to colorectal cancer, and no targeted therapies ... more Purpose: KRAS mutations confer adverse prognosis to colorectal cancer, and no targeted therapies have shown efficacy in this patient subset. Paracrine, nongenetic events induced by KRAS-mutant tumor cells are expected to result in specific deregulation and/or relocation of tumor microenvironment (TME) proteins, which in principle can be exploited as alternative therapeutic targets. Experimental Design: A multimodal strategy combining ex vivo/in vitro phage display screens with deep-sequencing and bioinformatics was applied to uncover TME-specific targets in KRAS-mutant hepatic metastasis from colorectal cancer. Expression and localization of BCAM and LAMA5 were validated by immunohistochemistry in preclinical models of human hepatic metastasis and in a panel of human specimens (n = 71). The antimetastatic efficacy of two BCAM-mimic peptides was evaluated in mouse models. The role of BCAM in the interaction of KRAS-mutant colorectal cancer cells with TME cells was investigated by adh...