Narrative Medicine: A Digital Diary in the Management of Bone and Soft Tissue Sarcoma Patients. Preliminary Results of a Multidisciplinary Pilot Study

Background. Guidelines for the implementation of narrative medicine in clinical practice exist; however, in Italy, no standard methodology is currently available for the management of oncological patients. Since 2017, at the “Regina Elena” National Cancer Institute, studies using “digital narrative diaries” (DNMLAB platform) have been carried out; this article focuses on a pilot, uncontrolled, real-life study aiming to evaluate the utility of DNM integrated with the care pathway of patients with bone and limb soft tissue sarcomas. Methods. Adult patients completed the diary during treatment or follow-up by writing their narrative guided by a set of narrative prompts. The endpoints were: (a) patients’ opinions about therapeutic alliance, awareness, and coping ability; (b) healthcare professionals’ (HCPs’) opinions about communication, therapeutic alliance, and information collection. Open- and closed-ended questions (Likert score: 1–5) were used to assess the items. Results. At the interim analysis of data from seven patients and five HCPs, DNM was shown to improve: (a) the expression of patients’ point of view, the perception of effective taking charge, disease awareness, and self-empowerment (score: 4.8/5); (b) patients’ communication, relationships, and illness knowledge (score: 4.6–4.8/5). Conclusions. The preliminary results supported the need to integrate patients’ narratives with clinical data and encourage further research.

Sarcomas of the extremities and the pelvis: comparing local recurrence after incisional and after core-needle biopsy

Background The degree of contamination of healthy tissue with tumor cells during a biopsy in bone or soft tissue sarcomas is clearly dependant on the type of biopsy. Some studies have confirmed a clinically relevant contamination of the biopsy tract after incisional biopsies, as opposed to core-needle biopsies. The aim of our prospective study was to evaluate the risk of local recurrence depending on the biopsy type in extremity and pelvis sarcomas. Methods We included 162 patients with a minimum follow-up of 6 months after wide resection of extremity sarcomas. All diagnostic and therapeutic procedures were performed at a single, dedicated sarcoma center. The excision of the biopsy tract after an incisional biopsy was performed as a standard with all tumor resections. All patients received their follow-up after the conclusion of therapy at our center by means of regional MRI studies and, at a minimum, CT of the thorax to rule out pulmonary metastatic disease. The aim of the study was the evaluation of the influence of the biopsy type and of several other clinical factors on the rate of local recurrence and on the time of local recurrence-free survival. Results One hundred sixty-two patients with bone or soft tissue tumors of the extremities and the pelvis underwent either an incisional or a core-needle biopsy of their tumor, with 70 sarcomas (43.2%) being located in the bone. 84.6% of all biopsies were performed as core-needle biopsies. The median follow-up time was 55.6 months, and 22 patients (13.6%) developed a local recurrence after a median time of 22.4 months. There were no significant differences between incisional and core-needle biopsy regarding the risk of local recurrence in our subgroup analysis with differentiation by kind of tissue, grading of the sarcoma, and perioperative multimodal therapy. Conclusions In a large and homogenous cohort of extremity and pelvic sarcomas, we did not find significant differences between the groups of incisional and core-needle biopsy regarding the risk of local recurrence. The excision of the biopsy tract after incisional biopsy in the context of the definitive tumor resection seems to be the decisive factor for this result.

Blockade of beta-adrenergic receptors reduces cancer growth and enhances the response to anti-CTLA4 therapy by modulating the tumor microenvironment

The development of immune checkpoint inhibitors (ICI) marks an important breakthrough of cancer therapies in the past years. However, only a limited fraction of patients benefit from such treatments, prompting the search for immune modulating agents that can improve the therapeutic efficacy. The nonselective beta blocker, propranolol, which for decades has been prescribed for the treatment of cardiovascular conditions, has recently been used successfully to treat metastatic angiosarcoma. These results have led to an orphan drug designation by the European Medicines Agency for the treatment of soft tissue sarcomas. The anti-tumor effects of propranolol are suggested to involve the reduction of cancer cell proliferation as well as angiogenesis. Here, we show that oral administration of propranolol delays tumor progression of MCA205 fibrosarcoma model and MC38 colon cancer model and increases the survival rate of tumor bearing mice. Propranolol works by reducing tumor angiogenesis and facilitating an anti-tumoral microenvironment with increased T cell infiltration and reduced infiltration of myeloid-derived suppressor cells (MDSCs). Using T cell deficient mice, we demonstrate that the full anti-tumor effect of propranolol requires the presence of T cells. Flow cytometry-based analysis and RNA sequencing of FACS-sorted cells show that propranolol treatment leads to an upregulation of PD-L1 on tumor associated macrophages (TAMs) and changes in their chemokine expression profile. Lastly, we observe that the co-administration of propranolol significantly enhances the efficacy of anti-CTLA4 therapy. Our results identify propranolol as an immune modulating agent, which can improve immune checkpoint inhibitor therapies in soft tissue sarcoma patients and potentially in other cancers.

Efficacy and Safety of Trans-Arterial Yttrium-90 Radioembolization in Patients with Unresectable Liver-Dominant Metastatic or Primary Hepatic Soft Tissue Sarcomas

Patients with liver-dominant metastatic or primary hepatic soft tissue sarcomas (STS) have poor prognosis. Surgery can prolong survival, but most patients are not surgical candidates, and treatment response is limited with systemic chemotherapy. Liver-directed therapies have been increasingly employed in this setting, and Yttrium-90 trans-arterial radioembolization (TARE) is an understudied yet promising treatment option. This is a retrospective analysis of 35 patients with metastatic or primary hepatic STS who underwent TARE at a single institution between 2006 and 2020. The primary outcomes that were measured were overall survival (OS), liver progression-free survival (LPFS), and radiologic tumor response. Clinical and biochemical toxicities were assessed 3 months after the procedure. Median OS was 20 months (95% CI: 13.9–26.1 months), while median LPFS was 9 months (95% CI: 6.2–11.8 months). The objective response rate was 56.7%, and the disease control rate was 80.0% by mRECIST at 3 months. The following correlated with better OS post-TARE: liver disease control (DC) at 6 months (median OS: 40 vs. 17 months, p = 0.007); LPFS ≥ 9 months (median OS: 50 vs. 8 months, p < 0.0001); ECOG status 0–1 vs. 2 (median OS: 22 vs. 6 months, p = 0.042); CTP class A vs. B (median OS: 22 vs. 6 months, p = 0.018); and TACE post-progression (median OS: 99 vs. 16 months, p = 0.003). The absence of metastases at diagnosis was correlated with higher median LPFS (7 vs. 1 months, p = 0.036). Two grade 4 (5.7%) and ten grade 3 (28.6%) laboratory toxicities were identified at 3 months. There was one case of radioembolization-induced liver disease and two cases of radiation-induced peptic ulcer disease. We concluded that TARE could be an effective and safe treatment option for patients with metastatic or primary hepatic STS with good tumor response rates, low incidence of severe toxicity, and longer survival in patients with liver disease control post-TARE.

Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Rhabdomyosarcomas (RMS) are mesenchyme-derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for high-risk patients. Discovery of new therapies would benefit from additional preclinical models. Here we describe the generation of a collection of pediatric RMS tumor organoid (tumoroid) models comprising all major subtypes. For aggressive tumors, tumoroid models can often be established within four to eight weeks, indicating the feasibility of personalized drug screening. Molecular, genetic and histological characterization show that the models closely resemble the original tumors, with genetic stability over extended culture periods of up to six months. Importantly, drug screening reflects established sensitivities and the models can be modified by CRISPR/Cas9 with TP53 knockout in an embryonal RMS model resulting in replicative stress drug sensitivity. Tumors of mesenchymal origin can therefore be used to generate organoid models, relevant for a variety of preclinical and clinical research questions.

Chemotherapy Combined With Recombinant Human Endostatin (Endostar) Significantly Improves the Progression-Free Survival of Stage IV Soft Tissue Sarcomas

PurposeOur previously study showed that recombinant human endostatin (Endostar) combined with chemotherapy had significant activity to increase the mPFS in patients with advanced sarcomas with tolerable side effects. However, the small cohort size and short follow-up time made it difficult to screen sensitive sarcoma subtypes and determine whether there is an overall survival benefit. With the largest sarcoma cohort to our knowledge, we try to confirm the efficacy and safety of chemotherapy combined with Endostar in stage IV sarcomas, with the specific purpose of finding out the sensitive sarcoma types for this combined treatment.MethodsAfter the exclusion of ineligible patients, 156 patients with stage IV bone and soft tissue sarcomas were included in this study according to the inclusion criteria.ResultsBy the end of follow-up, the ORR was 10.7% (9/84) vs 1.4% (1/72) (p=0.041), the DCR was 26.2% (22/84) vs 5.6% (4/72) (p=0.001) in the combined group and chemotherapy group, respectively. The mPFS of combined group was significantly longer than the chemotherapy group (10.42 vs 6.87 months, p=0.003). The mOS were 26.84 months and 23.56 months, without significant difference (p= 0.481). In osteogenic sarcoma, there was no statistically significant difference in the mPFS between the two groups (p=0.59), while in the soft tissue sarcoma, the mPFS in the combined group was significantly higher than that of the chemotherapy group (11.27 vs 8.05 months, p=0.004). Specifically, undifferentiated polymorphic sarcoma (UPS) was the possible sarcoma subtypes that benefited from the combined therapy. For the 38 UPS patients (28 patients in the combined group and 10 patients in the chemotherapy group), the mPFS in the combined group was up to 14.88 months, while it was only 7.1 months in the chemotherapy group, with a significant difference (p=0.006). The most common adverse events in the combined group were myelosuppression, gastrointestinal reactions and abnormal liver function, without significant difference in two groups.ConclusionChemotherapy plus Endostar could prolong mPFS and improve ORR and DCR in patients with stage IV soft tissue sarcoma, suggesting that the combined therapy could improve the patient prognosis in soft tissue sarcomas, especially the UPS patients.

Lymphatic Complications Prevention and Soft Tissue Reconstruction after Soft Tissue Sarcoma Resection in the Limbs

Background and Objectives: The definitive treatment of soft tissue sarcomas (STS) requires a radical surgical removal of the tumor, which often leads to large soft tissue defects. When they are located in the limbs, significant damage to the lymphatic pathways is not uncommon. In the present article, we present different techniques aimed at both reconstructing the defect and restoring sufficient lymph drainage, thus preventing short- and long-term lymphatic complications. Materials and Methods: Between 2018 and 2020, 10 patients presenting a soft tissue defect with lymphatic impairment received a locoregional reconstruction by means of either pedicled or free SCIP flap. Seven patients required a second flap to reach a good dead space obliteration. In six cases, we performed an interpositional flap, namely a soft tissue transfer with lymphatic tissue preservation, and in four cases a lymphatic flow-through flap. In all cases, the cause of the defect was STS surgical excision. The average age was 60.5 years old (ranging 39–84), seven patients were females and six were males. Results: All the patients were successfully treated. In two cases, minor post-operative complications were encountered (infected seroma), which were conservatively managed. No secondary procedures were required. The average follow-up was 8.9 months (ranging 7–12 months). No signs of lymphedema were reported during this time. In all cases, complete range of motion (ROM) and a good cosmetic result were achieved. Conclusions: A reconstructive procedure that aims not only to restore the missing volume, but also the lymphatic drainage might successfully reduce the rate of postoperative complications. Both lymphatic interpositional flaps and lymphatic flow-through flaps could be effective, and the right choice must be done according to each patient’s needs.

Immunologic constant of rejection signature is prognostic in soft-tissue sarcoma and refines the CINSARC signature

BackgroundSoft-tissue sarcomas (STSs) are heterogeneous and aggressive tumors, with high metastatic risk. The immunologic constant of rejection (ICR) 20-gene signature is a signature of cytotoxic immune response. We hypothesized that ICR might improve the prognostic assessment of early-stage STS.MethodsWe retrospectively applied ICR to 1455 non-metastatic STS and searched for correlations between ICR classes and clinicopathological and biological variables, including metastasis-free survival (MFS).ResultsThirty-four per cent of tumors were classified as ICR1, 27% ICR2, 24% ICR3, and 15% ICR4. These classes were associated with patients’ age, pathological type, and tumor depth, and an enrichment from ICR1 to ICR4 of quantitative/qualitative scores of immune response. ICR1 class was associated with a 59% increased risk of metastatic relapse when compared with ICR2-4 class. In multivariate analysis, ICR classification remained associated with MFS, as well as pathological type and Complexity Index in Sarcomas (CINSARC) classification, suggesting independent prognostic value. A prognostic clinicogenomic model, including the three variables, was built in a learning set (n=339) and validated in an independent set (n=339), showing greater prognostic precision than each variable alone or in doublet. Finally, connectivity mapping analysis identified drug classes potentially able to reverse the expression profile of poor-prognosis tumors, such as chemotherapy and targeted therapies.ConclusionICR signature is independently associated with postoperative MFS in early-stage STS, independently from other prognostic features, including CINSARC. We built a robust prognostic clinicogenomic model integrating ICR, CINSARC, and pathological type, and suggested differential vulnerability of each prognostic group to different systemic therapies.