Istituto Nazionale Tumori Research Articles

Abstract PO3-13-06: TILs are an independent prognostic factor in early-stage TNBC patients achieving pathologic complete response after neoadjuvant chemotherapy

Abstract Introduction: In patients with triple negative breast cancer (TNBC) the achievement of pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) is associated with better long-term clinical outcomes. However, the attainment of pCR does not guarantee cure, since ~ 10% of patients undergo disease relapse. Higher levels of tumor infiltrating lymphocytes (TILs) are associated with better prognosis in TNBC patients undergoing upfront surgery and in patients with residual disease after NACT. However, the prognostic role of TILs among TNBC patients undergoing pCR during NACT has not been investigated so far. Methods: We included 134 TNBC patients (ER cutoff< 10%) who achieved pCR after NACT. These cases were identified from a cohort of 348 TNBC patients who received NACT at Istituto Oncologico Veneto (Padova) and Istituto Nazionale Tumori (Milano) from April 2004 to April 2021. TILs were quantified in pre-NACT tumor biopsy according to International guidelines. We assessed the association between TILs and relapse-free survival (RFS) or overall survival (OS). Results: Main patients characteristics were: median age 48 years; ductal histotype 92.8%; histologic grade 3 95.2%; stage I 9.7%, stage II 71.6%, stage III 18.7%. Almost all patients received anthracyclines (98.5%) and taxanes (99.3%) as part of NACT for a median number of 4 cycles each; 55.2% of patients received carboplatin. At a median FU of 4.6 years, the 5-yr RFS and OS rates were 90.4% and 94.4%, respectively. As a continuous variable (1% increment), TILs were independently associated with better RFS and OS after adjusting for patient age and tumor stage: HR 0.90 (95%CI 0.83-0.98), p=0.015 and HR 0.89 (95%CI 0.80-1.00), p=0.041, respectively. The best prognostic TILs cut-off in this cohort was 20%. Patients with TILs>20% showed a 100% 5-yr RFS rate (0/63 events) vs 82.6% (12/71 events) for patients with TILs< 20% (log-rank p< 0.001). OS rates at 5 years were 100% and 90.1% for high vs low TILs (log-rank p=0.007). Conclusions: This is the first demonstration of an independent prognostic role of baseline TILs in TNBC patients achieving pCR after NACT. Baseline TILs may discriminate patients who are cured after achieving pCR from patients at risk of disease relapse despite the achievement of pCR. These latter may be candidate to treatment escalation in the context of clinical trials. Our work provides relevant data in the ongoing debate on the role of adjuvant therapy (primarily pembrolizumab) following pCR. Citation Format: Maria Vittoria Dieci, Claudio Vernieri, Davide Massa, Lorenzo Nicolè, Gaia Griguolo, Federica Miglietta, Andrea Vingiani, Riccardo Lobefaro, Fabio Girardi, Grazia Vernaci, Tommaso Giarratano, Carlo Alberto Giorgi, Giancarlo Pruneri, Matteo Fassan, Filippo De Braud, Valentina Guarneri. TILs are an independent prognostic factor in early-stage TNBC patients achieving pathologic complete response after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-13-06.

PROACT 2.0: A new open-source tool to improve patient-doctor communication in clinical trials.

The use of Digital Healthcare Products is leading to significant improvements in clinical practice. Herein, we discuss the development of PROACT 2.0 (Patient Reported Opinions About Clinical Tolerability v2.0), a novel open-source mobile and web application developed at Fondazione IRCCS Istituto Nazionale Tumori in Milan. It was developed in collaboration with The Christie, Manchester, in the context of work package 2 of the UpSMART Accelerator project, involving a consortium of referral cancer centers from the UK, Spain and Italy. PROACT 2.0 enhances communication between patients and healthcare providers in cancer clinical trials, allowing patients to report adverse events and side effects, and healthcare teams to collect valuable patient-reported outcome measures for treatment management. PROACT 2.0 supports text, audio, and video messaging, offering a secure, non-urgent communication channel that integrates with, or replaces, traditional methods. Its user-friendly and multilingual interface provides a new route for patient engagement and streamlines the handling of logistical information. Positive feedback from initial testing warrants future enhancements for broader applicability in cancer research and treatment.

Sentinel Lymph Node Biopsy (SLNB) for Early-Stage Head and Neck Squamous-Cell Carcinoma of the Tongue: Twenty Years of Experience at I.N.T. "G.Pascale".

Oral tongue squamous-cell carcinoma (OTSCC) is the most prevalent malignancy in the head and neck region. Lymphatic spread, particularly to cervical lymph nodes, significantly impacts 5-year survival rates, emphasizing the criticality of precise staging. Metastatic cervical lymph nodes can decrease survival rates by 50%. Yet, elective neck dissection (END) in T1-2 cN0 patients proves to be an overtreatment in around 80% of cases. To address this, sentinel lymph node biopsy (SLNB) was introduced, aiming to minimize postoperative morbidity. This study, conducted at the ENT and Maxillofacial Surgery department of the Istituto Nazionale Tumori in Naples, explores SLNB's efficacy in early-stage oral tongue squamous-cell carcinoma (OTSCC). From January 2020 to January 2022, 122 T1/T2 cN0 HNSCC patients were enrolled. Radioactive tracers and lymphoscintigraphy identified sentinel lymph nodes, aided by a gamma probe during surgery. Results revealed 24.6% SLN biopsy positivity, with 169 SLNs resected and a 21.9% positivity ratio. The study suggests SLNB's reliability for T1-2 cN0 OTSCC patient staging and early micrometastasis detection.

Molecular Tumor Board as a Clinical Tool for Converting Molecular Data Into Real-World Patient Care.

The investigation of multiple molecular targets with next-generation sequencing (NGS) has entered clinical practice in oncology, yielding to a paradigm shift from the histology-centric approach to the mutational model for personalized treatment. Accordingly, most of the drugs recently approved in oncology are coupled to specific biomarkers. One potential tool for implementing the mutational model of precision oncology in daily practice is represented by the Molecular Tumor Board (MTB), a multidisciplinary team whereby molecular pathologists, biologists, bioinformaticians, geneticists, medical oncologists, and pharmacists cooperate to generate, interpret, and match molecular data with personalized treatments. Since May 2020, the institutional MTB set at Fondazione IRCCS Istituto Nazionale Tumori of Milan met weekly via teleconference to discuss molecular data and potential therapeutic options for patients with advanced/metastatic solid tumors. Up to October 2021, among 1,996 patients evaluated, we identified >10,000 variants, 43.2% of which were functionally relevant (pathogenic or likely pathogenic). On the basis of functionally relevant variants, 711 patients (35.6%) were potentially eligible to targeted therapy according to European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets tiers, and 9.4% received a personalized treatment. Overall, larger NGS panels (containing >50 genes) significantly outperformed small panels (up to 50 genes) in detecting actionable gene targets across different tumor types. Our real-world data provide evidence that MTB is a valuable tool for matching NGS data with targeted treatments, eventually implementing precision oncology in clinical practice.

Superomedial pedicle skin-reducing mastectomy in ptotic and large-sized breasts with two-stage reconstruction through transaxillary video-assisted technique: An effective surgical and anesthetic approach.

Skin-reducing mastectomy has been applied to several surgical techniques in which subcutaneous mastectomy is associated with various types of skin reduction, with preservation of a lower dermal flap to reinforce the inferior lateral seat of an implant. The aim of the study is to present a case series of patients with pendulous/ptotic and/or large-sized breasts treated for breast cancer at the Breast Surgery Unit of Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Naples, Italy, with the superomedial pedicle skin-reducing mastectomy technique, two-stage reconstruction, and transaxillary video-assisted technique, when a postoperative radiotherapy was indicated. We verified its effectiveness by discussing its results, especially in patients who are candidates for postmastectomy radiotherapy. A single-center retrospective study was performed between January 2020 and March 2021 on a prospectively filled database of conservative mastectomies. Of the 64 patients who underwent nipple/skin-sparing mastectomies in the mentioned period, 17 (mean age 46 years, range 30-62 years) were treated with superomedial pedicle skin-reducing mastectomy, with two-stage breast reconstruction through transaxillary video-assisted replacement expander with definitive prosthesis and contralateral symmetrization, selected for postmastectomy radiotherapy. We had only three minor complications. No flap necrosis, no infections, no breast seromas, and no reconstructive failures were observed. During follow-up of the patients treated with video-assisted reconstruction, there were no cases of infection, hematoma, implant rupture, or suture dehiscence in the reconstructed breast. Skin-reducing mastectomy with superomedial pedicle is a safe and reliable procedure to treat breast cancer in selected patients, i.e., those with pendulous/ptotic and or large-sized breasts. Particularly, in patients who undergo postmastectomy radiotherapy, the two-stage reconstruction with video-assisted transaxillary endoscopic approach can find its main indication, using incisions positioned far from the mammary region, offering numerous advantages.

Implementation of a Hybrid Care Model for Telemedicine-based Cancer Pain Management at the Cancer Center of Naples, Italy: A Cohort Study.

Telemedicine, the remote delivery of healthcare services, represents a great opportunity for cancer pain management. A care model of telemedicine that combines remote visits and hospital access could be an effective and safe strategy for pain management of cancer patients. A retrospective study was conducted using the dataset of the telemedicine program at the Istituto Nazionale Tumori of Naples, Italy for assessing the efficacy of a telehealth-based model of care. Demographic, clinical, and process variables were investigated. A total of 226 cases and 489 visits were included in the analysis. The mean age of patients was 63.4 years (SD=12.4 years), and no sex differences were observed. Approximately 55% of patients were ECOG-PS ≤2 and 87% suffered from metastatic disease. More than half of the patients were treated with high doses of opioids. Each patient had a mean of 2 remote visits and half of the patients had more than 1 telehealth consultation. The dropout ratio was 5.3%. Most visits (n=472) were conducted on patients in the Campania Region, Italy. The maximum covered distance from the Cancer Center and the patients' location was 555.22 Km. A significant difference in the overall number of visits (p=0.006) and the number of pro-capita remote visits (p=0.010) was found, in favor of the group of patients treated before the end of the Covid-19 emergency in Italy, compared to those treated after the pandemic. Despite various positive outcomes, the analysis highlights several weaknesses, such as the need to assist patients with advanced and non-advanced disease located outside the regional territory. Overall, the telehealth processes should be adapted to post-pandemic scenarios towards their implementation in routine clinical practice.

Outpatient palliative care referral system (PCRS) for patients with advanced cancer: an impact evaluation protocol

IntroductionEarly palliative care (PC) in the clinical pathway of advanced cancer patients improves symptom control, quality of life and has a positive impact on overall quality of care. At present,...

1056P KRAS and LKB1 mutation conferring prognostic and predictive role on liquid biopsy in advanced NSCLC

Liquid biopsy (LB) is a feasible tool able to detect genomic alterations in cancer at baseline and also as a longitudinal monitoring to identify resistance mutations. In patients (pts) with mNSCLC, when tissue biopsy remains a difficult procedure, LB might be crucial for therapeutical options, especially in the immunotherapy (IO) and target therapy era. The aim of this bicentric study is to assess the prognostic value of LB in mNSCLC. Data from mNSCLC with any gene alteration/PD-L1 expression were collected at Istituto Nazionale Tumori of Milan and Policlinico Universitario of Naples. Liquid biopsy was performed by 73-gene Guardant360® CDx / 29-gene Archer® LiquidPlex™panels. Effects of circulating genomic alterations on Overall Survival (OS) (from 4-stage diagnosis to death/last FUP) were assessed using Cox proportional hazard model cell free. Kaplan-Meier curves were performed to assess OS between IO and non-IO treatments arms. Of 488 pts underwent LB, most were male (56.9%), former smoker (46.3%), with adenocarcinoma (73.6%) and PD-L1 > 1% (55.6%). 301/488 patients (62.6%) were treated with IO alone or in combination with chemotherapy, in first (47.0%) or second line (102 – 29.2%). In 133 (32.1%) cases, LB was performed at IO baseline, while in 101 (24.5%) cases at IO progression. Among the most relevant genes, STK11+/LKB1+ confers the worst OS (HR for OS 2.12 months, CI 95% 1.26 – 3.56; p = 0.005), regardless treatments. LKB1+/KRAS+ have a poorer OS than LKB1-/KRAS- (OS: 13 vs 24 m, HR 2.34 95% IC 1.19 – 4.61) and LKB1-/KRAS+ (OS: 13 vs 34 m HR 2.99 95% IC 1.36-6.54). When analyzing the effect of KRAS on IO and non-IO arms, KRAS-/IO have the best prognosis compared to KRAS+/non-IO which have the worst prognosis, while KRAS+/IO seems to have a similar prognosis to KRAS-/non-IO pts (HR 0.82 95% IC 0.43 – 1.58). Results reported on LB confirmed previous reports on tissue: STK11+ pts, have the worst prognosis regardless treatments. KRAS+ compare to STK11+/KRAS+ pts and STK11-/KRAS- pts seems to have the best prognosis. IO seems to play a relevant role on survival regardless KRAS status, in fact when using IO the negative prognostic effect of KRAS+ pts decreases and becomes similar to KRAS-/non-IO pts.

Validation of a Nomogram to Predict Recurrence in Patients with Mucinous Neoplasms of the Appendix with Peritoneal Dissemination After Cytoreductive Surgery and HIPEC.

Survival of patients affected by mucinous appendiceal neoplasms with peritoneal dissemination (PD) is mainly related to histopathological features. However, prognostic stratification is still a concern, as the clinical course of the disease is often unpredictable. The aim of this study is to construct and externally validate a nomogram predicting disease-free survival (DFS) in mucinous appendiceal neoplasms with PD treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Patients treated in two referral centers were included: Hospital General Universitario Gregorio Marañón, Madrid, Spain (derivation cohort) and Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy (validation cohort). Cox regression analysis identified factors associated with shorter DFS in the derivation cohort. The nomogram performance was externally evaluated in the validation cohort using concordance index and calibration plots. Histology was classified according to the Peritoneal Surface Oncology Group International (PSOGI). The derivation cohort included 95 patients, and the validation cohort 348. Five-year DFS rates were 51.5 and 62%, respectively. Cox regression analysis (derivation cohort) identified PSOGI histology of the peritoneal components, number of preoperative elevated tumor marker, and peritoneal disease extent, as assessed by peritoneal carcinomatosis index, to be predictors of DFS. The model's predictive capacity was higher than that of PSOGI classification alone, with respective concordance indexes of 0.702 ± 0.023 and 0.610 ± 0.018 (validation cohort). The nomogram approximated the perfect model in the calibration plots at 3- and 5-year DFS. An easy-to-use model that provides better prognostic stratification than histopathological features has been constructed. This nomogram may help clinicians in individualized survival predictions and informed clinical decision-making.

Central venous catheters-related-thrombosis and risk factors in oncological patients: A retrospective evaluation of recent risk scores.

Insertions of central venous catheters (CVC) has become a common practice in Onco-Hematologic Units to administer systemic treatments. Unfortunately they can cause complications influencing patient's care-pathway significantly. Oncological patients have a higher thrombotic risk than the general population, therefore specific recent risk scores are spreading through the clinical practice, such as Khorana, Protecht, COMPASS-CAT, and Michigan scores. A retrospective cohort of 177 out of a total of 3046 outpatients accessing the Medical Day Hospital of Istituto Nazionale Tumori di Milano from March 2019 to February 2021 aged ⩾ 18 years who developed CVC complications was analyzed extracting clinical data from their medical records. Focusing on the risk factors, especially through recent risk scores to estimate the thrombotic risk we used Wilcoxon-test for continuous variables and the Pearson-Chi-Square test for categorical variables. Anticoagulants resulted a protective factor mostly for partial CVC occlusion (p = 0.0001), preventing CVC occlusions. CVC occlusions were significantly associated with epitelial tumor histotype, (p = 0.0061). Complete CVC occlusions were significantly associated with peripherical inserted central venous catheters (PICC) (p < 0.0001). Catheter-related-thrombosis (CRT) was significantly associated with peripherical-inserted-central-venous-catheter, both when it was diagnosed clinically (p = 0.0121) and radiographically (p = 0.0168).There was a strong association between CRT and a high grade of Khorana Score (p = 0.0195), Protecht Score (p = 0.0412), COMPASS-CAT Score (p = 0.0027). A positive statistical trend was observed between the Michigan Score and CRT in patients carrying PICC (p = 0.053). There are many different and various factors associated with higher or lower risk of CVC thrombotic complications, so it could be useful to test the recent risk scores to estimate thrombotic risk in oncological patients in clinical practice.

Patient-reported outcome measurements in post-mastectomy implant-based breast reconstruction and radiotherapy: Analysis of BREAST-Q data.

Breast reconstruction has become a standard of care in patients undergoing mastectomy, greatly improving their quality of life. An increasing number of patients-reported outcome measurements (PROMs) have been developed over the years to better analyze patients' subjective overall experience. BREAST-Q is the PROMs for breast surgery introduced in our practice to assess patients' experiences when undergoing implant-based breast reconstruction and radiotherapy along with the use of Peak Plasma Blade and acellular dermal matrix. The pre-operative version of the Reconstruction BREAST-Q was administered to all 88 patients enrolled between December 2017 and December 2018 in the Plastic Reconstructive Surgery Unit at Fondazione IRCCS Istituto Nazionale Tumori Milano through person-to-person interviews, while the post-operative version was administered to the 75 patients who completed a 12-month follow-up (four patients died during one-year follow-up and nine patients had major complications). The survey areas highlighted were: satisfaction with breast, psychosocial well-being, physical well-being and sexual well-being. From BREAST-Q questions regarding Satisfaction With The Appearance Of The Breast and Psychosocial Well-Being outcomes showed significant improvement from pre-operative data, as well as with Satisfaction With Overall Care, with the exception of Physical Well-Being Chest. BREAST-Q allows the assessment of patients' perception, not only for surgical results, but also for the overall experience with surgeons and medical staff.The women enrolled in our study reported an overall good patient satisfaction in most of the analyzed fields.

Epitheliod hemagioendothelioma (EHE) patient-derived model (PDX): Drug activity assessment and validation of novel biomarkers.

11566 Background: EHE is an ultra-rare sarcoma marked by two specific fusions, WWTR1-CAMTA1 (̃90%) and YAP1-TFE3 (̃10%). The clinical course of EHE ranges from indolent to highly aggressive, often associated with systemic paraneoplastic symptoms. Molecular predictors of clinical outcome are unknown. While surgery is the mainstay of treatment in the localized setting, management of advanced disease is challenging due to the rarity and poor sensitivity to conventional chemotherapy. This hampers the conduct of large prospective clinical trials. We report herein the first available EHE PDX (developed at the Istituto Nazionale Tumori, Milan, Italy) (INT), to assess the activity of old and new anticancer agents in EHE and inform future clinical studies. We also report on the preliminary results of a prospective observational study, ongoing in collaboration with The EHE Rare Cancer Charity (UK) and The EHE Foundation (US) aimed at identifying prognostic factors. Methods: A PDX of EHE in SCID mice was generated at INT from a patient (pt) suffering with the aggressive clinical variant, presenting with systemic symptoms. The PDX fully reproduces the originating clinical tumor in terms of morphology, biology ( WWTR1- CAMTA1 positive), overall transcriptomic profile. 2D (monolayer) and 3D (sferoids) cell cultures were established following PDX disaggregation. We have started assessing the comparative activity of currently available drugs (doxorubicin, sirolimus), while the efficacy of novel agents is undergoing. In parallel, we analyzed the presence of a selection of inflammatory cytokines in prospectively collected blood samples from EHE pts who entered an international observational study and we looked at their presence and modulation in the PDX model. Results: PDX experiments showed almost negligible activity of doxorubicin while sirolimus induced an 80% tumor volume inhibition. Biochemical analysis in tumors explanted from sirolimus-treated mice confirmed the down-regulation of mTOR downstream signaling. Among all cytokines, Growth and Differentiation Factor-15 (GDF-15) was found significantly over-expressed in serum of EHE pts (n = 23), particularly those with the most aggressive clinical variant, compared to healthy subjects (n = 23; p&lt; 0.01). Consistently, EHE PDX and cell culture were found to release in the blood/culture medium GDF-15. Sirolimus was found to down-regulate GDF-15 release in both in vivo and in vitro EHE models. Conclusions: Our preliminary results indicate that this EHE PDX model is suitable i) for comparatively assessing the activity of anticancer drugs, and ii) for identifying and pre-clinically validating novel biomarkers. The role of GDF-15 in EHE progression deserves further investigation.

COVID-19 Vaccination in Health Care Workers in Italy: A Literature Review and a Report from a Comprehensive Cancer Center.

The coronavirus disease 2019 pandemic still represents a global public health emergency, despite the availability of different types of vaccines that reduced the number of severe cases, the hospitalization rate and mortality. The Italian Vaccine Distribution Plan identified healthcare workers (HCWs) as the top-priority category to receive access to a vaccine and different studies on HCWs have been implemented to clarify the duration and kinetics of antibody response. The aim of this paper is to perform a literature review across a total of 44 studies of the serologic response to COVID-19 vaccines in HCWs in Italy and to report the results obtained in a prospective longitudinal study implemented at the Fondazione IRCCS Istituto Nazionale Tumori (INT) of Milan on 1565 HCWs. At INT we found that 99.81% of the HCWs developed an antibody response one month after the second dose. About six months after the first serology evaluation, 100% of the HCWs were still positive to the antibody, although we observed a significant decrease in its levels. Overall, our literature review results highlight a robust antibody response in most of the HCWs after the second vaccination dose. These figures are also confirmed in our institutional setting seven months after the completion of the cycle of second doses of vaccination.

Paraneoplastic neurological syndromes in patients affected by SCLC: a case series.

Paraneoplastic syndromes occur in about 0.1% of patients affected by neoplastic diseases. In some types of tumors, such as Small Cell Lung Cancer (SCLC), Thymoma, and particular forms of Plasmacytoma, the association with Paraneoplastic Neurological Syndromes (PNS) is much more frequent. It seems that these syndromes are triggered by tumor production of factors normally expressed only by the individual's nervous system. The immune system stimulates an autoimmune response against these factors that induce neurological symptoms. Also, in light of the latest updates on the relationship between immunotherapy and PNS as well as of the introduction of first-line immunotherapy in SCLC, it seems that the use of immunotherapy in SCLC is associated with concomitant increase in autoimmune neurological syndromes.In this article, we report our experience at Istituto Nazionale Tumori of Milan with three patients affected by SCLC and PNS. Our experience seems to confirm that the oncological treatment scarcely impacts the paraneoplastic neurological deficits. Further research is needed to improve the treatment and recovery of patients affected by PNS.

Uterine serous carcinoma: role of surgery, risk factors and oncologic outcomes. Experience of a tertiary center

ObjectiveTo evaluate factors impacting survival outcomes in patients with uterine serous carcinoma (USC). MethodsData of consecutive patients diagnosed with USC undergoing surgery between 2000 and 2020 at Fondazione IRCCS Istituto Nazionale Tumori of Milan (Italy) were reviewed. Progression-free (PFS) and overall survival (OS) outcomes were evaluated using Kaplan-Meier and Cox proportional hazard models. ResultsRecords of 147 consecutive patients meeting the inclusion criteria were analyzed. Stage distribution was: 67 (45.6%) patients with early-stage with uterine confined disease and 80 (54.4%) with advanced stages disease. Minimally invasive surgery was performed in 43 patients (29.5%). The median follow-up period was 78.6 months (IQ range = 35.7–117.3 months). The overall recurrence rate was 41% (60 patients): 19/67 patients (28.4%) with early-stage disease and 41/80 patients (51.3%) with advanced stage. The 5-year PFS rate was 35.0% (95% confidence interval [CI]: 27.5–44.7%). In multivariate analysis, age, BMI, depth of myometrial invasion, cytology, and optimal cytoreduction with postoperative residual tumor absent significantly impacted on PFS. The 5-year OS rates were 46.5% (95% CI: 38.1–56.8). The result of multivariate analysis showed that there was significant difference in OS based only on optimal cytoreduction and accuracy of retroperitoneal surgery. ConclusionsIn apparent early-stage USC, peritoneal and retroperitoneal staging allows to identify patients with disease harboring outside the uterus. Optimal cytoreduction is the most significant prognostic factor. Further collaborative studies are warranted in order to improve outcomes of USC patients.

Lung metastasectomy for osteosarcoma in children, adolescents, and young adults: proof of permanent cure.

Surgical resection of pulmonary metastases has been associated with increased survival at 5 years for osteosarcoma, but limited information is available on long-term outcome, role of repeated metastasectomies, and surgical sequelae in a pediatric population. We analyzed a consecutive series of children, adolescents, and young adults (AYA) treated by repeated lung metastasectomies during a period >40 years to estimate the clinical benefit and potential cure rate of salvage surgery. All patients who underwent lung metastasectomy for osteosarcoma at the IRCCS Istituto Ortopedico Rizzoli of Bologna, University of Modena, and IRCCS Istituto Nazionale Tumori of Milan from May 1973 to January 2014 were included. Overall survival (OS) at 20 years from the first metastasectomy was calculated. A total of 463 consecutive children and AYA were analyzed. Median age was 15.9 years (range 0.2-23.2 years) and median follow-up 18.6 years. The 5- and 20-year OS were 34.0% and 29.7% (95% CI 25.5-34.0%). Among the 138 (29.8%) alive patients, 42 (30.4%) had disease recurrence cured by repeated metastasectomies. Disease-free interval from primary tumor, number of metastases, and complete resection were the most relevant survival predictors at multivariable model analysis. The extended follow-up of this consecutive series shows that repeated lung metastasectomy can achieve a permanent cure when offered to properly selected patients with metastases from osteosarcoma.

Children and adolescent solid tumours and high-intensity end-of-life care: what can be done to reduce acute care admissions?

Despite improvements in survival, cancer remains the leading cause of non-accidental death in children and adolescents, who risk receiving high-intensity end-of-life (HI-EOL) care.ObjectiveTo analyse treatments for relapses (particularly in the...

Clinical Categorization Algorithm (CLICAL) and Machine Learning Approach (SRF-CLICAL) to Predict Clinical Benefit to Immunotherapy in Metastatic Melanoma Patients: Real-World Evidence from the Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy

Simple SummaryImmune checkpoint inhibitors have improved the prognosis for patients with advanced melanoma. Despite the recent success of immunotherapy, many patients still do not benefit from these treatments, and their real-life application may yield different outcomes compared to the advantage presented in clinical trials. There is therefore a need to select patients who can really benefit from these treatments. We have focused our study on a real-life retrospective analysis of metastatic melanoma patients treated with immunotherapy at a single institution—the Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale” of Napoli, Italy. With the help of AI and machine learning we validated an algorithm based on clinical variables of patients—namely, the Clinical Categorization Algorithm (CLICAL)—that defines five predictable cohorts of benefit to immunotherapy with 95% accuracy. It can be a useful tool for the stratification of metastatic melanoma patients who may or may not improve from immunotherapy treatment.The real-life application of immune checkpoint inhibitors (ICIs) may yield different outcomes compared to the benefit presented in clinical trials. For this reason, there is a need to define the group of patients that may benefit from treatment. We retrospectively investigated 578 metastatic melanoma patients treated with ICIs at the Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale” of Napoli, Italy (INT-NA). To compare patients’ clinical variables (i.e., age, lactate dehydrogenase (LDH), neutrophil–lymphocyte ratio (NLR), eosinophil, BRAF status, previous treatment) and their predictive and prognostic power in a comprehensive, non-hierarchical manner, a clinical categorization algorithm (CLICAL) was defined and validated by the application of a machine learning algorithm—survival random forest (SRF-CLICAL). The comprehensive analysis of the clinical parameters by log risk-based algorithms resulted in predictive signatures that could identify groups of patients with great benefit or not, regardless of the ICI received. From a real-life retrospective analysis of metastatic melanoma patients, we generated and validated an algorithm based on machine learning that could assist with the clinical decision of whether or not to apply ICI therapy by defining five signatures of predictability with 95% accuracy.

COVID-19 Pandemic: Huge Stress Test for Health System Could Be a Great Opportunity to Update the Workflow in a Modern Surgical Pathology.

Simple SummaryThe COVID-19 pandemic has hit Northern Italy’s regions hard in terms of deaths since February 2020. Containment measures have been applied to avoid contagion and reduce the patient infection rate. In this manuscript, we report the experience of the Pathology Department of the Fondazione IRCCS Istituto Nazionale Tumori in Milan, during the period of the first lockdown that occurred in Lombardy from March to May 2020, focusing on the variation in terms of exams between the pre-COVID-19 and COVID-19 periods and describing the measures applied to guarantee the safeguarding of workers. Moreover, we calculated if changes introduced within the workflow affected the average diagnosis time using Turn-Around-Time (TAT) metrics released by the Lombardy Region. We showed a sharp slowdown in exams during the first wave of COVID-19 and that the measures applied for the safeguarding of the personnel turned out to be feasible and did not affect the overall performance of the Pathology Department.Background: On December 2019, an outbreak of atypical pneumonia, known as COVID-19, was identified in Wuhan, China. This disease, characterized by the rapid human-to-human transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly in more than 200 countries. Northern Italy’s regions have been hit hard in terms of deaths. Here, we report the experience of the Pathology Department of the Fondazione IRCCS Istituto Nazionale Tumori (INT) in Milan, the first Italian public cancer center, in the period of the lockdown that took place in Lombardy from March to May 2020. Method: The variation in terms of exams was calculated in two different timeframes: December 2019–February 2020 (pre-COVID-19) and March–May 2020 (COVID-19). During these periods, Turn-Around-Time (TAT) metrics released by the Lombardy Region were calculated to assess if changes applied to guarantee the safeguarding of workers affected the average diagnosis time. Results: In the COVID-19 period, there was a decrease for all the performed exams. The most considerable decrease was observed for PAP tests (−81.6%), followed by biopsies (−48.8%), second opinions (−41.7%), and surgical (−31.5%), molecular (−29.4%) and cytological (−18.1%) tests. Measures applied within the Pathology Department, such as digital pathology, remote working, rotations and changes in operating procedures, improved the diagnostic performance as required by the guidelines of the Lombardy Region in terms of TAT. At the same time, the measures applied for the safeguarding of the personnel turned out to be feasible and did not affect the overall performance of the Pathology Department. Conclusions: The sharp slowdown in cancer screening during the first wave of COVID-19 could seriously endanger cancer prevention in the near future.

Intention-to-Treat Analysis of Allogeneic Stem Cell Transplantation for Relapsed/Refractory Peripheral T-Cell Non-Hodgkin Lymphomas: A Large Italian Single-Center Experience

Introduction: Peripheral T-cell lymphomas (PTCL) encompass rare and heterogeneous forms of aggressive non-Hodgkin lymphoma generally associated with dismal clinical outcome. Given the poor prognosis, allogeneic stem cell transplantation (allo-HSCT) has been integrated in the treatment algorithms in the relapsed/refractory setting; however poor response to salvage therapies often hampers the possibility to benefit from this potentially curative approach. We report our institutional experience on the outcome of patients with relapsed PTCL eligible to allo-HSCT in an intention to treat (ITT) analysis.Methods and Results: We identified 108 adult patients with relapsed/refractory PTCL treated at the Istituto Nazionale Tumori from 1992 to 2016. Of these 108 patients, 22 (20%) were transplant-ineligible because of age >65 years; 86 patients (80%) were considered transplant-eligible upon failure of 1st line therapy: 48 (45%) received allo-HSCT, while 38 (35%) did not proceed to transplant. Main reason for failure to achieve transplantation was disease progression (35 patients, 92%).We sought to determine if specific characteristics at diagnosis and/or 1st relapse were associated to the failure to achieve transplantation. In univariate analyses, patients unable to proceed to allo-HSCT at diagnosis were older (median age 56 years vs. 46 for transplanted patients; p=0.014) and more frequently had >1 extranodal site involvement (p=0.001), however none of these variables was confirmed in multivariate analysis. As expected, patients who were not transplanted had a shorter time to 1st relapse as compared to transplanted patients (p=0.002), indicating a more aggressive, chemoresistant disease.As assessed by ITT (Figure 1A and B), the estimated 5-year overall survival (OS) for transplant-eligible patients was 35%: notably survival curves significantly differed when transplanted and not transplanted patients were separated, with 5-year OS being 49% and 16%, respectively (p<0.0001).Within the transplanted patients' cohort, clinical status at transplantation was CR in 19 patients (40%), PR in 17 (35%), SD/PD in 12 (25%). Thirty-one patients (65%) underwent a reduced intensity conditioning, 17 (35%) underwent myeloablative conditioning, with most patients (n=39, 81%) receiving a thiotepa/fludarabine/cyclophosphamide-based regimen. Donor type was matched related for 13 patients (27%), matched unrelated for 24 (50%) and haploidentical for 11 (23%). GvHD prophylaxis consisted mainly in methotrexate-cyclosporine (n=31) plus ATG in case of unrelated donor grafts. PT-Cy or ex vivo T cell depletion were employed in the haploidentical setting. With a median follow up for surviving patients of 45 months (range 2 - 208 months), the 3-year cumulative incidence of non-relapse mortality and relapse were 19% and 48%, respectively. Estimated 5-year progression-free survival (PFS) was 45%. Importantly, outcomes were more favorable in patients transplanted in CR (5-year PFS 68%, OS 70%) vs. patients transplanted in PR (5-year PFS 43%, OS 49%) or active disease (5-year PFS 0%, OS 25%; PFS: p=0.0001; OS: p=0.011) (Figure 1C and D).Conclusions: This study supports the curative potential of allo-HSCT in relapsed PTCL patients with otherwise poor survival. Allo-HSCT can provide long-term remissions and indeed a PFS plateau appears beyond 5 years for patients transplanted in CR/PR. Unfortunately, the primary barrier to curative therapy remains achieving a sufficient response to salvage therapy and future studies should be aimed at increasing the response rate in this population. [Display omitted] DisclosuresCorradini:Roche: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Amgen: Honoraria.