Publications by authors named "Virginia Ferraresi"

62 Publications

Symptoms and their implications on quality of life and psychological distress in sarcoma patients.

Future Oncol 2021 Mar 29;17(7):817-823. Epub 2021 Jan 29.

Psychology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

The aim of this study was to investigate symptoms, their variation over time and their relationship with quality of life (QoL)/psychological distress in sarcoma patients, as few data regarding QoL and psychological distress in this set of patients are currently available. A total of 188 sarcoma patients from an Italian referral center were involved. Symptoms and financial difficulties were evaluated with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire from the first treatment and over the follow-up period, up to 6 years. The authors found that patients with sarcoma experience several symptoms, especially fatigue and pain, which may dramatically worsen QoL and psychological distress. In conclusion, patients with sarcoma often experience fatigue, pain and financial difficulties, which negatively impacts QoL and psychological distress. To ameliorate overall QoL, proper control of symptoms is necessary.
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http://dx.doi.org/10.2217/fon-2020-0572DOI Listing
March 2021

Desmoid Tumors Characteristics, Clinical Management, Active Surveillance, and Description of Our FAP Case Series.

J Clin Med 2020 Dec 11;9(12). Epub 2020 Dec 11.

Gastroenterology and Digestive Endoscopy, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy.

(1) Background: desmoid tumors (DTs) are common in patients with familial adenomatous polyposis (FAP). An active surveillance approach has been recently proposed as a valuable alternative to immediate treatment in some patients. However, no clear indication exists on which patients are suitable for active surveillance, how to establish the cut-off for an active treatment, and which imaging technique or predictive factors should be used during the surveillance period. (2) Results: we retrospectively analyzed 13 FAP patients with DTs. A surveillance protocol consisting of scheduled follow-up evaluations depending on tumor location and tissue thickening, abdominal computed tomography (CT) scan/Magnetic resonance imaging (MRI) allowed prompt intervention in 3/11 aggressive intra-abdominal DTs, while sparing further interventions in the remaining cases, despite worrisome features detected in three patients. Moreover, we identified a possible predictive marker of tumor aggressiveness, i.e., the "average monthly growth rate" (AMGR), which could distinguish patients with very aggressive/life-threatening tumor behavior (AMGR > 0.5) who need immediate active treatment, from those with stable DTs (AMGR < 0.1) in whom follow-up assessments could be delayed. (3) Conclusion: surveillance protocols may be a useful approach for DTs. Further studies on larger series are needed to confirm the usefulness of periodic CT scan/MRI and the value of AMGR as a prognostic tool to guide treatment strategies.
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http://dx.doi.org/10.3390/jcm9124012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764110PMC
December 2020

An Italian Retrospective Survey on Bone Metastasis in Melanoma: Impact of Immunotherapy and Radiotherapy on Survival.

Front Oncol 2020 15;10:1652. Epub 2020 Sep 15.

Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy.

Background: We performed a multicenter retrospective observational study to investigate the impact of clinical-pathological features and therapeutic strategies on both the complications and survival of patients with bone metastases (BMs) from malignant melanoma.

Patients And Methods: A total of 305 patients with melanoma and radiological evidence of BMs were retrospectively enrolled from 19 Italian centers. All patients received conventional treatments in accordance with each own treating physician's practice. Both univariate and multivariate models were used to explore the impact of melanoma features, including skeletal-related events (SREs), and different treatments on both overall survival (OS) and time-to-SREs. The chi-squared test evaluated the suitability of several parameters to predict the occurrence of SREs.

Results: Eighty-three percent of patients had metachronous BMs. The prevalent (90%) bone metastatic site was the spine, while 45% had involvement of the appendicular skeleton. Forty-seven percent experienced at least one SRE, including palliative radiotherapy (RT) in 37% of cases. No melanoma-associated factor was predictive of the development of SREs, although patients receiving early treatment with bone-targeted agents showed 62% lower risk and delayed time of SRE occurrence. Median OS from the diagnosis of bone metastasis was 10.7 months. The multivariate analysis revealed as independent prognostic factors the number of BMs, number of metastatic organs, baseline lactate dehydrogenase levels, and treatment with targeted therapy or immunotherapy. Subgroup analyses showed the best OS (median = 16.5 months) in the subset of patients receiving both immunotherapy and palliative RT.

Conclusion: Based on our results, patients undergoing immunotherapy and palliative RT showed an OS benefit suggestive of a possible additive effect. The apparent protective role of bone targeting agent use on SREs observed in our analysis should deserve prospective evaluation.
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http://dx.doi.org/10.3389/fonc.2020.01652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523509PMC
September 2020

Diagnostic and Clinical Impact of 18F-FDG PET/CT in Staging and Restaging Soft-Tissue Sarcomas of the Extremities and Trunk: Mono-Institutional Retrospective Study of a Sarcoma Referral Center.

J Clin Med 2020 Aug 6;9(8). Epub 2020 Aug 6.

Medical Oncology 1, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy.

Background: Soft-tissue sarcomas (STS) represent a wide heterogeneous class of rare tumors. The exact role F-fluorodeoxyglucose positron emission/computed tomography (F-FDG PET/CT) in the evaluation of STS is not well established. The aim of the present study was to evaluate how the use of F-FDG PET/CT in STS could influence patient therapy planning, looking for a possible added value over computed tomography and magnetic resonance imaging-the most used modalities in the study of STS. Differences in SUV according to histologic subtype and tumor grade were also considered.

Methods: a total of 345 consecutive F-FDG PET/CT scans performed for initial staging ( = 171) or for suspected disease relapse ( = 174) in 282 patients with STS extracted from the local Information System database were retrospectively reviewed.

Results: F-FDG PET/CT altered therapy planning in 80 cases (16.4% for staging and 29.9% in restaging), both for disease upstaging (58.8%) and downstaging (41.2%) Conclusions: F-FDG PET/CT could significantly influence management of patients with STS, particularly for restaging.
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http://dx.doi.org/10.3390/jcm9082549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463806PMC
August 2020

The Real-Life Journey of Elderly Patients in Soft Tissue and Bone Sarcomas: A Retrospective Analysis from a Sarcoma Referral Center.

J Clin Med 2020 Aug 4;9(8). Epub 2020 Aug 4.

Oncological Orthopaedics Unit, IRCCS-Regina Elena National Cancer Institute, 00161 Rome, Italy.

The high complexity of multimodality treatment frequently results in undertreatment of elderly sarcoma patients, and this may be one of the factors that influence their prognosis. We describe the real-life approach to a population of patients aged over 70 with both soft tissue (STS) and bone sarcomas (BS) followed by our Sarcoma Disease Management Team from 2012 to 2017. One-hundred and twenty-three patients with a median age of 77 years (range: 70-92) were identified. STS were the most common histological subtypes (94%) and the grade was high in 79/123 patients (64%). At diagnosis, 88% of patients had localized disease (LD) and 12% were metastatic (MD). Overall, 96% of patients with LD underwent surgery, 46/54 (85%) with high grade STS patients underwent complementary radiotherapy, and 10/54 (19%) received adjuvant treatments. Twelve out of 33 patients who relapsed (36%) underwent local therapies. Seventeen (52%) and eight (24%) patients were treated with first-line and second-line medical treatments, respectively. Tolerability to systemic treatments was fairly good. Overall, 21% of the patients with advanced disease were candidates for best supportive care alone. Our case series of elderly patients with both STS and BS shows that personalized multidisciplinary treatment can nevertheless be offered to this frail population in order to control the evolution of disease.
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http://dx.doi.org/10.3390/jcm9082503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465593PMC
August 2020

PTEN Function at the Interface between Cancer and Tumor Microenvironment: Implications for Response to Immunotherapy.

Int J Mol Sci 2020 Jul 27;21(15). Epub 2020 Jul 27.

Division of Oncology, University of Verona, 37126 Verona, Italy.

Mounting preclinical and clinical evidence indicates that rewiring the host immune system in favor of an antitumor microenvironment achieves remarkable clinical efficacy in the treatment of many hematological and solid cancer patients. Nevertheless, despite the promising development of many new and interesting therapeutic strategies, many of these still fail from a clinical point of view, probably due to the lack of prognostic and predictive biomarkers. In that respect, several data shed new light on the role of the tumor suppressor phosphatase and tensin homolog on chromosome 10 (PTEN) in affecting the composition and function of the tumor microenvironment (TME) as well as resistance/sensitivity to immunotherapy. In this review, we summarize current knowledge on PTEN functions in different TME compartments (immune and stromal cells) and how they can modulate sensitivity/resistance to different immunological manipulations and ultimately influence clinical response to cancer immunotherapy.
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http://dx.doi.org/10.3390/ijms21155337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432882PMC
July 2020

Pimasertib Versus Dacarbazine in Patients With Unresectable -Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover.

Cancers (Basel) 2020 Jun 29;12(7). Epub 2020 Jun 29.

Department of Dermato Cancerology, CIC 1413, CRCINA Inserm 1232, CHU Nantes, 44093 Nantes, France.

This study investigated the efficacy and safety of pimasertib (1/2 inhibitor) versus dacarbazine (DTIC) in patients with untreated -mutated melanoma. Phase II, multicenter, open-label trial. Patients with unresectable, stage IIIc/IVM1 -mutated cutaneous melanoma were randomized 2:1 to pimasertib (60 mg; oral twice-daily) or DTIC (1000 mg/m; intravenously) on Day 1 of each 21-day cycle. Patients progressing on DTIC could crossover to pimasertib. Primary endpoint: investigator-assessed progression-free survival (PFS); secondary endpoints: overall survival (OS), objective response rate (ORR), quality of life (QoL), and safety. Overall, 194 patients were randomized (pimasertib = 130, DTIC = 64), and 191 received treatment (pimasertib = 130, DTIC = 61). PFS was significantly improved with pimasertib versus DTIC (median 13 versus 7 weeks, respectively; hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.42-0.83; = 0.0022). ORR was improved with pimasertib (odds ratio 2.24, 95% CI 1.00-4.98; = 0.0453). OS was similar between treatments (median 9 versus 11 months, respectively; HR 0.89, 95% CI 0.61-1.30); 64% of patients receiving DTIC crossed over to pimasertib. Serious adverse events (AEs) were more frequent for pimasertib (57%) than DTIC (20%). The most common treatment-emergent AEs were diarrhea (82%) and blood creatine phosphokinase (CPK) increase (68%) for pimasertib, and nausea (41%) and fatigue (38%) for DTIC. Most frequent grade ≥3 AEs were CPK increase (34%) for pimasertib and neutropenia (15%) for DTIC. Mean QoL scores (baseline and last assessment) were similar between treatments. Pimasertib has activity in -mutated cutaneous melanoma and a safety profile consistent with known toxicities of inhibitors. Trial registration: ClinicalTrials.gov, NCT01693068.
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http://dx.doi.org/10.3390/cancers12071727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408351PMC
June 2020

Reorganization Tips from a Sarcoma Unit at Time of the COVID-19 Pandemic in Italy: Early Experience from a Regional Referral Oncologic Center.

J Clin Med 2020 Jun 15;9(6). Epub 2020 Jun 15.

Department of Medical Oncology 1, IRCCS-Regina Elena National Cancer Institute, 00144 Rome, Italy.

Since the World Health Organization declared the novel coronavirus outbreak a global health emergency, Italy's lockdown was declared on 9 March 2020. Elective orthopedic surgery was forced to stop to allow the healthcare system to face the emergency. However, many orthopedic oncology cases could not be postponed. The aim of this study was to report the experience in managing sarcoma patients and the reorganization of a cancer center in an attempt to maintain it free from COVID-19. A Coronavirus Crisis Unit was established by the health directorate coordination in order to adopt specific procedures. General rules of screening and social distancing were applied in different health settings (entrance check point, hospital inward, outpatient clinic, operative room). Regarding oncologic orthopedics, priority was given to bone and soft tissue sarcomas, metastases and aggressive benign tumors at risk of impending or pathologic fracture. Precise indications were followed to manage first outpatient visits, patients undergoing surgery and follow-up. Meticulous adherence to rules among patients and personnel and collaboration between leadership and medical staff in order to continue to perform multidisciplinary treatment protocols, maintain the availability of infrastructural spaces and source protective equipment, swabs and screening samples have been successful in the aim towards a safe cure for cancer patients.
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http://dx.doi.org/10.3390/jcm9061868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357067PMC
June 2020

Overall survival at 5 years of follow-up in a phase III trial comparing ipilimumab 10 mg/kg with 3 mg/kg in patients with advanced melanoma.

J Immunother Cancer 2020 06;8(1)

Center for Immuno-Oncology, University Hospital of Siena, Instituto Toscano Tumori, Siena, Italy.

Background: We have previously reported significantly longer overall survival (OS) with ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with advanced melanoma, with higher incidences of adverse events (AEs) at 10 mg/kg. This follow-up analysis reports a 5-year update of OS and safety.

Methods: This randomized, multicenter, double-blind, phase III trial included patients with untreated or previously treated unresectable stage III or IV melanoma. Patients were randomly assigned (1:1) to ipilimumab 10 mg/kg or 3 mg/kg every 3 weeks for 4 doses. The primary end point was OS.

Results: At a minimum follow-up of 61 months, median OS was 15.7 months (95% CI 11.6 to 17.8) at 10 mg/kg and 11.5 months (95% CI 9.9 to 13.3) at 3 mg/kg (HR 0.84, 95% CI 0.71 to 0.99; p=0.04). In a subgroup analysis, median OS of patients with asymptomatic brain metastasis was 7.0 months (95% CI 4.0 to 12.8) in the 10 mg/kg group and 5.7 months (95% CI 4.2 to 7.0) in the 3 mg/kg group. In patients with wild-type or mutant tumors, median OS was 13.8 months (95% CI 10.2 to 17.0) and 33.2 months (95% CI 19.4 to 45.2) in the 10 mg/kg group, and 11.2 months (95% CI 9.2 to 13.8) and 19.7 months (95% CI 11.6 to 25.3) in the 3 mg/kg group, respectively. The incidence of grade 3/4 treatment-related AEs was 36% in the 10 mg/kg group vs 20% in the 3 mg/kg group, and deaths due to treatment-related AEs occurred in four (1%) and two patients (1%), respectively.

Conclusions: This 61-month follow-up of a phase III trial showed sustained long-term survival in patients with advanced melanoma who started metastatic treatment with ipilimumab monotherapy, and confirmed the significant benefit for those who received ipilimumab 10 mg/kg vs 3 mg/kg. These results suggest the emergence of a plateau in the OS curve, consistent with previous ipilimumab studies.

Trial Registration Number: NCT01515189.
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http://dx.doi.org/10.1136/jitc-2019-000391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279645PMC
June 2020

Neoadjuvant Chemotherapy in High-Risk Soft Tissue Sarcomas: Final Results of a Randomized Trial From Italian (ISG), Spanish (GEIS), French (FSG), and Polish (PSG) Sarcoma Groups.

J Clin Oncol 2020 07 18;38(19):2178-2186. Epub 2020 May 18.

Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Purpose: To determine whether the administration of histology-tailored neoadjuvant chemotherapy (HT) was superior to the administration of standard anthracycline plus ifosfamide neoadjuvant chemotherapy (A+I) in high-risk soft tissue sarcoma (STS) of an extremity or the trunk wall.

Patients And Methods: This was a randomized, open-label, phase III trial. Patients had localized high-risk STS (grade 3; size, ≥ 5 cm) of an extremity or trunk wall, belonging to one of the following five histologic subtypes: high-grade myxoid liposarcoma (HG-MLPS); leiomyosarcoma (LMS), synovial sarcoma (SS), malignant peripheral nerve sheath tumor (MPNST), and undifferentiated pleomorphic sarcoma (UPS). Patients were randomly assigned in a 1:1 ratio to receive three cycles of A+I or HT. The HT regimens were as follows: trabectedin in HG-MLPS; gemcitabine plus dacarbazine in LMS; high-dose prolonged-infusion ifosfamide in SS; etoposide plus ifosfamide in MPNST; and gemcitabine plus docetaxel in UPS. Primary and secondary end points were disease-free survival (DFS) and overall survival (OS), estimated using the Kaplan-Meier method and compared using Cox models adjusted for treatment and stratification factors. The study is registered at ClinicalTrials.gov (identifier NCT01710176).

Results: Between May 2011 and May 2016, 287 patients (UPS: n = 97 [33.8%]; HG-MLPS: n = 65 [22.6%]; SS: n = 70 [24.4%]; MPNST: n = 27 [9.4%]; and LMS: n = 28 [9.8%]) were randomly assigned to either A+I or HT. At the final analysis, with a median follow-up of 52 months, the projected DFS and OS probabilities were 0.55 and 0.47 (log-rank = .323) and 0.76 and 0.66 (log-rank = .018) at 60 months in the A+I arm and HT arm, respectively. No treatment-related deaths were observed.

Conclusion: In a population of patients with localized high-risk STS, HT was not associated with a better DFS or OS, suggesting that A+I should remain the regimen to choose whenever neoadjuvant chemotherapy is used in patients with high-risk STS.
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http://dx.doi.org/10.1200/JCO.19.03289DOI Listing
July 2020

Clinical and Immunological Outcomes in High-Risk Resected Melanoma Patients Receiving Peptide-Based Vaccination and Interferon Alpha, With or Without Dacarbazine Preconditioning: A Phase II Study.

Front Oncol 2020 6;10:202. Epub 2020 Mar 6.

Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

Clinical studies based on novel rationales and mechanisms of action of chemotherapy agents and cytokines can contribute to the development of new concepts and strategies of antitumor combination therapies. In previous studies, we investigated the paradoxical immunostimulating effects of some chemotherapeutics and the immunoadjuvant activity of interferon alpha (IFN-α) in preclinical and clinical models, thus unraveling novel rationales and mechanisms of action of chemotherapy agents and cytokines for cancer immunotherapy. Here, we carried out a randomized, phase II clinical trial, in which we analyzed the relapse-free (RFS) and overall survival (OS) of 34 completely resected stage III-IV melanoma patients, treated with peptide-based vaccination (Melan-A/MART-1 and NY-ESO-1) in combination with IFN-α2b, with (arm 2) or without (arm 1) dacarbazine preconditioning. All patients were included in the intention-to-treat analysis. At a median follow-up of 4.5 years (interquartile range, 15.4-81.0 months), the rates of RFS were 52.9 and 35.3% in arms 1 and 2, respectively. The 4.5-year OS rates were 68.8% in arm 1 and 62.7% in arm 2. No significant differences were observed between the two arms for both RFS and OS. Interestingly, the RFS and OS curves remained stable starting from 18 and 42 months, respectively. Grade 3 adverse events occurred in 5.9% of patients, whereas grade 4 events were not observed. Both treatments induced a significant expansion of vaccine-specific CD8 T cells, with no correlation with the clinical outcome. However, treatment-induced increase of polyfunctionality and of interleukin 2 production by Melan-A-specific CD8 T cells and expansion/activation of natural killer cells correlated with RFS, being observed only in nonrelapsing patients. Despite the recent availability of different therapeutic options, low-cost, low-toxic therapies with long-lasting clinical effects are still needed in patients with high-risk resected stage III/IV melanoma. The combination of peptide vaccination with IFN-α2b showed a minimal toxicity profile and resulted in encouraging RFS and OS rates, justifying further evaluation in clinical trials, which may include the use of checkpoint inhibitors to further expand the antitumor immune response and the clinical outcome. https://www.clinicaltrialsregister.eu/ctr-search/search, identifier: 2008-008211-26.
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http://dx.doi.org/10.3389/fonc.2020.00202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069350PMC
March 2020

Comparison of 18F-FDG PET/CT Criteria for the Prediction of Therapy Response and Clinical Outcome in Patients With Metastatic Melanoma Treated With Ipilimumab and PD-1 Inhibitors.

Clin Nucl Med 2020 Mar;45(3):187-194

First Division of Medical Oncology.

: Immunotherapy currently represents one of the most effective therapies in metastatic melanoma. However, its indirect antineoplastic activity through the immune system has raised relevant challenges for diagnostic imaging in the evaluation of the response to treatment.

Purpose: The aim of this retrospective study was to compare the diagnostic accuracy of different F-FDG PET/CT criteria to predict therapy response and clinical outcome in melanoma patients treated with immune checkpoint inhibitors.

Patients And Methods: Fifty-seven patients with metastatic melanoma treated with ipilimumab (n = 25; group 1) or with PD-1 inhibitors (n = 32; group 2) who performed an F-FDG PET/CT scan before treatment (PET0) and 12 to 18 weeks later (PET1) were retrospectively evaluated. Response at PET1 was evaluated according to RECIST 1.1, EORTC, PERCIMT (PET Response Evaluation Criteria for Immunotherapy), and by percentage change of metabolic tumor volume (MTV) and total lesion glycolysis of up to 5 target lesions. Performance of each criterion at PET1 to predict clinical benefit at 6 months since starting immunotherapy was assessed and correlated to progression-free survival.

Results: In group 1, the best predictor of therapy response was MTV combined with PERCIMT criteria (accuracy, 0.96). In group 2, overlapping results were found for EORTC, MTV, and total lesion glycolysis (accuracy, 0.97). The reliability of the above parameters was also confirmed in the progression-free survival analysis.

Conclusions: F-FDG PET/CT performed after 3 to 4 months since starting immunotherapy can correctly evaluate response to treatment and can also able to predict long-term clinical outcome. Performance of F-FDG PET/CT and criteria for response assessment is influenced by the class of treatment.
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http://dx.doi.org/10.1097/RLU.0000000000002921DOI Listing
March 2020

Impact of Antiretroviral Therapy on the Risk of Recurrence in HIV-1 Infected Patients with Kaposi Sarcoma: A Multicenter Cohort Experience.

J Clin Med 2019 Nov 23;8(12). Epub 2019 Nov 23.

Infectious Dermatology and Allergology, San Gallicano Dermatological Institute IRCCS, 00144 Rome, Italy.

Kaposi sarcoma (KS) remains a relevant malignancy in human immunodeficiency virus (HIV)-infected patients with a non-standardized management; despite past suggestions that ritonavir-boosted protease inhibitor (bPI)-based regimens could be preferable, no combination antiretroviral therapy (cART) regimen was demonstrated to outperform the others and the impact of new drugs, drug classes or paradigms was never investigated nor proven better than previous therapeutic regimes. In order to do this, we retrospectively collected data regarding HIV-infected patients with a diagnosis of KS last seen in six Italian centers after 1 January 2013. A total of 104 KS cases in 99 patients was analyzed for 945.34 patient-year follow-up (PYFU). Twenty-six patients had visceral localizations. Thirty-three patients were treated with chemotherapy, four with electrochemotherapy, and 12 with α-interferon (α-IFN). At censor, 22% received a bPI-based, 14% a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based, and 28% an integrase inhibitor (INI)-based standard cART, 24% a less drug regimen and 12% a mega-cART. Twelve recurrence episodes were observed in seven patients for an incidence of 1.27 per 100 PYFU. Two patients with no evidence of recurrence episodes died for other reasons. In our experience, KS recurrence episodes were infrequent. Despite the increasing use of new antiretroviral drug classes and new treatment paradigms, no excess of recurrence episodes was observed in patients receiving such cART regimens.
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http://dx.doi.org/10.3390/jcm8122062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947508PMC
November 2019

Sarcoma patients' quality of life from diagnosis to yearly follow-up: experience from an Italian tertiary care center.

Future Oncol 2019 Sep 12;15(27):3125-3134. Epub 2019 Sep 12.

Psychology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

To investigate sarcoma patients' perception of quality of life and psychosocial distress across the different disease's stages.  Total 329 sarcoma patients were monitored from diagnosis up to a maximum of six consecutive follow-up visits. Functional status worsened over time with the lowest value after surgery and a full recovery not earlier than the second follow-up visit. Married and single patients exhibited similar quality of life pattern. High levels of psychological distress were observed from diagnosis to active treatment periods with a progressive improvement during follow-up. Psychological distress pattern over time varied by marital status and age. Our study suggests the importance of integrating psychosocial care to medical therapy across the entire sarcoma journey.
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http://dx.doi.org/10.2217/fon-2019-0237DOI Listing
September 2019

Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial.

Eur J Cancer 2019 09 7;119:1-10. Epub 2019 Aug 7.

Formerly at European Institute of Oncology, Milan, Italy.

Background: Since 2015, adjuvant therapy with ipilimumab is an approved treatment for stage III melanoma based on a significantly prolonged recurrence-free survival (RFS). At a median follow-up of 5.3 years, RFS, distant metastasis-free survival (DMFS) and overall survival (OS) were each significantly prolonged in the ipilimumab group compared with the placebo group, despite a 53.3% (ipilimumab) versus 4.6% (placebo) treatment discontinuation rate due to adverse events. We present now long-term follow-up results of this European Organisation for Research and Treatment of Cancer 18071 trial.

Patients, Methods And Results: A total of 99 sites randomised 951 patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes to receive intravenous infusions of ipilimumab 10 mg/kg or placebo, every 3 weeks for 4 doses, then every 3 months for up to 3 years. The RFS, DMFS and OS, as reported by the local investigators, were assessed by the intention-to-treat analysis. Among 431 patients randomised at 63 sites and who were still alive at the analysis reported in 2016, recent follow-up information could be obtained for 264 patients. The median OS follow-up was 6.9 years. The RFS (hazard ratio [HR] 0.75, 95% confidence interval 0.63-0.88; P < 0.001), DMFS (HR 0.76, 0.64-0.90; P = 0.002) and OS (HR 0.73, 0.60-0.89; P = 0.002) benefit observed in the ipilimumab group was durable with an 8.7% absolute difference at 7 years for OS. The benefit was consistent across subgroups.

Conclusions: Adjuvant therapy with ipilimumab prolongs RFS, DMFS and OS significantly. The benefit is sustained long term and consistent across subgroups.
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http://dx.doi.org/10.1016/j.ejca.2019.07.001DOI Listing
September 2019

F-FDG PET/CT in the evaluation of cartilaginous bone neoplasms: the added value of tumor grading.

Ann Nucl Med 2019 Nov 8;33(11):813-821. Epub 2019 Aug 8.

Oncological Orthopaedics Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy.

Objectives: Cartilaginous bone tumors represent a wide variety of neoplasms ranging from benign to extremely aggressive malignant lesions. Unlike other tumors, the biopsy cannot easily predict the histological grade, sometimes not allowing choosing the best therapeutic approach. The aim of the study was to evaluate the ability of F-FDG PET/CT to differentiate enchondroma from chondrosarcoma and to predict the histological grade as compared to biopsy.

Methods: F-FDG PET/CT of 95 patients with chondroid lesions were retrospectively evaluated. The best SUV cutoff to predict the post-surgical histological grade were correlated to those of biopsy and to several radiologic aggressiveness features, which were summarized in the parameter "Radiologic Aggressiveness Score" (AgSCORE).

Results: A concordance between the preoperative biopsy and the definitive histological grade was observed overall in 78.3% of patients, the lowest accuracy (58.6%) being in the identification of intermediate/high-grade chondrosarcoma (G2/G3). The best SUV cutoff was 2.6 to discriminate enchondroma vs. low-grade chondrosarcoma (sensitivity 0.68, specificity 0.86), 3.7 to differentiate low-grade vs. intermediate/high-grade chondrosarcoma (sensitivity 0.83, specificity 0.84) and 7.7 to differentiate intermediate/high-grade vs. dedifferentiated chondrosarcoma (sensitivity 0.92, specificity 0.9). The AgSCORE also showed a high accuracy to differentiate between G1 and G2/G3 chondrosarcoma (cutoff = 4; sensitivity 0.76; specificity 0.89). An even higher accuracy was observed in those cases in which both SUV and AgSCORE cutoff were concordant.

Conclusions: Results in this large series of patients suggest a potential role of F-FDG PET/CT for histological grading of cartilaginous tumors, thus helping the orthopedic surgeon towards the most appropriate surgical procedure.
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http://dx.doi.org/10.1007/s12149-019-01392-3DOI Listing
November 2019

Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients.

Oncoimmunology 2018;7(12):e1465163. Epub 2018 Sep 11.

Unit of Tumor Immunology and Immunotherapy, Department of Research, Advanced Diagnostics and Technological Innovation, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

We have recently described that DNA-damage inducing drug DTIC, administered before peptide (Melan-A and gp100)-vaccination, improves anti-tumor CD8 Melan-A-specific T-cell functionality, enlarges the Melan-A TCR repertoire and impacts the overall survival of melanoma patients. To identify whether the two Ags employed in the vaccination differently shape the anti-tumor response, herein we have carried out a detailed analysis of phenotype, anti-tumor functionality and TCR repertoire in treatment-driven gp100-specific CD8 T cells, in the same patients previously analyzed for Melan-A. We found that T-cell clones isolated from patients treated with vaccination alone possessed an Early/intermediate differentiated phenotype, whereas T cells isolated after DTIC plus vaccination were late-differentiated. Sequencing analysis of the TCRBV chains of 29 treatment-driven gp100-specific CD8 T-cell clones revealed an oligoclonal TCR repertoire irrespective of the treatment schedule. The high anti-tumor activity observed in T cells isolated after chemo-immunotherapy was associated with low PD-1 expression. Differently, T-cell clones isolated after peptide-vaccination alone expressed a high level of PD-1, along with LAG-3 and TIM-3, and were neither tumor-reactive nor polyfunctional. Blockade of PD-1 reversed gp100-specific CD8 T-cell dysfunctionality, confirming the direct role of this co-inhibitory molecule in suppressing anti-tumor activity, differently from what we have previously observed for Melan-ACD8 T cells, expressing PD-1 but highly functional. These findings indicate that the functional advantage induced by combined chemo-immunotherapy is determined by the tumor antigen nature, T-cell immune-checkpoints phenotype, TCR repertoire diversity and anti-tumor T-cell quality and highlights the importance of integrating these parameters to develop effective immunotherapeutic strategies.
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http://dx.doi.org/10.1080/2162402X.2018.1465163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279427PMC
September 2018

HMGA1/E2F1 axis and NFkB pathways regulate LPS progression and trabectedin resistance.

Oncogene 2018 11 6;37(45):5926-5938. Epub 2018 Jul 6.

Cellular Network and Molecular Therapeutic Target Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Roma, Italy.

Although the medical treatments of sarcoma have evolved in the last years, a significant portion of patients develops recurrence after therapies suggesting the need to identify novel targets to improve the treatments. By the use of patient-derived and established cell lines from liposarcoma, as well as specimens from patient biopsies, we found that HMGA1 is involved in the progression of dedifferentiated and myxoid liposarcoma. The immunohistochemical and RT-PCR analyses of 68 liposarcoma specimens revealed a significant high expression of HMGA1, at the protein and RNA levels, both in myxoid and dedifferentiated liposarcoma subtypes compared with differentiated ones. Loss- and gain-of-function experiments by HMGA1-specific depletion and overexpression in dedifferentiated and myxoid liposarcoma cells showed the contribution of this oncogenic factor in cell proliferation, motility, invasion, and drug resistance. The in vitro and in vivo treatment of myxoid liposarcoma with trabectedin, a drug with a potent anti-tumor activity, revealed downregulation of HMGA1, E2F1, and its-downstream targets, vimentin and ZEB1, indicating a critical role of trabectedin in inhibiting the mesenchymal markers of these tumors through the HMGA1/E2F1 axis. These data were also confirmed in patients' tumor biopsies being HMGA1, E2F1, and vimentin expression significantly reduced upon trabectedin therapy, administered as neo-adjuvant chemotherapy. Furthermore, trabectedin treatment inhibits in vitro NFkB pathway in mixoyd liposarcoma sensitive but not in resistant counterparts, and the inhibition of NFkB pathway re-sensitizes the resistant cells to trabectedin treatment. These data support the rational for combining NFkB inhibitors with trabectedin in liposarcoma patients, who have become resistant to the drug.
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http://dx.doi.org/10.1038/s41388-018-0394-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224401PMC
November 2018

Precision diagnostics of Ewing's sarcoma by liquid biopsy: circulating fusion transcripts.

Ther Adv Med Oncol 2018 1;10:1758835918774337. Epub 2018 Jun 1.

Oncogenomics and Epigenetics, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Background: Limited information is available on the applicative value of liquid biopsy (LB) in rare tumors, including Ewing's sarcoma (ES). The accepted precision diagnostics standards would greatly benefit from a non-invasive LB test monitoring pathognomonic gene rearrangements in the bloodstream.

Methods: Tissue and blood samples were collected from six and four ES patients, respectively. Plasma was cleared by two successive rounds of centrifugation and stored frozen until RNA extraction by the QIAmp CNA kit. RNA was retro-transcribed and subjected to real-time quantitative polymerase chain reaction (RT-qPCR) and digital polymerase chain reaction (dPCR). Reactions were set up using two custom primer sets identifying types 1 and 2 fusion transcripts.

Results: The two prevalent types of rearrangements could be identified using only two sets of polymerase chain reaction primers, regardless of patient-specific DNA breakpoints. RT-qPCR and dPCR discriminated the two variants in five tumor tissue RNAs and in four circulating tumor RNAs (ctRNAs). Of note, molecular diagnosis was possible using blood samples even when tumor tissue was not available. ctRNA levels correlated ( < 0.05) with volume-based positron emission tomography (PET) parameters (metabolic tumor volume and total lesion glycolysis), and allowed the fine tracking of disease course after surgery, during adjuvant as well as neoadjuvant chemotherapy, and at follow up in one patient.

Conclusions: To our knowledge, this is one of the few single-marker LB assays in solid tumors specifically designed to detect rearranged RNAs in blood, and the first study describing circulating tumor RNAs in ES patients. Altogether, our results support the idea that LB may have a considerable impact on ES patient monitoring and management.
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http://dx.doi.org/10.1177/1758835918774337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985603PMC
June 2018

Fibrous dysplasia: an unusual case of a very aggressive form with costo-vertebral joint destruction and invasion of the contralateral D7 vertebral body.

Skeletal Radiol 2018 Nov 23;47(11):1571-1576. Epub 2018 May 23.

Medical Oncology "A", IFO-Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

Fibrous dysplasia (FD) is a benign fibro-osseous disease of the bone that may be solitary or multicentric. It is important to distinguish this type of lesion from low-grade osteosarcomas (LGOS) and from secondary sarcomas, because malignant transformation has rarely been reported. It is classically described as having a ground-glass appearance, endosteal scalloping, and thinning of the cortex. Cortical disruption is considered evidence of malignancy, but it can also be present in benign FD with aggressive behavior. We present an unusual case of aggressive FD of the 7th left rib, already diagnosed more than 22 years ago, where cortical and costo-vertebral joint disruption and 7th thoracic vertebral body involvement were not evidence of malignant behavior. From a histological perspective, FD and LGOS are similar; even if histology is of fundamental importance, the diagnosis has to be made based on the clinical and radiological aspects as well, although at imaging, differentiation between FD and LGOS can be difficult. In the present case, even though the histological examination suggested a benign lesion, the radiological examination instead consistently suggests malignancy. It is for this reason that there should be a high index of suspicion during follow-up and a new biopsy should be scheduled in case any changes occur during follow-up.
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http://dx.doi.org/10.1007/s00256-018-2961-1DOI Listing
November 2018

Intralesional vs. extralesional procedures for low-grade central chondrosarcoma: a systematic review of the literature.

Arch Orthop Trauma Surg 2018 Jul 10;138(7):929-937. Epub 2018 Apr 10.

Nuclear Medicine Department, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome, Italy.

Introduction: Chondroid lesions are very common bone tumors. In most cases, they are benign enchondromas (EC) and, in a minor percentage, chondrosarcomas (CSs), the malignant counterpart. In the latter cases, surgery is the mainstay treatment, because they are chemo- and radio-resistant unless dedifferentiation occurs. If resection is recognized as the gold standard for intermediate-, high-grade tumors, and for low-grade chondrosarcoma (LG-CS) located in the spine and pelvis to reduce the risk of local recurrence, there is still no consensus in literature on the treatment of central low-grade chondrosarcoma (cLG-CS) located in the limbs. Our aim is to perform a review of literature on evidence supporting this approach or not.

Materials And Methods: An electronic research of the medical archives was carried out in March 2017 seeking papers evaluating the results of curettage and resection in cLG-CS.

Results: We selected 13 studies corresponding to our criteria. Unfortunately, they were descriptive, retrospective, non-randomized studies. We identified a population of 471 patients for a total of 473 low-grade chondrosarcomas. Two hundred and ninety-nine lesions were treated with curettage and 174 with wide surgery. The two groups were not homogeneous for diagnosis, size and staging, so no comparison between resection and curettage was possible. The global weighted average percentage of local recurrence was 6.7% (20 cases) and 10.9% (19 cases) after curettage and resection, respectively. No cases of metastasis were reported in the group treated with intralesional surgery, compared to five cases reported in the group treated with resection. Indications for surgery were given in most cases based on symptoms and imaging.

Conclusions: The absence of a preoperative histological diagnosis and the lack of a scientific method to conduct the studies do not sufficiently support curettage for low-grade chondrosarcomas. In the absence of this, resection must be considered a general rule for every malignancy. In our opinion, based on the low biological growth rate of low-grade chondrosarcoma, every chondromatous lesion can be followed-up. Biopsies must be performed based on clinical and radiological suspicions such as pain, scalloping or increase in size, rather than on performing a PET scan to evidence more informative high metabolic areas.
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http://dx.doi.org/10.1007/s00402-018-2930-0DOI Listing
July 2018

Nilotinib in locally advanced pigmented villonodular synovitis: a multicentre, open-label, single-arm, phase 2 trial.

Lancet Oncol 2018 05 20;19(5):639-648. Epub 2018 Mar 20.

Department of Medical Oncology, Centre Léon Bérard, Lyon, France; University Claude Bernard Lyon 1, Lyon, France. Electronic address:

Background: Pigmented villonodular synovitis (alternatively known as diffuse-type giant cell tumour) is a rare, locally aggressive tumour driven by a specific translocation resulting in the overexpression of colony-stimulating factor 1 (CSF1). CSF1 receptor (CSF1R) inhibitors (ie, tyrosine kinase inhibitors and antibodies) induce a response in patients with pigmented villonodular synovitis. We investigated the safety and efficacy of a CSF1R tyrosine kinase inhibitor, nilotinib, in patients with locally advanced non-resectable pigmented villonodular synovitis.

Methods: In this phase 2, open-label, single-arm study, we enrolled patients from 11 cancer centres of hospitals in four countries (France, Netherlands, Italy, and Australia). Eligible patients were aged at least 18 years with a WHO performance status of 2 or less, and histologically confirmed progressive or relapsing pigmented villonodular synovitis that was inoperable, or resectable only with mutilating surgery. Patients received oral nilotinib (400 mg twice per day) until disease progression, unacceptable toxicity, or completion of 1 year of treatment. The primary endpoint was the proportion of patients who were progression free at 12 weeks, which was centrally assessed according to Response Evaluation Criteria in Solid Tumors version 1.1. Analyses were by modified intention to treat (ie, all patients with no major protocol violations who were treated with nilotinib for at least 3 weeks were included). All participants who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT01261429, and the results presented here are the final analysis of the trial.

Findings: Between Dec 15, 2010, and Sept 28, 2012, we enrolled 56 patients with pigmented villonodular synovitis and treated them with nilotinib. Five (9%) patients discontinued study treatment before week 12; therefore, 51 patients were evaluable for the primary endpoint at 12 weeks. The estimated proportion of patients who were progression free at 12 weeks was 92·6% (95% credible interval 84·3-97·9). 54 (96%) of 56 patients had a treatment-related adverse event. Six (11%) of 56 patients had at least one grade 3 treatment-related adverse event (headache, dizziness, and hepatic disorders [n=1], pruritus and toxidermia [n=1], diarrhoea [n=1], increased γ-glutamyl transferase concentration [n=1], anorexia [n=1], and increased headache [n=1]). No grade 4 or 5 adverse events were reported. One patient had a treatment-related serious adverse event (toxidermia) and two patients had serious adverse events not considered to be related to the study drug (borderline ovarian tumour [n=1] and pilonidal cyst excision [n=1]).

Interpretation: More than 90% of patients with locally advanced unresectable progressive pigmented villonodular synovitis achieved disease control with 12 weeks of nilotinib treatment. These results indicate that CSF1R tyrosine kinase inhibitors have anti-tumour activity with manageable toxicity in patients with inoperable progressive pigmented villonodular synovitis. Randomised trials investigating the efficacy of nilotinib for patients with unresectable pigmented villonodular synovitis are warranted.

Funding: Novartis, Institut National du Cancer, EuroSARC, French National Cancer Institute, General Directorate of Care Supply, Lyon Research Innovation for Cancer, L'Agence nationale de la recherche, Laboratory of Excellence, Fondation ARC pour la recherche sur le cancer, Ligue contre le Cancer (comité de l'Ain), Info Sarcomes, and Association DAM'S.
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http://dx.doi.org/10.1016/S1470-2045(18)30143-8DOI Listing
May 2018

Histone deacetylase inhibitor ITF2357 leads to apoptosis and enhances doxorubicin cytotoxicity in preclinical models of human sarcoma.

Oncogenesis 2018 Feb 23;7(2):20. Epub 2018 Feb 23.

Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Sarcomas are rare tumors with generally poor prognosis, for which current therapies have shown limited efficacy. Histone deacetylase inhibitors (HDACi) are emerging anti-tumor agents; however, little is known about their effect in sarcomas. By using established and patient-derived sarcoma cells with different subtypes, we showed that the pan-HDACi, ITF2357, potently inhibited in vitro survival in a p53-independent manner. ITF2357-mediated cell death implied the activation of mitochondrial apoptosis, as attested by induction of pro-apoptotic BH3-only proteins and a caspases-dependent mechanism. ITF2357 also induced autophagy, which protected sarcoma cells from apoptotic cell death. ITF2357 activated forkhead box (FOXO) 1 and 3a transcription factors and their downstream target genes, however, silencing of both FOXO1 and 3a did not protect sarcoma cells against ITF2357-induced apoptosis and upregulated FOXO4 and 6. Notably, ITF2357 synergized with Doxorubicin to induce cell death of established and patient-derived sarcoma cells. Furthermore, combination treatment strongly impaired xenograft tumor growth in vivo, when compared to single treatments, suggesting that combination of ITF2357 with Doxorubicin has the potential to enhance sensitization in different preclinical models of sarcoma. Overall, our study highlights the therapeutic potential of ITF2357, alone or in rational combination therapies, for bone and soft tissue sarcomas management.
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http://dx.doi.org/10.1038/s41389-018-0026-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833676PMC
February 2018

EURO-B.O.S.S.: A European study on chemotherapy in bone-sarcoma patients aged over 40: Outcome in primary high-grade osteosarcoma.

Tumori 2018 Jan-Feb;104(1):30-36

7 Department of Orthopedic Pathology, HELIOS Klinikum Emil von Behring GmbH, Berlin - Germany.

Introduction: The EUROpean Bone Over 40 Sarcoma Study (EURO-B.O.S.S.) was the first prospective international study for patients 41-65 years old with high-grade bone sarcoma treated with an intensive chemotherapy regimen derived from protocols for younger patients with high-grade skeletal osteosarcoma.

Methods: Chemotherapy based on doxorubicin, cisplatin, ifosfamide, and methotrexate was suggested, but patients treated with other regimens at the investigators' choice were also eligible for the study.

Results: The present report focuses on the subgroup of 218 patients with primary high-grade osteosarcoma. With a median follow-up of 47 months, the 5-year probability of overall survival (OS) was 66% in patients with localized disease and 22% in case of synchronous metastases. The 5-year OS in patients with localized disease was 29% in pelvic tumors, and 70% and 73% for extremity or craniofacial locations, respectively. In primary chemotherapy, tumor necrosis ≥90% was reported in 21% of the patients. There were no toxic deaths; however, hematological toxicity was considerable with 32% of patients experiencing 1 or more episodes of neutropenic fever. The incidence of nephrotoxicity and neurotoxicity (mainly peripheral) was 28% and 24%, respectively. After methotrexate, 23% of patients experienced delayed excretion, in 4 cases with nephrotoxicity.

Conclusions: In patients over 40 years of age with primary high-grade osteosarcoma, an aggressive approach with chemotherapy and surgery can offer the probability of survival similar to that achieved in younger patients. Chemotherapy-related toxicity is significant and generally higher than that reported in younger cohorts of osteosarcoma patients treated with more intensive regimens.
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http://dx.doi.org/10.5301/tj.5000696DOI Listing
May 2018

Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial.

Lancet Oncol 2017 06 9;18(6):812-822. Epub 2017 May 9.

Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.

Background: Previous trials from our group suggested an overall survival benefit with five cycles of adjuvant full-dose epirubicin plus ifosfamide in localised high-risk soft-tissue sarcoma of the extremities or trunk wall, and no difference in overall survival benefit between three cycles versus five cycles of the same neoadjuvant regimen. We aimed to show the superiority of the neoadjuvant administration of histotype-tailored regimen to standard chemotherapy.

Methods: For this international, open-label, randomised, controlled, phase 3, multicentre trial, patients were enrolled from 32 hospitals in Italy, Spain, France, and Poland. Eligible patients were aged 18 years or older with localised, high-risk (high malignancy grade, 5 cm or longer in diameter, and deeply located according to the investing fascia), soft-tissue sarcoma of the extremities or trunk wall and belonging to one of five histological subtypes: high-grade myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumour, and undifferentiated pleomorphic sarcoma. Patients were randomly assigned (1:1) to receive three cycles of full-dose standard chemotherapy (epirubicin 60 mg/m per day [short infusion, days 1 and 2] plus ifosfamide 3 g/m per day [days 1, 2, and 3], repeated every 21 days) or histotype-tailored chemotherapy: for high-grade myxoid liposarcoma, trabectedin 1·3 mg/m via 24-h continuous infusion, repeated every 21 days; for leiomyosarcoma, gemcitabine 1800 mg/m on day 1 intravenously over 180 min plus dacarbazine 500 mg/m on day 1 intravenously over 20 min, repeated every 14 days; for synovial sarcoma, high-dose ifosfamide 14 g/m, given over 14 days via an external infusion pump, every 28 days; for malignant peripheral nerve sheath tumour, intravenous etoposide 150 mg/m per day (days 1, 2, and 3) plus intravenous ifosfamide 3 g/m per day (days 1, 2, and 3), repeated every 21 days; and for undifferentiated pleomorphic sarcoma, gemcitabine 900 mg/m on days 1 and 8 intravenously over 90 min plus docetaxel 75 mg/m on day 8 intravenously over 1 h, repeated every 21 days. Randomisation was stratified by administration of preoperative radiotherapy and by country of enrolment. Computer-generated random lists were prepared by use of permuted balanced blocks of size 4 and 6 in random sequence. An internet-based randomisation system ensured concealment of the treatment assignment until the patient had been registered into the system. No masking of treatment assignments was done. The primary endpoint was disease-free survival. The primary and safety analyses were planned in the intention-to-treat population. We did yearly futility analyses on an intention-to-treat basis. The study was registered with ClinicalTrials.gov, number NCT01710176, and with the European Union Drug Regulating Authorities Clinical Trials, number EUDRACT 2010-023484-17, and is closed to patient entry.

Findings: Between May 19, 2011, and May 13, 2016, 287 patients were randomly assigned to a group (145 to standard chemotherapy and 142 to histotype-tailored chemotherapy), all of whom, except one patient assigned to standard chemotherapy, were included in the efficacy analysis (97 [34%] with undifferentiated pleomorphic sarcoma; 64 [22%] with high-grade myxoid liposarcoma; 70 [24%] with synovial sarcoma; 27 [9%] with malignant peripheral nerve sheath tumour; and 28 [10%] with leiomyosarcoma). At the third futility analysis, with a median follow-up of 12·3 months (IQR 2·75-28·20), the projected disease-free survival at 46 months was 62% (95% CI 48-77) in the standard chemotherapy group and 38% (22-55) in the histotype-tailored chemotherapy group (stratified log-rank p=0·004; hazard ratio 2·00, 95% CI 1·22-3·26; p=0·006). The most common grade 3 or higher adverse events in the standard chemotherapy group (n=125) were neutropenia (107 [86%]), anaemia (24 [19%]), and thrombocytopenia (21 [17%]); the most common grade 3 or higher adverse event in the histotype-tailored chemotherapy group (n=114) was neutropenia (30 [26%]). No treatment-related deaths were reported in both groups. In agreement with the Independent Data Monitoring Committee, the study was closed to patient entry after the third futility analysis.

Interpretation: In a population of patients with high-risk soft-tissue sarcoma, we did not show any benefit of a neoadjuvant histotype-tailored chemotherapy regimen over the standard chemotherapy regimen. The benefit seen with the standard chemotherapy regimen suggests that this benefit might be the added value of neoadjuvant chemotherapy itself in patients with high-risk soft-tissue sarcoma.

Funding: European Union grant (Eurosarc FP7 278472).
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http://dx.doi.org/10.1016/S1470-2045(17)30334-0DOI Listing
June 2017

Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial.

Lancet Oncol 2017 05 27;18(5):611-622. Epub 2017 Mar 27.

University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.

Background: A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3-4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit-risk profile of ipilimumab 10 mg/kg versus 3 mg/kg.

Methods: This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189.

Findings: Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6-42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9-29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6-17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9-13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70-0·99; p=0·04). The most common grade 3-4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events.

Interpretation: In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment.

Funding: Bristol-Myers Squibb.
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http://dx.doi.org/10.1016/S1470-2045(17)30231-0DOI Listing
May 2017

Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial.

Lancet Oncol 2017 03 3;18(3):393-403. Epub 2017 Feb 3.

Gustave Roussy Cancer Campus Grand Paris, Villejuif, France.

Background: The EORTC 18071 phase 3 trial compared adjuvant ipilimumab with placebo in patients with stage III melanoma. The primary endpoint, recurrence-free survival, was significantly longer in the ipilimumab group than in the placebo group. Investigator-reported toxic effects of ipilimumab consisted mainly of skin, gastrointestinal, endocrine, and hepatic immune-related adverse events. Adjuvant treatment with ipilimumab in this setting was approved in October, 2014, by the US Food and Drug Administration based on the results of the primary outcome of this trial. Here, we report the results of the secondary endpoint, health-related quality of life (HRQoL), of this trial.

Methods: EORTC 18071 was a multinational, double-blind, randomised, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) in 19 countries worldwide. Participants were randomly assigned (1:1) centrally by an interactive voice response system, to receive either ipilimumab 10 mg/kg or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. HRQoL was assessed with the EORTC QLQ-C30 quality-of-life instrument at baseline, weeks 4, 7, 10, and 24, and every 12 weeks thereafter up to 2 years, irrespective of disease progression. Results were summarised by timepoint and in a longitudinal manner in the intention-to-treat population. Two summary scores were calculated for each HRQoL scale: the average score reported during induction (ipilimumab or placebo at a dose of 10 mg/kg, administered as one single dose at the start of days 1, 22, 43, and 64-ie, four doses in 3 weeks), and the average score reported after induction. A predefined threshold of a 10 point difference between arms was considered clinically relevant. The primary HRQoL endpoint was the global health scale, with the predefined hypothesis of no clinically relevant differences after induction between groups. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168.

Findings: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to treatment: 475 in the ipilimumab group and 476 in the placebo group. Compliance with completing the HRQoL questionnaire was 893 (94%) of 951 patients at baseline, 693 (75%) of 924 at week 24, and 354 (51%) of 697 at week 108. Patient mean global health scores during (77·32 [SD 17·36] vs 72·96 [17·82]; p=0·00011) and after induction (76·48 [17·52] vs 72·32 [18·60]; p=0·00067) were statistically significantly different between groups but were not clinically relevant. Mean global health scores differed most between the groups at week 7 (77 [SD 19] in the placebo group vs 72 [22] in the ipilimumab group) and week 10 (77 [20] vs 70 [23]). Mean HRQoL scores differed by more than 10 points at week 10 between treatment groups for diarrhoea (7·67 [SD 17·05] for placebo vs 18·17 [28·35] for ipilimumab) and insomnia (15·17 [22·53] vs 25·60 [29·19]).

Interpretation: Despite increased toxicity, which led to treatment discontinuation for most patients during the induction phase of ipilimumab administration, overall HRQoL, as measured by the EORTC QLQ-C30, was similar between groups, as no clinically relevant differences (10 points or more) in global health status scores were observed during or after induction. Clinically relevant deterioration for some symptoms was observed at week 10, but after induction, no clinically relevant differences remained. Together with the primary analysis, results from this trial show that treatment with ipilimumab results in longer recurrence-free survival compared with that for treatment with placebo, with little impairment in HRQoL despite grade 3-4 investigator-reported adverse events.

Funding: Bristol-Myers Squibb.
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http://dx.doi.org/10.1016/S1470-2045(17)30015-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636622PMC
March 2017

Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy.

N Engl J Med 2016 11 7;375(19):1845-1855. Epub 2016 Oct 7.

From Gustave Roussy Cancer Campus Grand Paris, Villejuif (A.M.M.E., C.R.), Aix-Marseille University, Hôpital de La Timone, Marseille (J.-J.G.), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris (C.L.), University Lille, INSERM Unité-1189, Centre Hospitalier Universitaire (CHU) Lille, Service de Dermatologie, Lille (L.M.), and CHU Lyon, Lyon (L.T.) - all in France; the Oncology Institute of Veneto-Istituto di Ricovero e Cura a Carattere Scientifico, Padua (V.C.-S.), Istituto Nazionale Tumori Fondazione G. Pascale, Naples (P.A.A.), Istituti Fisioterapici Ospitalieri, Rome (V.F.), University Hospital of Siena, Istituto Toscano Tumori, Siena (M.M.), and the European Institute of Oncology, Milan (A.T.) - all in Italy; University of Zurich Hospital, Zurich, Switzerland (R.D.); Memorial Sloan Kettering Cancer Center, New York (J.D.W.); Aarhus University Hospital, Aarhus (H.S.), and Odense University Hospital, Odense (L.B.) - both in Denmark; the Angeles Clinic and Research Institute, Los Angeles (O.H.); Oncology Specialists, Park Ridge, IL (J.M.R.); Cross Cancer Institute, Edmonton, AB, Canada (M.S.); H. Lee Moffitt Cancer Center, Tampa, FL (J.S.W.); Broomfield Hospital, Chelmsford, United Kingdom (S.T.); Universitätsklinikum Schleswig-Holstein, Kiel (A.H.), and University Hospital Heidelberg, Heidelberg (J.C.H.) - both in Germany; Dana-Farber Cancer Institute, Boston (F.S.H.); Bristol-Myers Squibb, Princeton, NJ (C.T., V.P.); and the European Organization for Research and Treatment of Cancer, Brussels (G.S., S.S.).

Background: On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma.

Methods: After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis-free survival, and safety.

Results: At a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001). The rate of distant metastasis-free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P=0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events.

Conclusions: As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00636168 , and EudraCT number, 2007-001974-10 .).
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http://dx.doi.org/10.1056/NEJMoa1611299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648545PMC
November 2016

Polyfunctional Melan-A-specific tumor-reactive CD8(+) T cells elicited by dacarbazine treatment before peptide-vaccination depends on AKT activation sustained by ICOS.

Oncoimmunology 2016 May 1;5(5):e1114203. Epub 2016 Feb 1.

Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute , Rome, Italy.

The identification of activation pathways linked to antitumor T-cell polyfunctionality in long surviving patients is of great relevance in the new era of immunotherapy. We have recently reported that dacarbazine (DTIC) injected one day before peptide-vaccination plus IFN-α improves the antitumor lytic activity and enlarges the repertoire of Melan-A-specific T-cell clones, as compared with vaccination alone, impacting the overall survival of melanoma patients. To identify the mechanisms responsible for this improvement of the immune response, we have analyzed the endogenous and treatment-induced antigen (Ag)-specific response in a panel of Melan-A-specific CD8(+) T-cell clones in terms of differentiation phenotype, inhibitory receptor profile, polyfunctionality and AKT activation. Here, we show that Melan-A-specific CD8(+) T cells isolated from patients treated with chemoimmunotherapy possess a late differentiated phenotype as defined by the absence of CD28 and CD27 co-stimulatory molecules and high levels of LAG-3, TIM-3 and PD-1 inhibitory receptors. Nevertheless, they show higher proliferative potential and an improved antitumor polyfunctional effector profile in terms of co-production of TNF-α, IFNγ and Granzyme-B (GrB) compared with cells derived from patients treated with vaccination alone. Polyfunctionality is dependent on an active AKT signaling related to the engagement of the co-stimulatory molecule ICOS. We suggest that this phenotypic and functional signature is dictated by a fine-tuned balance between TCR triggering, AKT activation, co-stimulatory and inhibitory signals induced by chemoimmunotherapy and may be associated with antitumor T cells able to protect patients from tumor recurrence.
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http://dx.doi.org/10.1080/2162402X.2015.1114203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910730PMC
May 2016

Bilateral spontaneous pneumothorax and massive pneumomediastinum under Pazopanib therapy.

Thorac Cancer 2015 Jan 7;6(1):110-1. Epub 2015 Jan 7.

Department of Surgical Oncology, Thoracic Surgery Unit, Regina Elena National Cancer Institute - IFO Rome, Italy.

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http://dx.doi.org/10.1111/1759-7714.12165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448468PMC
January 2015