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Supplementary Table from A Prospective Observational Study of Active Surveillance in Primary Desmoid Fibromatosis

Purpose:To prospectively assess the behavior of primary sporadic (not familial adenomatous polyposis–associated) desmoid fibromatosis (DF) managed by active surveillance (AS).ExperimentalDesign:This is an Italian prospective, multicenter, observational study (NCT 02547831) including patients ≥16 years with primary sporadic DF at any site. Patients were assessed by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Primary endpoint was progression-free survival (PFS) at 3 years. Treatment-free survival (TFS) was also analyzed. PFS and TFS were calculated by Kaplan–Meier plots and compared by log-rank test. Cox proportional hazard multivariable regression analyses were performed.Results:From 2013 to 2018, 108 consecutive patients were included (82% female); median age was 39 years; median size was 51 mm. CTNNB1 mutations were T41A (50%), S45F (12%), other (19%), wild-type (19%). At 32.3-month median follow-up, 42 of 108 (39%) showed RECIST progression. Spontaneous regression was initially observed in 27 of 108 (25%), while it followed dimensional progression in another 33 of 108 (31%). PFS at 36 months was 54.5% [95% confidence interval (CI), 44.9%–66.1%]. Thirty-five of 108 (32%) patients received active treatment, 18 of 108 (17%) after RECIST progression and 17 of 108 (15%) after symptomatic progression. TFS at 36 months was 65.9% (95% CI, 57.3%–75.9%). Larger tumor size and extremity location were associated to shorter TFS and a trend for S45F mutation was also observed (P = 0.06), while none of the mentioned variables was significantly associated with PFS.Conclusions:In primary DF, AS can be proposed, because disease stabilization and spontaneous regression frequently occur. However, extra care should be taken for patients with tumors of larger size, extremity location, and S45F mutation.See related commentary by Greene and Van Tine, p. 3911

Introduction: Cannabidiol (CBD), the nonintoxicating constituent of cannabis, is largely employed for pharmaceutical and cosmetic purposes. CBD can be extracted from the plant or chemically synthesized. Impurities of psychotropic cannabinoids Δ9-tetrahydrocannabinol (Δ9-THC) and Δ8-THC have been found in extracted CBD, thus hypothesizing a possible contamination from the plant. Materials and Methods: In this study, synthetic and extracted CBD samples were analyzed by ultrahigh-performance liquid chromatography coupled to high-resolution mass spectrometry and the parameters that can be responsible of the conversion of CBD into THC were evaluated by an accelerated stability test. Results: In synthetic and extracted CBD no trace of THC species was detected. In contrast, CBD samples stored in the dark at room temperature on the benchtop for 3 months showed the presence of such impurities. Experiments carried out under inert atmosphere in the absence of humidity or carbon dioxide led to no trace of THC over time even at high temperature. Conclusions: The results suggested that the copresence of carbon dioxide and water from the air could be the key for creating the acidic environment responsible for the cyclization of CBD. These findings suggest that it might be appropriate to review the storage conditions indicated on the label of commercially available CBD.

Cannabidiolic acid (CBDA) and trans-Δ

Purpose: To prospectively assess the behavior of primary sporadic (not familial adenomatous polyposis–associated) desmoid fibromatosis (DF) managed by active surveillance (AS). Experimental Design: This is an Italian prospective, multicenter, observational study (NCT 02547831) including patients ≥16 years with primary sporadic DF at any site. Patients were assessed by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Primary endpoint was progression-free survival (PFS) at 3 years. Treatment-free survival (TFS) was also analyzed. PFS and TFS were calculated by Kaplan–Meier plots and compared by log-rank test. Cox proportional hazard multivariable regression analyses were performed. Results: From 2013 to 2018, 108 consecutive patients were included (82% female); median age was 39 years; median size was 51 mm. CTNNB1 mutations were T41A (50%), S45F (12%), other (19%), wild-type (19%). At 32.3-month median follow-up, 42 of 108 (39%) showed RECIST progression. Spontaneous regression was initially observed in 27 of 108 (25%), while it followed dimensional progression in another 33 of 108 (31%). PFS at 36 months was 54.5% [95% confidence interval (CI), 44.9%–66.1%]. Thirty-five of 108 (32%) patients received active treatment, 18 of 108 (17%) after RECIST progression and 17 of 108 (15%) after symptomatic progression. TFS at 36 months was 65.9% (95% CI, 57.3%–75.9%). Larger tumor size and extremity location were associated to shorter TFS and a trend for S45F mutation was also observed (P = 0.06), while none of the mentioned variables was significantly associated with PFS. Conclusions: In primary DF, AS can be proposed, because disease stabilization and spontaneous regression frequently occur. However, extra care should be taken for patients with tumors of larger size, extremity location, and S45F mutation. See related commentary by Greene and Van Tine, p. 3911

[Background] This observational, retrospective effort across Europe, US, Australia, and Asia aimed to assess the activity of systemic therapies in EHE, an ultra-rare sarcoma, marked by WWTR1-CAMTA1 or YAP1-TFE3 fusions., [Methods] Twenty sarcoma reference centres contributed data. Patients with advanced EHE diagnosed from 2000 onwards and treated with systemic therapies, were selected. Local pathologic review and molecular confirmation were required. Radiological response was retrospectively assessed by local investigators according to RECIST. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method., [Results] Overall, 73 patients were included; 21 had more than one treatment. Thirty-three patients received anthracyclines regimens, achieving 1 (3%) partial response (PR), 25 (76%) stable disease (SD), 7 (21%) progressive disease (PD). The median (m-) PFS and m-OS were 5.5 and 14.3 months respectively. Eleven patients received paclitaxel, achieving 1 (9%) PR, 6 (55%) SD, 4 (36%) PD. The m-PFS and m-OS were 2.9 and 18.6 months, respectively. Twelve patients received pazopanib, achieving 3 (25%) SD, 9 (75%) PD. The m-PFS and m-OS were.2.9 and 8.5 months, respectively. Fifteen patients received INF-α 2b, achieving 1 (7%) PR, 11 (73%) SD, 3 (20%) PD. The m-PFS and m-OS were 8.9 months and 64.3, respectively. Among 27 patients treated with other regimens, 1 PR (ifosfamide) and 9 SD (5 gemcitabine +docetaxel, 2 oral cyclophosphamide, 2 others) were reported., [Conclusion] Systemic therapies available for advanced sarcomas have limited activity in EHE. The identification of new active compounds, especially for rapidly progressive cases, is acutely needed.

The recent discovery of the novel heptyl phytocannabinoids cannabidiphorol (CBDP) and Δ9-tetrahydrocannabiphorol (Δ9-THCP) raised a series of questions relating to the presence and abundance of these new unorthodox compounds in cannabis inflorescence or derived products. As fresh inflorescence contains mainly their acid precursors, which are not commercially available, an ad hoc stereoselective synthesis was performed in order to obtain cannabidiphorolic acid (CBDPA) and Δ9-tetrahydrocannabiphorolic acid (THCPA) to be used as analytical standards for quantitative purposes. The present work reports an unprecedented targeted analysis of both pentyl (C5) and heptyl (C7) CBD- and THC-type compounds in forty-nine cannabis samples representing four different chemotypes. Moreover, the ultrahigh performance liquid chromatography coupled to high-resolution mass spectrometry-based method was applied for the putative identification of other heptyl homologs of the most common phytocannabinoid acids, including cannabigerophorolic acid (CBGPA), cannabichromephorolic acid (CBCPA), cannabinophorolic acid (CBNPA), cannabielsophorolic acid (CBEPA), cannabicyclophorolic acid (CBLPA), cannabitriophorolic acid (CBTPA), and cannabiripsophorolic acid (CBRPA).

e23521 Background: Regorafenib (REG) is a multikinase inhibitor approved as third-line treatment in gastrointestinal stromal tumors (GIST). Although its proven activity, REG can present a relevant adverse profile which often leads to treatment modifications and transient or permanent discontinuation; thus, in clinical practice physicians usually adopt various dosing and interval schedules to counteract REG-related adverse events (AEs) and avoid treatment interruption. The aim of this real-world study was to investigate the efficacy and safety of personalized schedules of REG in metastatic GIST patients, in comparison with the standard schedule (160 mg daily, 3-weeks-on, 1-week-off schedule). Methods: Institutional registries across seven Italian reference centers were retrospectively reviewed and data of interest retrieved to identify GIST patients who had received REG from February 2013 to January 2021. The primary endpoint was Progression-Free Survival (PFS), with Overall Survival (OS) also assessed as secondary endpoint. The Kaplan-Meier method was used to estimate survival and the log-rank test to make comparisons. The impact of variables on survival was assessed through univariate and multivariate analysis. Results: A total of 152 GIST patients (82 male and 70 female) were included and split in two groups on the basis of the REG treatment plan received (standard vs personalized). Among the 103 patients for whom the treatment was personalized (38 since the beginning and 65 during the treatment course), the main strategies adopted were the following: 120 mg/day d1-21 e28 (n = 56; 54.4%); 80 mg/day d1-21 e28 (n = 22; 21.4%); 160 mg/day d1-5 e7 (n = 13; 12.6%). At a median follow-up of 36.5 months, median Overall Survival (OS) was 16.6 months (95% CI 14.1-21.8) and 20.5 months (95% CI 15.0-25.4) in the standard-dose and the personalized schedule groups, respectively (HR 0.75; 95% CI 0.49-1.22; p = 0.16). Median Progression-Free Survival (PFS) was 5.6 months (95% CI 3.3-not reached) and 9.7 months (95% CI 7.9-14.5) in the same groups (HR 0.51; 95% CI 0.34-0.75; p = 0.00052). Conclusions: Despite the expected limits of a retrospective analysis, we confirm that REG personalized schedules are commonly adopted in everyday clinical practice of high-volume GIST expert centers and correlate with significant improvement of therapeutic outcomes. Based on these results, REG treatment optimization in GIST patients may represent the best strategy to maximize long-term therapy, preserving tolerability and quality of life.

Background Primary mesenteric soft tissue sarcomas (STS) are rare and limited evidence is available to inform management. Surgical resection is challenging due to the proximity of vital structures and a need to preserve enteric function. Objectives To determine the overall survival (OS) and recurrence-free survival (RFS) for patients undergoing primary resection for mesenteric STS. Methods The Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) is an intercontinental collaborative comprising specialist sarcoma centers. Data were collected retrospectively for all patients with mesenteric STS undergoing primary resection between 2000 and 2019. Results Fifty-six cases from 15 institutions were included. The spectrum of pathology was similar to the retroperitoneum, although of a higher grade. R0/R1 resection was achieved in 87%. Median OS was 56 months. OS was significantly shorter in higher-grade tumors (p = .018) and extensive resection (p < .001). No significant association between OS and resection margin or tumor size was detected. Rates of local recurrence (LR) and distant metastases (DM) at 5 years were 60% and 41%, respectively. Liver metastases were common (60%), reflecting portal drainage of the mesentery. Conclusion Primary mesenteric sarcoma is rare, with a modest survival rate. LR and DM are frequent events. Liver metastases are common, highlighting the need for surveillance imaging.

L-Kynurenine (KYN) and kynurenic acid (KYNA) are products of the metabolism of L-tryptophan (TRP) in the central nervous system of animals, but they are not commonly found in plants. In particular, KYNA is known for its interesting pharmacological properties (anti-oxidative, anti-inflammatory, hypolipidemic, and neuroprotective), which suggest a potential functional food ingredient role. The three compounds were identified in samples of Cannabis sativa L. by means of high-performance liquid chromatography coupled to high-resolution mass spectrometry using an untargeted metabolomics approach. Their concentrations were evaluated using a targeted metabolomics method in three organs of the plant (roots, stem, and leaves) in soil at two different growth stages and in hydroponics conditions. The distribution of TRP, KYN and KYNA was found tendentially higher in leaves compared to stem and roots and changed over time. Moreover, the levels of KYNA found in this study are unprecedentedly high compared to those found so far in other plant species, suggesting that Cannabis sativa L. could be a promising alternative source of this metabolite.

A sensitive and straightforward HPLC-UV method was developed for the simultaneous quantification of the two main impurities in “pure” commercial cannabigerol (CBG) samples. The identification of such impurities, namely cannabigerovarin (CBGV) and cannabigerobutol (CBGB), the propyl and butyl homologs of CBG, respectively, was accomplished employing the high-resolution mass spectrometry (HRMS) technique, and subsequently confirmed by comparison with the same compounds obtained by chemical synthesis. Complete spectroscopic characterization (NMR, FT-IR, UV, and HRMS) of both impurities is reported in the present work. The method was validated in terms of linearity, which was assessed in the range 0.01–1.00 μg/mL, sensitivity, selectivity, intra- and inter-day accuracy and precision, and short-term stability, which all satisfied the acceptance criteria of the ICH guidelines. Application of the method to the analysis of four commercial CBG samples highlighted a certain variability in the impurity profile that might be ascribed to the hemp variety of the starting plant material. With these new analytical standards in hand, it would be interesting to investigate their concentrations in different hemp varieties and expand the scope of a phytocannabinomics approach for a comprehensive profiling of this remarkable class of natural compounds.

Background Despite its proven activity as third-line treatment in gastrointestinal stromal tumors (GIST), regorafenib can present a poor tolerability profile which often leads to treatment modifications and transient or permanent discontinuation; thus, in clinical practice physicians usually adopt various dosing and interval schedules to counteract regorafenib-related adverse events and avoid treatment interruption. The aim of this real-world study was to investigate the efficacy and safety of personalized schedules of regorafenib in patients with metastatic GIST, in comparison with the standard schedule (160 mg daily, 3-weeks-on, 1-week-off). Patients and methods Institutional registries across seven Italian reference centers were retrospectively reviewed and data of interest retrieved to identify patients with GIST who had received regorafenib from February 2013 to January 2021. The Kaplan–Meier method was used to estimate survival and the log-rank test to make comparisons. Results Of a total of 152 patients with GIST, 49 were treated with standard dose, while 103 received personalized schedules. At a median follow-up of 36.5 months, median progression-free survival was 5.6 months [95% confidence interval (CI) 3.73-11.0 months] versus 9.7 months (95% CI 7.9-14.5 months) in the standard-dose and the personalized schedule groups, respectively [hazard ratio (HR) 0.51; 95% CI 0.34-0.75; P = 0.00052]. Median overall survival was 16.6 months (95% CI 14.1-21.8 months) versus 20.5 months (95% CI 15.0-25.4 months), respectively (HR 0.75; 95% CI 0.49-1.22; P = 0.16). Conclusions Regorafenib-personalized schedules are commonly adopted in daily clinical practice of high-volume GIST expert centers and correlate with significant improvement of therapeutic outcomes. Therefore, regorafenib treatment optimization in patients with GIST may represent the best strategy to maximize long-term therapy., Highlights • Regorafenib-personalized schedules are commonly adopted in daily clinical practice. • Regorafenib-personalized schedules correlate with statistically significant improvement of therapeutic outcomes. • A prompt personalization of regorafenib could help clinicians avoid early treatment discontinuation due to adverse events. • A patient-tailored approach could be applied to other metastatic solid tumors treated with regorafenib.

The introduction of immune checkpoint inhibitors represented a true revolution in the treatment of melanoma and a few other cancer subtypes. Unfortunately, the use of these drugs did not achieve the same beneficial results in other neoplasms, such as soft tissue sarcoma and gastrointestinal stromal tumor. These failures encouraged deeper research into the complex interactions between cancer and host immune system, to try to shed light on the ability of cancer cells to escape immunologic surveillance. Key elements to explain tumor immune escape were found in the tumor microenvironment. The main actors in this complex network are lymphocytes, cytokines and innate immunity cells such as macrophages and antigen presenting cells. Thus, immuno-oncologists are studying the different components of the tumor microenvironment to identify possible new therapeutic targets. In this paper, we summarize the most important aspects of these interactions, and provide an overview of the newer and more promising immunotherapeutic strategies.

We report the case of a 51 year-old patient affected by an advanced uterine leiomyosarcoma treated with eribulin as fourth-line therapy. The patient, with a previous history of leiomyomas of the myometrium, had undergone total hysterectomy for repeated metrorrhagias. After 7 years, metastases in the liver, bone and lung were documented. A fine needle liver biopsy demonstrated leiomyosarcoma metastasis. The patient was treated with first-line doxorubicin chemotherapy; after six cycles, disease progression was observed. A second-line trabectedin chemotherapy and a third-line gemcitabine chemotherapy were performed; no objective responses were seen after two cycles. The patient was then treated with eribulin on the basis of an EORTC Phase II trial showing preliminary activity in uterine leiomyosarcoma. After six cycles, CT scan showed partial remission of liver lesion. Disease progression was observed after nine cycles with eribulin, without severe side effects and preserving a good quality of life.

European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group., [Background] The optimal treatment for advanced leiomyosarcoma is still debated. Given histotype‐specific prospective controlled data lacking, this study retrospectively evaluated doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone as first‐line treatments for advanced/metastatic leiomyosarcoma treated at European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC‐STBSG) sites., [Methods] The inclusion criteria were a confirmed histological diagnosis, treatment between January 2010 and December 2015, measurable disease (Response Evaluation Criteria in Solid Tumors 1.1), an Eastern Cooperative Oncology Group performance status ≤2, and an age ≥ 18 years. The endpoints were progression‐free survival (PFS), overall survival (OS), and overall response rate (ORR). PFS was analyzed with methods for interval‐censored data. Patients were matched according to their propensity scores, which were estimated with a logistic regression model accounting for histology, grade, age, sex, performance status, tumor site, and tumor extent., [Results] Three hundred three patients from 18 EORTC‐STBSG sites were identified. One hundred seventeen (39%) received doxorubicin plus dacarbazine, 71 (23%) received doxorubicin plus ifosfamide, and 115 (38%) received doxorubicin. In the 2:1:2 propensity score–matched population (205 patients), the estimated median PFS was 9.2 months (95% confidence interval [CI], 5.2‐9.7 months), 8.2 months (95% CI, 5.2‐10.1 months), and 4.8 months (95% CI, 2.3‐6.0 months) with ORRs of 30.9%, 19.5%, and 25.6% for doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone, respectively. PFS was significantly longer with doxorubicin plus dacarbazine versus doxorubicin (hazard ratio [HR], 0.72; 95% CI, 0.52‐0.99). Doxorubicin plus dacarbazine was associated with longer OS (median, 36.8 months; 95% CI, 27.9‐47.2 months) in comparison with both doxorubicin plus ifosfamide (median, 21.9 months; 95% CI, 16.7‐33.4 months; HR, 0.65; 95% CI, 0.40‐1.06) and doxorubicin (median, 30.3 months; 95% CI, 21.0‐36.3 months; HR, 0.66; 95% CI, 0.43‐0.99). Adjusted analyses retained an effect for PFS but not for OS. None of the factors selected for multivariate analysis had a significant interaction with the received treatment for both PFS and OS., [Conclusions] This is the largest retrospective study of first‐line treatment for advanced leiomyosarcoma. In the propensity score–matched population, doxorubicin and dacarbazine showed favorable activity in terms of both ORR and PFS and warrants further evaluation in prospective trials., European Organisation for Research and Treatment of Cancer.

11537 Background: SDH- deficient GIST, as defined by the loss of expression of SDHB, account up to about 10% of all gastric GIST and generally affect younger population. Germline mutations in SDHB, SDHC, and SDHD occur in about 20–30% of SDH- deficient, that may be referred to a hereditary condition known as hereditary GIST-paraganglioma syndrome (Carney-Stratakis Syndrome), whereas germline SDHA mutations have been rarely described in apparently sporadic cases. Currently, even germline testing is recommended for SDH- deficient GIST, there are no clear guidelines for genetic counselling and follow-up of SDH x mutation carriers and relatives, especially for SDHA mutant GIST not yet linked to well-defined hereditary syndrome. The aim of this work was to study the SDHA gene in the normal DNA of patients with SDHA mutant GIST. Methods: Thirteen patients carrying SDHA-mutant GIST were studied (8F/5M). Median age of diagnosis was 45,9 years (range 25-74). All GIST were located in the stomach and 3 patients out 13 presented a metastatic disease. In all cases except one, the GIST was the only cancer presentation and no personal or familial history of cancer was revealed. All cases were negative for SDHB immunohistochemistry. Germline mutations were identified through Sanger sequencing of SDHA in the normal counterpart. Results: Germline mutations were identified in all patients for which normal counterpart was available: 4 cases harboured truncating mutations (S384X, R31X and W119X); 5 cases carried pathogenic missense mutations (G233V, R171H, R589Q, G257A and R600Q) and 2 cases had splice site alterations (c.457-3_457-1 delCAG and c.456+9 C > T). In 8 cases the tumor DNA showed the loss of the corresponding wild-type allele, while in the other 3 cases compound heterozygosity for an additional somatic mutation was detected (R589W, R451C,and R171C). In 2 patients, unfortunately, normal DNA was not available, however both tumours carried two mutational hits on SDHA (one with heterozygous G419R and E564K, and one with homozygous R585Q). Of note, 5 patients presented un-usaul SDHA related clinical characteristics as were not young adult ( > 50 years-old) or no multifocal GIST. Conclusions: We demonstrated that germline SDHA mutations are highly frequent in SDHA- deficient GIST. Therefore, although a clear syndrome has not been defined, genetic counselling and follow-up of SDHA mutation carriers and relatives should be clarified.

11570 Background: In recent years evidence of long term stabilization and spontaneous regression of primary sporadic DT resulted in a paradigm shift towards more conservative approaches. We present herein the results of an observational study aimed at prospectively assess the behavior of primary sporadic DT initially managed by active surveillance and its relation to CTNNB1 mutational status. Methods: This is an Italian prospective, multicenter, observational study (NCT 02547831) to evaluate primary sporadic DT behavior in patients (pts) >16 years with primary naive or incompletely resected and measurable disease, at any site, with CTNNB1 mutational status available. Pts were assessed by contrast enhanced MRI or CT scan at baseline, at 3, 6, 9, 12 months, then every 6 months until the third year. Tumor changes were assessed by RECIST. In case of dimensional or symptomatic progression active treatment could be proposed on an individualized basis CTNNB1 mutational status was obtained in all patients by Sanger and deep sequencing was performed in wild-type cases. Primary end-point was progression-free survival (PFS) at 3 yrs. Treatment-free survival (TFS) was also analyzed. PFS and TFS were calculated using survival analysis methods, including Kaplan-Meier plots, log-rank test for survival curves comparison, and Cox proportional-hazard multivariable regression (age, size, anatomic site and CTNNB1 mutational status). Results: From April 2013 to February 2018 108 pts were included (82% female, 18% male); median age was 39 (interquartile range, IQR 34-48) and median size 50 mm (IQR, 40-80 mm). Tumor location was: 4/108 (4%) = head&neck, 25/108 (23%) = trunk, 59/108 (55%) = abdominal wall, 3/108 (3%) = intra-abdominal, 17/108 (16%) = extremities. CTNNB1 mutations were as follow: T41A 54/108 (50%), S45F 13/108 (12%), WT 20/108 (19%), other mutations 21/108 (19%). At a m-FU of 32.3 months, the 3-year PFS was 54.5% (95% CI, 44.9%-66.1%). 42/108 (39%) pts showed a RECIST progression, with equal distribution among the different anatomic sites. None of the variables analyzed were associated to PFS. Spontaneous regression was initially observed in 27/108 (25%) patients, while it followed dimensional progression in another 33/108 (30%). 35/108 (32%) pts received active treatment, 18/42 (43%) after RECIST progression and 17/66 (26%) after symptomatic progressions. TFS at 36 months was 65.9% (95% CI, 57.3%-75.9%). S45F mutation, larger tumor size and extremity location were associated to a shorter TFS. No dimensional or symptomatic progression were observed after 36 months of FU. Conclusions: Active surveillance was marked by spontaneous regressions in 60/108 (55%) pts. An active treatment was needed in 32%. If no events occur after 3 yrs of FU, more relaxed FU schedules can be considered given the low risk of subsequent progression. Attention should be paid to patients with DT located to the extremity and/or carrying a S45F mutation. Clinical trial information: NCT 02547831.

11571 Background: Despite surgically resectable pulmonary metastases may lead to cure patients with B-STS (Chudgar NP 2017), a substantial proportion of patients will eventually relapse. Presently, patient selection is based on unique organ involvement, number of metastases, interval between previous surgery and pulmonary progression or relapse. We assessed the impact of anatomical site of metastasis into the lung (as if the pleural site might ease further tumor spreading) and nodule growth rate as additional predictive/prognostic factors of lung progression-free survival (L-PFS) and overall survival (OS). Methods: In our prospectively collected database, we retrospectively evaluated patients operated for B-STS pulmonary progression at 3 different centers from 2005 to 2019. Beyond patients’ clinical features at both baseline and disease progression in the lungs, we focused on whether the relapse occurred into the parenchyma or nearby the pleura (Welter S 2012); secondly, we estimated lung metastasis growth rate, defined as tumor doubling time (TDT) (Nakamura T 2011). Statistical analyses were carried out with IBM SPSS (v. 20.0). Survival outcomes were estimated by Kaplan-Meier method. Hazard ratios (HR) were estimated by Cox regression. Multivariate analysis was performed for both L-PFS and OS according to Cox proportional hazard model. All tests were 2-sided with their corresponding 95% confidence intervals (CI95%). Results: We identified 138 patients who underwent lung metastasectomy [(F=66 (48%); median age at surgery 50 (14-78)]. Median PFS and L-PFS were 8.7 months (CI95% 6.6-10.9) and 8.6 months (CI95% 6.2-11.0), respectively. Median OS was 40.6 months (CI 95% 32.8-48.5). Univariate analysis showed a statistically significant impact of the following variables for both L-PFS and OS: ECOG 0, nodule number 40 days. Disease-free interval ≤ 24 months and absence of metastases at diagnosis showed significant correlation with L-PFS and OS, respectively. At multivariate analyses the following variables retained statistical significance for L-PFS: TDT >40 days (HR 0.53, CI95% 0.31-0.93, p=0.028); nodule number 40 days (HR 0.36, CI95% 0.18-0.72, p=0.004), nodule number

Background Pazopanib is a multikinase inhibitor registered for the treatment of advanced renal clear cell carcinoma (RCC) and as second or further-line therapy in advanced non-adipocytic soft tissue sarcoma (STS). It is a relatively well-tolerated compound, but, as with many other tyrosine kinase inhibitors (TKI), chronic toxicity may become a challenge that both patient and physician need to take into account when starting treatment. This retrospective study investigated toxicities and their management in STS patients treated with pazopanib in routine clinical practice in Italy. Materials and Methods Data were collected between January 2013 and May 2016 at Candiolo Cancer Institute and Prato Medical Oncology Unit. The primary objective was to describe observed toxicities in a real-life setting, and use this information to inform strategies for adverse event management. Results A total of 43 patients with advanced STS who received treatment with pazopanib were included. Median progression-free survival was 4 months and median overall survival was 18 months. The most common toxicities were fatigue (74.4%), hypertension (72%), hair hypopigmentation (74.4%) and diarrhea (60.5%). Liver toxicities occurred in less than one-third of patients. Severe adverse events, requiring drug interruption, were relatively rare. Conclusions This study confirms the safety and efficacy of pazopanib in pretreated unresectable or metastatic soft tissue sarcoma, and highlights the importance of close follow-up and patient support to improve compliance and treatment duration.

In the last few years, cancer immunotherapy has changed the natural history and treatment strategies of a number of solid tumors, including melanoma and lung cancer. The anti-PD-1 nivolumab showed a survival benefit compared with everolimus in the second-line treatment of renal cell carcinoma, resulting in a radical shift in perspective in the treatment of this neoplasia and suggesting a new scenario beyond tyrosine kinase inhibitors. Checkpoint inhibitors might also improve the treatment of urothelial cancer, considering the promising results achieved so far and the relatively low efficacy of currently available treatments. Sipuleucel-T was the first approved immunotherapy for prostate cancer, showing a clear benefit in overall survival, and paved the way for the clinical testing of other novel cancer vaccines. This review provides a comprehensive overview of the current knowledge and new perspectives of immunotherapy in the treatment of urogenital malignancies.

e23518 Background: In patients with GIST, literature reports a risk of second primary tumors between 4.5% and 33% with different distribution in the worldwide. The network of 7 italian EURACAN centers has collected clinical and molecular features of GIST patients with second primary tumors. Methods: We reviewed the clinical characteristics of 201 patients with GIST and second primary tumors in order to evaluate association between risk of dead and each possible factor, using Kaplan meier curve, log-rank test and Cox model for Hazard Ratio and it’s interval Confidence 95% estimation. Furthermore, NGS analysis ( 56 gene onco panel) in 72 patients with GIST was performed. Results: On the basis of the significant correlation previously observed between the Miettinen risk criteria of GIST (low/very low) and the incidence of second primary tumors (gastrointestinal tumors),P < 0.001 (Abstr 11032 ASCO 2019), we observed in these patients a median age of diagnosis of GIST of 68, with prevalent gastric site localization ( KIT exon 11 mutation), NF1 and Lynch (kit/pdgfra WT) syndromes in the low risk subgroup. The more frequent site of second epithelial tumor in gastrointestinal tract was the colon followed by gastric, pancreatic and biliary tract. In patients with GIST with low-very low risk according Miettinen classification, after a median follow-up period of 25 years, we have observed that the gastroenteric site of second tumors occurrence is significantly related to the survival (p < .0003). In the NGS analysis of the GIST we observed the pathogenetic somatic mutations in the following genes: BRCA 2 (p.Thr2125fs), but germline test negative, TP53 (p.Arg192*,p.Gly244Ser,p.His168Leu), RET (p.Lys120Asn, p.His168Leu, p.Thr930Met ), NRAS (p.Gly134Asp), CTNNB1 (p.Ser45Phe), MSH6 (P.Ala164Val), SMARCB1 (p.Arg192), VHL (p.Gly93Val), PTEN(p.Val158Ile, p.Asn323fs), STK1I (p.Arg40Cys), SMO (p.Glu194Lys), EGFR (p.Gly721Asp), ATM (p.Asp2708Asn), ERBB4 (p.Asn181Ile). Conclusions: In our analysis patients with GIST (low-very low classes according to Miettinen) have significant risk to death because of second primary tumors in gastrointestinal tract. Specific attention to gastrointestinal screening during the follow-up of GIST (low and very low risk) is required.

e23546 Background: Although sarcomas may arise in any site of the body, the intrinsic challenge of BS is to affect the female most frequent cancer site with a completely different and rare set of heterogeneous tumors. Unfortunately, we lack BS-specific prospective trials to precisely guide the clinical decision-making and BS patients are often sent to sarcoma referral centers only after surgery without upfront BS MTB evaluation. Recent evidences reported a significant prognosis improvement with upfront MTB evaluation in retroperitoneal or extremity sarcomas, but whether this strategy might benefit also BS is still not defined. We retrospectively evaluated our prospectively collected database to test whether an upfront MTB evaluation at BS referral centers might impact prognosis and/or the need of subsequent surgeries. Methods: Detailed information on primary surgery, diagnosis, and ≥2 years of follow-up for non-recurring patients were required. We tested the following outcomes: event-free survival (EFS), local EFS (LEFS), distant metastases EFS (DMEFS), overall survival (OS), margin status, subsequent surgeries rate. We evaluated the different outcomes according to upfront MTB evaluation. Kaplan-Meier method was used for survival analyses. Comparisons used hazard ratios (HR). Results: We included 93 patients treated between 1/2000 and 10/2019 at 2 reference BS Centers, median age 53 years (IQR 41-70), ECOG (0;1;2) 67:16:10, high/low grade 60:33. Histotypes were: malignant phyllodes tumor 42 (45%), angiosarcoma 26 (28%), other STS 25 (27%). 27 (29%) cases were considered radiation-induced with a median time from RT of 105 months (IQR 70-127). 44 patients (47%) were discussed upfront in BS MTB, whereas 49 (53%) were not. With a median follow up of 43 months, 5-year EFS, LEFS, DMEFS, and OS for the whole population were 54%, 64%, 60%, and 62%, respectively. LEFS at 5 years had a strong association with margin status (R0 74%; R1 55%, R2 0%, p < 0.001). Regardless of histology, upfront MTB was associated with a significant lower rate of subsequent surgeries (OR 0.16, 0.06-0.41), and with better EFS, LEFS, DMEFS, and OS (HRs 0.57, 0.54, 0.63, and 0.43, respectively). Conclusions: Though retrospective, this series is one of the largest reported to date in BS. Our results highlight the need for early inter-tumor board sharing of BS to take into account sarcoma specificity in the overall disease planning. Given BS rarity, these data will hardly ever be verified in a prospective fashion. Therefore, validation of these results in the Italian Sarcoma Group database is planned.

Summary Background Trabectedin is an alkylating drug with a unique mechanism of action causing single-strand and double-strand DNA breaks that activate DNA damage-response pathways. Based on our preclinical data, we hypothesised that poly(ADP-ribose) polymerase 1 (PARP1) inhibitors might be an ideal partner of trabectedin and aimed to assess the safety, identify the recommended phase 2 dose, and explore preliminary signs of activity of trabectedin and olaparib combination treatment in patients with bone and soft-tissue sarcoma. Methods We did an open-label, multicentre, phase 1b study, recruiting patients from the national Italian sarcoma network aged 18 years and older with histologically confirmed bone and soft-tissue sarcoma progressing after standard treatments with Eastern Cooperative Oncology Group performance status of 1 or less. In a classic 3 + 3 design, patients received a 24 h infusion of trabectedin on day 1 and olaparib orally twice a day in 21-day cycles across six dose levels (trabectedin 0·675–1·3 mg/m2 every 3 weeks; olaparib 100–300 mg twice a day from day 1 to 21). Intermediate dose levels were permitted to improve safety and tolerability. The primary endpoint was determination of the recommended phase 2 dose (the maximum tolerated dose). Safety and antitumour activity were assessed in all patients who received at least one dose of the study drugs. We report the results of the dose-escalation and dose-expansion cohorts. The trial is still active but closed to enrolment, and follow-up for patients who completed treatment is ongoing. This trial is registered with ClinicalTrials.gov, number NCT02398058. Findings Between Nov 17, 2014, and Jan 30, 2017, of 54 patients assessed for eligibility, we enrolled 50 patients: 28 patients in the dose-escalation cohort and 22 patients in the dose-expansion cohort. Patients received a median of four cycles of treatment (IQR 2–6; range 1–17 [the patients who received the highest number of cycles are still on treatment]) with a median follow-up of 10 months (IQR 5–23). Considering all dose levels, the most common grade 3–4 adverse events were lymphopenia (32 [64%] of 50 patients), neutropenia (31 [62%]), thrombocytopenia (14 [28%]), anaemia (13 [26%]), hypophosphataemia (20 [40%]), and alanine aminotransferase concentration increase (9 [18%]). No treatment-related life-threatening adverse events or deaths occurred. One (2%) patient interrupted treatment without progression without reporting any specific toxicity. Observed dose-limiting toxicities were thrombocytopenia, neutropenia for more than 7 days, and febrile neutropenia. We selected intermediate dose level 4b (trabectedin 1·1 mg/m2 every 3 weeks plus olaparib 150 mg twice a day) as the recommended phase 2 dose. Seven (14%; 95% CI 6–27) of 50 patients achieved a partial response according to Response Evaluation Criteria In Solid Tumors 1.1. Interpretation Trabectedin and olaparib in combination showed manageable toxicities at active dose levels for both drugs. Preliminary data on antitumour activity are encouraging. Two dedicated phase 2 studies are planned to assess activity of this combination in both ovarian cancer (EudraCT2018-000230-35) and soft-tissue sarcomas. Funding Italian Association for Cancer Research, Italian Sarcoma Group, Foundation for Research on Musculoskeletal and Rare Tumors, and Italian Ministry of Health.

e22508 Background: Advanced OS still represents an unmet medical need. Chemotherapy and targeted therapies have only limited activity in this disease. Moreover, OS is considered a radioresistant tumor at doses conventionally achieved by EBRT. We retrospectively evaluated the impact of palliative EBRT in patients (pts) with advanced OS. Methods: Main inclusion criteria: confirmed histological diagnosis of OS; EBRT for advanced/metastatic disease deemed unresectable after multidisciplinary tumor board discussion; ECOG performance status ≤3, age ≥18 years at RT start; progressive disease at site of irradiation with symptoms (e.g., pain or neurological deficit) or involving critical structures (e.g., superior vena cava compression). Endpoints: progression-free survival (PFS), PFS for RT-treated lesions (RT-PFS), best response with RT, overall survival. All survival endpoints were computed from RT start. We calculated the equivalent total dose in 2 Gy fractions (EQD2). Results: 23 pts, 15 males, median age at diagnosis 33 (17-82), median age at RT start 36 (20-83) were included. All pts had grade 3-4 OS (12 osteoblastic; 6 chondroblastic; 5 other), 7 were metastatic at diagnosis. At time of RT, median metastatic sites were 2 (1-5), 15 pts were symptomatic (11 pain, 4 neurological deficit) and were mainly heavily pretreated [median previous chemotherapies 2 (1-5), median previous surgery 1 (0-2)]. Overall, 45 lesions underwent EBRT. Median EBRT dose per lesion was 33 Gy (IQR 25 - 46.5) with a median dose per fraction of 3 Gy (IQR 3-7.5). Calculated median EQD2 was 50 Gy (IQR 36 - 88). Median PFS, RT-PFS, and overall survival were 5 (95%CI 2-9), 11 (5-15), and 12 months (8-16), respectively. Compared to systemic progression, median progression delay of irradiated lesions was 6 months (95%CI 2 - 12). In 40 lesions evaluable for dimensional response, we observed tumor shrinkage > 30% in 7 lesions, stability in 24, and progression in 9. Conclusions: EBRT might have a role in the treatment of advanced OS. In consideration of the limited activity of medical treatments, EBRT might help in disease control in the advanced setting, delaying progression especially at critical sites.

Follow-up aims to precociously identify recurrences, metastases or treatment-related adverse events so as to undertake the appropriate therapy. Guidelines admit lack of knowledge on optimal surveillance schedule, but suggest follow-up based on experts' opinion and risk stratification. To identify the impact, if any, of regular follow-up, we interrogated our prospectively collected database whether early detection of recurrences affected both clinical management and, likely, the outcome.We required information to be available on primary surgery and ≥3°years of follow-up for non-recurring patients. We analysed recurrence characteristics (asymptomatic versus symptomatic, low- versus high tumour burden) and computed tomography (CT) scan counts to detect one recurrence. Kaplan-Meier method estimated recurrence-free survival (RFS), post-recurrence progression-free survival (PR-PFS), and disease-specific overall survival (OS). Comparisons used Hazard ratios (HR) with 95% confidence intervals (CIs). Multivariate analyses employed the Cox proportional hazards model. All tests were two-sided.Between 01/2001 and 12/2012 we found 233 study-eligible patients. Estimated 5- and 10-year RFS were 61.8% and 50.4%, respectively. After a 68-month median follow-up, we observed 94 (40.3%) recurrences [73/94 (77.7%) asymptomatic versus 21/94 (22.3%) symptomatic and 45/94 (47.9%) low- versus 49/94 (52.1%) high tumour burden]. Multivariate analysis revealed that symptomatic and high tumour burden recurrences were highly predictive of both worse PR-PFS (HR:3.19, P 0.001; HR:2.80, P = 0.003, respectively) and OS (HR:3.65, P 0.001; HR:2.38, P = 0.026, respectively). Finally, 29 second (primary) cancers were detected during follow-up.Regular follow-up detects recurrences at an earlier stage and may be associated with a better PR-PFS and OS for these patients. In the absence of randomised trials, these evidences support follow-up effort and cost.

Genitourinary cancers represent a heterogeneous group of malignancies arising from genitourinary tract, and are responsible for almost 359 000 newly diagnosed cases and 58 420 related deaths in USA. Continuous advances in cancer genetics and genomics have contributed towards changing the management paradigms of these neoplasms. Neoangiogenesis, through the activation of the tyrosine-kinase receptors signalling pathways, represents the key mediator event in promoting tumour proliferation, differentiation, invasiveness and motility. In the last decade, several treatments have been developed with the specific aim of targeting different cell pathways that have been recognized to drive tumour progression. The following review attempts to provide a comprehensive overview of the literature, focusing on new advances in targeted therapies for genitourinary tumours. Furthermore, the promising results of the latest clinical trials and future perspectives will be discussed.

Background Vanishing bile duct syndrome has been associated with different pathologic conditions (adverse drug reactions, autoimmune diseases, graft versus host disease, and cancer). Though its causes are unknown, an immune-related pathogenesis is the most likely one. Vanishing bile duct syndrome can evolve to hepatic failure and, eventually, to death. The treatment is uncertain, but it needs the resolution of the underlying pathologic condition. Case presentation We describe the association of Hodgkin’s lymphoma with a syndrome characterized by cholestasis, aminotransferase elevation and an histological picture of bile duct loss. All other causes of hepatic function impairment were excluded (in particular, drugs, viral and autoimmune related diseases) eventually leading to the diagnosis of vanishing bile duct syndrome. Despite the fact that the dysfunction is not caused by hepatic Hodgkin’s lymphoma involvement, liver impairment can limit the optimal therapy of Hodgkin’s lymphoma. A treatment consisting of ursodeoxycholic acid, prednisone, and full dose chemotherapy restored hepatic function and achieved complete and long-lasting remission of Hodgkin’s lymphoma. Conclusion We reviewed all case reports showing that vanishing bile duct syndrome is a dismal paraneoplastic syndrome being fatal in a high proportion of patients if not adequately treated. Indeed, this syndrome requires both an early recognition and an appropriate aggressive treatment consisting of full dose upfront chemotherapy which is the only way to achieve a resolution of the vanishing bile duct syndrome. Delayed or reduced intensity treatments unfavorably correlate with survival.

Anemia is one of the most prevalent clinic condition leading to a specialist medical consult. In 2014 our Internal Medicine unit started a Multidisciplinary Anemia Ambulatory (Internist, Immune-Hematologist, Hematologist) with the purpose to rapidly manage, diagnosis and treatment of anemic patients, giving a direct connection between general practitioners and hospital services. We treated and collected data on patients come to our attention in a tertiary care hospital in Genoa (Liguria), an area characterized by elderly population, which often carries more than one comorbidity with the purpose of better define the epidemiology of such a prevalent but underestimated issue. From January 1st 2014 a total of 212 patients came to our attention for internist consult due to anemia: 165 female and 47 male, medium age 63,23 years (F 58,86, M 78,57, range 19-100). A precise classification of anemia was determined for 187 patients: 130 had iron deficiency anemia (IDA, 61,32%), 17 multifactorial anemia (inflammatory disorders, chronic kidney disease and combined deficiency, 8,02%), 16 combined deficiency anemia (iron and vitamins, 7,55%), 9 chronic kidney disease related anemia (4,25%), 7 anemia secondary to inflammatory chronic disorder (3,30%), 5 B12 deficiency (2,36%), 2 both folate and B12 deficiency (0,94%), 1 folate deficiency (0,47%). Twenty-five patients were not classified due to lack of data. Severity of anemia was defined according to WHO criteria: 53 patients (25%) presented mild anemia (Hb 129 - 110 g/L), 123 (58%) moderate anemia (Hb 109 - 80 g/L), 33 (15,6%) severe anemia (Hb < 80 g/L). Three patients were not anemic at the baseline evaluation. We considered comorbidities of internistic relevance, which could be worsened by anemia: cardiovascular (coronary heart disease, arrhythmias, heart failure), 30 patients; neurologic (ischemic and degenerative diseases), 19 patients; respiratory disease (COPD and asthma), 11 patients. Eleven patients had 2 comorbidities (cardiovascular and respiratory or neurological) and 3 patients had all three comorbidities. Patients were treated according to clinical practice in relation to type, severity and clinical manifestation of anemia. One hundred and thirty patients needed more than one access to ambulatory to correct anemia; data from the second access were: patient responders (normalization of Hb levels or improvement of at least 20 g/L): 78 patients; partial responders (improvement of Hb levels from 5 to 20 g/L): 34 patients; non responders: 18 patients. Fourteen patients needed at least 1 blood red cells transfusion, 12 with severe anemia and 2 with moderate anemia. A total of 93 patients needed deep diagnostic insight through specialist pathways, such as hematologic (4 patients), gastroenterologic (39 patients), gynecologic (37 patients), both gastroenterologic and gynecologic (13 patients). All patients were managed as outpatients, except for 8 patients which required hospitalization due to severity of clinical findings: 4 patients were hospitalized in Internal Medicine ward, 1 patients in Gynecology and 3 patients needed access through Emergency Care Unit. Among IDA patients, 92 were treated with intravenous iron supplement: 32 with sodium ferric gluconate (SFG) (medium 16,68 vials, range 8-43) and 50 with ferric carboxymaltose (FC) (medium 1,04 vials). Nine patients treated with SFG experienced allergic reaction, so they were switched to FC. Patients treated with SFG were successfully treated for 69,56% and 26,08% responded partially. One patient treated with FC experienced allergic reaction, so he was switched to oral therapy. FC patients fully responded in 76% and 22% were partial responders. These preliminary data shows that Multidisciplinary Anemia Ambulatory and its diagnostic-therapeutic path, with the involvement of different Specialists and Operative Unit, resulted in an improvement of the coordination and continuity of care, reducing sanitary cost in terms of hospitalization, drugs rationalization and quality of life for patients. More data will derive from the newborn Anemia Regional Register, which will lead to a better comprehension of the real size of anemia in our local epidemiology, in which health derived costs are rising together with ageing of the comorbid population which often needs longitudinal assistance, coordination and continuity of care. Disclosures No relevant conflicts of interest to declare.

e21517 Background: Several evidences showed systemic inflammation is directly implicated in cancer development and progression. Accordingly, a relationship between inflammatory features (CRP, neutr...

11513 Background: Surgery is the mainstay of treatment for patients with retroperitoneal sarcoma (RPS), but this can be challenging, and recurrence rates are high. Novel treatment approaches are needed. In this study, we sought to 1) determine the frequency and potential predictors of radiologic tumor response and 2) assess clinical outcomes in patients with primary high risk RPS who were treated at sarcoma referral centers with neoadjuvant systemic therapy followed by surgery. Methods: Clinicopathologic data was retrospectively collected for eligible patients treated from 2008-2018 at 13 institutions within the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG). For each patient, preoperative objective response (RECIST1.1) was reported by each institution. Univariable and multivariable logistic models were performed to determine predictors of response. Kaplan-Meier plots were constructed for overall survival (OS) and cumulative incidences of local recurrence (LR) and distant metastasis (DM). Results: In total, 158 RPS patients were included in this study. A median of 3 cycles (IQ range 2-4) of neoadjuvant systemic therapy were given. No complete responses were observed. Partial response (PR) was seen in 37 patients (23%), stable disease (SD) in 88 (56%) and progressive disease (PD) in 33 (21%). Subtype-specific differences were seen including PR in 5 out of 11 (45%) patients with undifferentiated pleomorphic sarcoma. Overall, higher number of cycles given was positively associated with PR (p = 0.005). No other factors including receipt of neoadjuvant radiation therapy were predictive of PR. All patients underwent complete (R0/R1) resection with a major complication (Clavien-Dindo ≥3) rate of 23%. Differences in OS were observed based on preoperative response type (p = 0.005). In grade 3 dedifferentiated liposarcoma, patients who received adriamycin-ifosfamide versus another regimen had decreased LR and improved OS. In leiomyosarcoma, patients who received adriamycin-DTIC versus another regimen had a higher PR rate (37% vs. 16%), decreased LR, DM and improved OS. Limited by low numbers, these subtype-specific data did not reach statistical significance. Conclusions: In patients with high risk RPS, response to neoadjuvant systemic therapy is overall modest and may be regarded as an indicator of disease biology to predict survival after surgery. Subtype-specific regimens should be further validated and incorporated into prospective trials of neoadjuvant systemic therapy in RPS (e.g. STRASS2).