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Purpose: To determine the preferred conventional radiation therapy (CRT) practice, and willingness to randomize to high dose spine SBRT, in a group of patients with complex spinal metastases. Methods and Material: The survey was based on four complex spinal metastases cases, considered candidates for the proposed Phase 2 randomized controlled trial (RCT) comparing 24 Gy in 2 fractions delivered with SBRT to either 20 Gy in 5 fraction (frx) or 30 Gy in 10 frx CRT. Participants were asked to determine their preferred CRT practice, whether they would treat the same patient with SBRT, and if they would participate in the RCT. Two cases were of radioresistant histologies (renal cell and hepatocellular carcinoma), one had epidural disease, two were oligometastatic, and one consisted of a C2 level metastases with paraspinal extension. Results: 51 radiation oncologists from across the country participated. For each of the clinical scenarios, 20 Gy in 5 frx was the favored CRT practice. However, equivalence was noted for the one renal cell case. All respondents were comfortable with delivering the intended SBRT dose, and most would participate on the proposed RCT . With respect to the primary treatment intent, both local control (LC) and symptom relief were of primary importance; however, local control was more important than symptom relief for the two patients with oligometastatic disease and an expected long-term survival. 51 % of respondents would be able to randomize one patient per month and 35% could randomize 2 to 5 patients per month. Conclusion: 20Gy/5fx was the preferred CRT practice for the treatment of complex spinal metastases described in the survey. Most radiation oncologists surveyed would be willing to participate in the proposed Phase 2 RCT. Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

Purpose: Radiotherapy is a well-established treatment option for bone metastases. One of the commonly associated toxicities is pain flare, which can be broadly defined as a transient increase in pain during or immediately post-treatment. Previously published data indicates that incidence rates can be as high as 40% with conventional radiotherapy. With the emergence of stereotactic body radiotherapy (SBRT) as a high-dose alternative for spinal metastases, there is a need to define the pain flare phenomenon within this setting. The purpose of this prospective toxicity study was to determine the incidence rate of pain flare for SBRT of spinal metastases. Methods: From February 2010 to April 2012,41 patients were enrolled in this study. Pain scores were evaluated using the Brief Pain Inventory (BPI) before, during and 10 days after radiotherapy. Both analgesic and corticosteroid use was also documented. Pain flare was defined as per published criteria (i.e. two-point increase in worst pain on an 11-point numeric scale compared to baseline with no decrease in analgesic use, or 25% increase in analgesic intake with no decrease in worst pain score). The definition was slightly modified such that pain flare was also recorded if corticosteroids were initiated. Predictive factors were evaluated using univariate and multivariate logistic regression analysis. Results: Within this cohort, the mean (SD) age was 57.5 (12.4) years old with a median (range) KPS score of 80 (50-100). The most common primary sites were renal (36.6%), lung (24.4%) and breast (17.1%). The incidence of pain flare was 68.3% (28/41). The most common day of occurrence was day 1 post-radiotherapy (28.6%; 8/28). On multivariate logistic regression analysis, higher KPS (p=0.0174) and cervical (p=0.0498) or lumbar (p=0.0176) spine involvement were the factors significantly associated with pain flare. No association was noted for baseline pain scores, dose-fractionation schedule used or subsequent dosimetric data. Conclusions: With SBRT for spinal metastases, the incidence of pain flare was much higher than what would be expected for conventional radiotherapy. Our practice now is to offer prophylactic dexamethasone to all patients undergoing spine treatment. If validated with a larger cohort though, it may be possible to identify a high-risk subgroup that would allow for further individualization of care. At this time, this study represents the first attempt at characterizing pain flare secondary to spinal SBRT, the importance of which will only be underscored as its utility increases. Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

Objectives: To report the rate of post-stereotactic body radiotherapy (SBRT) vertebral compression fracture (VCF) specific to renal cell cancer (RCC) spinal metastases, and to identify potential anatomic and dosimetric predictive factors. Methods: 71 spinal segments in 37 RCC patients treated at the University of Toronto were retrospectively reviewed. All 71 spinal segments were scored at baseline according to the Spinal Instability Neoplastic Score (SINS) criteria to determine if the components of this scoring system are predictive for SBRT-induced VCF. Additional factors analysed included the use of anti-angiogenic therapies, biphosphonates, prior radiation, total dose and number of fractions, and various dose-volume histogram parameters. Post-operative tumours were considered separately. Results: According to the SINS criteria, 42/71 segments were stable, 24/71 potentially unstable, and 5/71 unstable at baseline. Of the 5 unstable segments, 2 underwent initial surgery prior to SBRT and 3 were considered inoperable and treated with SBRT alone. In total, post-operative SBRT was delivered for 10/71 spinal segments and the analysis confined to the 61 segments treated with SBRT alone. At baseline, 48/61 vertebral bodies had no fracture and 13 had some degree of fracture (4 had <10% and 9 had 10-33% of collapse). The median SBRT total dose and number of fractions were 24 Gy (range, 18-30) and 2 (range, 1-5), respectively. The median follow up was 12 months. 10 VCFs (16%) were observed with 3/10 being de novo fractures and 7/10 cases fracture progression. The 1-year fracture-free probability was 82%. The median time to VCF was 48 days. The risk of SBRT-induced VCF was significantly greater in patients with baseline VCF (7/13, 54%) compared to those with no baseline VCF (3/48, 6%). Multivariate analysis identified baseline VCF as the only significant predictor of SBRT-induced VCF (hazard ratio, 6.46; 95% CI, 1.04-40.17; p=0.05). Conclusion: We observe a manageable risk of SBRT-induced VCF in RCC patients. However, for spinal metastases with a baseline VCF, careful monitoring is required as they are at significantly greater risk of further collapse. Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

Objectives: Spine SBRT is increasingly being applied to the post-operative patient, as an alternative to conventional palliative radiotherapy, with the aim to improve upon existing rates of local control. As an emerging indication, our aim was to identify clinical and dosimetric predictors of local control and survival. Methods: 80 patients treated between October 2008 to February 2012 with post-operative SBRT within 8 weeks of surgery, were identified from our prospective database and retrospectively reviewed. The pre- and post-operative MR images were reviewed to characterize the disease extent within the spinal segment, and to grade epidural disease such that grade 0 is no epidural disease, grade 1 is dural compression without spinal cord displacement, grade 2 is cord compression with visible CSF and grade 3 is cord compression obliterating CSF. Other factors analyzed included type of surgery, use of systemic therapy post-SBRT, prior radiation exposure, total dose, dose per fraction and various dosimetric factors. Results: The median follow-up was 8.3 months (range, 0.2- 39.1). The most common primary histologies were breast (15%) and non-small cell lung cancer (15%), and 56% of tumors were in the thoracic spine. 69 (86%) patients underwent a decompressive surgery while 11 (14%) underwent a stabilization procedure alone. 35 (44%) patients were treated with 1 or 2 fractions (total dose ranging from 18-26), and 45 (56%) with 3 to 5 fractions (total dose ranging from 24-40). Pre- and postoperative epidural grade 0,1,2, and 3 were observed in 5%/7%, 35%/66%, 35%/10%, and 25%/0% of patients, respectively. 21 local failures (26%) were observed, and the 1-year local control (LC) and overall survival (OS) rates were 84% and 63%, respectively. The median time to local failure was 6.9 months (range, 0.2 - 37.4 months). The most common site of failure was within the epidural space (15/21,71%). We identified systemic therapy post-SBRT as the only significant predictor of OS (p=0.03). Multivariate proportional hazards analysis identified treatment with 1 or 2 fraction SBRT and a postoperative epidural disease grade of 0/1 as significant predictors of LC. Subset analysis for only those patients with a pre-operative epidural disease grade of 2 or 3 (n=48/80) indicated significantly greater LC rates when down-graded to 0/1 vs 2 (p=0.0009). Conclusions: At one year, 80% of patients remained progression free. 1 or 2 fraction SBRT and a postoperative epidural disease grade of 0 or 1 predicted for superior local control. Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate local control (LC) and overall survival (OS) after stereotactic body radiation therapy (SBRT) for renal cell cancer (RCC) spinal metastases, and to evaluate predictive and prognostic factors, respectively. Methods: 71 spinal segments in 37 RCC patients treated at the University of Toronto were retrospectively reviewed. LC was assessed based on each spinal segment treated and OS according to each patient treated, using the Kaplan-Meier method. Oligometastatic disease (less than 5 sites of metastatic disease), paraspinal extension, invasion of posterior elements, grade of epidural disease, targeted anti-angiogenic therapy, prior radiation, total dose and number of fractions, and various dose-volume histogram metrics were evaluated for their prognostic and predictive significance. Results: Of the 71 spinal segments treated with SBRT, 9 were cervical, 33 thoracic, 21 lumbar, and 8 sacral. 11/71 had been previously radiated, and 10/71 were treated with post-operative SBRT. The median SBRT total dose and number of fractions were 24 Gy (range, 18-30) and 2 (range, 1-5), respectively. The median follow up was 12 months. The 1-year OS and LC rates were 64% and 83%, respectively. Patterns of failure included progression within the epidural space (5/12), paraspinal tissue (2/12), vertebral segment bone (2/12) and mixed (including epidural space; 3/12). Multivariate analysis indicated oligometastatic disease (13/37 patients) as the only significant prognostic factor for OS (p=0.018). We did not found any predictor for LC; total dose and number of fractions were not predictive. Conclusion: We identified the oligometastatic state as prognostic for RCC, therefore, a group deserving aggressive local therapy. Spine SBRT yielded high rates of local tumour control in this population. Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

Aim: To evaluate Stereotactic body radiotherapy (SBRT) in metastatic colorectal cancer (mCRC) and identify the benefit of the treatment by using a predictive algorithm., Methods: 85 patients treated with SBRT for mCRC were retrospectively analyzed. The CLInical Categorical Algorithm (CLICAL©) was used to predict probability of relapse after SBRT. Variables pre-SBRT were tested for significance for time to relapse (TTR). The patients' CLICAL© score was the mean of sub-scores of each significant variable's effect on the endpoint. Patients with similar scores were grouped into four signatures dependent on level of benefit after SBRT., Results: Median age was 69 years (42-88), 63 % had a performance status 0 and 47 % were treated for a single metastasis. At the time of the analysis, 90 % had relapsed (95 % out-of-field). Median TTR was 7.3 months (4.6-8.5), and the 2-year relapse-free rate was 15 % (95 %CI = 7-22). The CLICAL© signature III-IV predicted a low risk of relapse if receiving high dose SBRT to all metastases or to lung metastases only. Signature I-II had a short TTR, why SBRT for these patients was judged non-beneficial., Conclusion: The benefit from SBRT varies among mCRC patients. CLICAL© may serve as a screening tool for SBRT referrals but needs to be validated., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

In the past decade, immunotherapy with checkpoint inhibitors has revolutionized the field of oncology. Checkpoint inhibitors have been approved for several types of cancer and thousands of patients in Sweden now receive oncological immunotherapy annually. Immune-related side effects are common and can occur in almost any organ. These side effects are different from those that occur with traditional oncological treatments. The side effects are usually mild, but can be serious and even lethal. In a short time, health care providers have had to readjust to be able to handle these side effects. Early and correct diagnosis of immune-related side effects, proper management and a multidisciplinary approach is crucial. Here, we give an overview of the presentation, diagnosis and treatment of immune-related side effects, with emphasis on endocrine, rheumatologic and skin toxicity.

Inter-case variations in immune cell and fibroblast composition are associated with prognosis in solid tumors, including colon cancer. A series of experimental studies suggest immune-modulatory roles of marker-defined fibroblast populations, including FAP-positive fibroblasts. These studies imply that the fibroblast status of tumors might affect the prognostic significance of immune-related features. Analyses of a population-based colon cancer cohort demonstrated good prognosis associations of FAP intensity and CD8a density. Notably, a significant prognostic interaction was detected between these markers ( p = 0.013 in nonadjusted analyses and p = 0.003 in analyses adjusted for cofounding factors) in a manner where the good prognosis association of CD8 density was restricted to the FAP intensity-high group. This prognostic interaction was also detected in an independent randomized trial-derived colon cancer cohort ( p = 0.048 in nonadjusted analyses). In the CD8-high group, FAP intensity was significantly associated with a higher total tumor density of FoxP3-positive immune cells and a higher ratio of epithelial-to-stromal density of CD8a T cells. The study presents findings relevant for the ongoing efforts to improve the prognostic performance of CD8-related markers and should be followed by additional validation studies. Furthermore, findings support, in general, earlier model-derived studies implying fibroblast subsets as clinically relevant modulators of immune surveillance. Finally, the associations between FAP intensity and specific immune features suggest mechanisms of fibroblast-immune crosstalk with therapeutic potential.

Blockade of the PD-1 receptor has revolutionized the treatment of metastatic melanoma, with significant increases in overall survival (OS) and a dramatic improvement in patient quality of life. Despite the success of this approach, the number of benefitting patients is limited and there is a need for predictive biomarkers as well as a deeper mechanistic analysis of the cellular populations involved in clinical responses. With the aim to find predictive biomarkers for PD-1 checkpoint blockade, an in-depth immune monitoring study was conducted in 36 advanced melanoma patients receiving pembrolizumab or nivolumab treatment at Karolinska University Hospital. Blood samples were collected before treatment and before administration of the second and fourth doses. Peripheral blood mononuclear cells were isolated and stained for flow cytometric analysis within 2 h of sample collection. Overall survival and progression-free survival (PFS) were inversely correlated with CD69 expression NK cells. In the myeloid compartment, high frequencies of non-classical monocytes and low frequencies of monocytic myeloid derived suppressor cells (MoMDSCs) correlated with response rates and OS. A deeper characterization of monocytic subsets showed that PD-L1 expression in MDSCs, non-classical and intermediate monocytes was significantly increased in patients with shorter PFS in addition to correlating inversely with OS. Our results suggest that cellular populations other than T cells can be critical in the outcome of PD-1 blockade treatment. Specifically, the frequencies of activated NK cells and monocytic subsets are inversely correlated with survival and clinical benefit, suggesting that their role as predictive biomarkers should be further evaluated., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Development of T cell-directed immune checkpoint inhibitors (ICI) has revolutionized metastatic melanoma (MM) therapy, but <50% of treated patients experience durable responses. This phase I trial (NCT01946373) investigates the safety/feasibility of tumor-infiltrating lymphocyte (TIL) adoptive cell therapy (ACT) combined with dendritic cell (DC) vaccination in MM patients progressing on ICI. An initial cohort (5 patients) received TIL therapy alone to evaluate safety and allow for optimization of TIL expansion protocols. A second cohort (first-in-man, 5 patients) received TIL combined with autologous tumor lysate-loaded DC vaccination. All patients received cyclophosphamide/fludarabine preconditioning prior to, and intravenous (i.v.) IL-2 after, TIL transfer. The DC vaccine was given as five intradermal injections after TIL and IL-2 administration. [ 18 F]-FDG PET/CT radiology was performed to evaluate clinical response, according to RECIST 1.1 (on the CT part). Immunological monitoring was performed by flow cytometry and T-cell receptor (TCR) sequencing. In the safety/optimization cohort, all patients had a mixed response or stable disease, but none durable. In the combination cohort, two patients experienced complete responses (CR) that are still ongoing (>36 and >18 months, respectively). In addition, two patients had partial responses (PR), one still ongoing (>42 months) with only a small bone-lesion remaining, and one of short duration (<4 months). One patient died early during treatment and did not receive DC. Long-lasting persistency of the injected TILs was demonstrated in blood. In summary, we report clinical responses by TIL therapy combined with DC vaccination in 4 out of 4 treated MM patients who previously failed ICI., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

There are increasing demands for informative cancer biomarkers, accessible via minimally invasive procedures, both for initial diagnostics and for follow-up of personalized cancer therapy, including immunotherapy. Fine-needle aspiration (FNA) biopsy provides ready access to relevant tissue samples; however, the minute amounts of sample require sensitive multiplex molecular analysis to be of clinical biomarker utility. We have applied proximity extension assays (PEA) to analyze 167 proteins in FNA samples from patients with breast cancer (BC; n = 25) and benign lesions (n = 32). We demonstrate that the FNA BC samples could be divided into two main clusters, characterized by differences in expression levels of the estrogen receptor (ER) and the proliferation marker Ki67. This clustering corresponded to some extent to established BC subtypes. Our analysis also revealed several proteins whose expression levels differed between BC and benign lesions (e.g., CA9, GZMB, IL-6, VEGFA, CXCL11, PDL1, and PCD1), as well as several chemokines correlating with ER and Ki67 status (e.g., CCL4, CCL8, CCL20, CXCL8, CXCL9, and CXCL17). Finally, we also identified three signatures that could predict Ki67 status, ER status, and tumor grade, respectively, based on a small subset of proteins, which was dominated by chemokines. To our knowledge, expression profiles of CCL13 in benign lesions and BC have not previously been described but were shown herein to correlate with proliferation (P = 0.00095), suggesting a role in advanced BC. Given the broad functional range of the proteins analyzed, immune-related proteins were overrepresented among the observed alterations. Our pilot study supports the emerging role of chemokines in BC progression. Due to the minimally traumatic sampling and clinically important molecular information for therapeutic decisions, this methodology is promising for future immunoscoring and monitoring of treatment efficacy in BC., (© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Dendritic cell (DC) vaccines have been demonstrated to elicit immunological responses in numerous cancer immunotherapy trials. However, long-lasting clinical effects are infrequent. We therefore sought to establish a protocol to generate DC with greater immunostimulatory capacity. Immature DC were generated from healthy donor monocytes by culturing in the presence of IL-4 and GM-CSF and were further differentiated into mature DC by the addition of cocktails containing different cytokines and toll-like receptor (TLR) agonists. Overall, addition of IFNγ and the TLR7/8 agonist R848 during maturation was essential for the production of high levels of IL-12p70 which was further augmented by adding the TLR3 agonist poly I:C. In addition, the DC matured with IFNγ, R848, and poly I:C also induced upregulation of several other pro-inflammatory and Th1-skewing cytokines/chemokines, co-stimulatory receptors, and the chemokine receptor CCR7. For most cytokines and chemokines the production was even further potentiated by addition of the TLR4 agonist LPS. Concurrently, upregulation of the anti-inflammatory cytokine IL-10 was modest. Most importantly, DC matured with IFNγ, R848, and poly I:C had the ability to activate IFNγ production in allogeneic T cells and this was further enhanced by adding LPS to the cocktail. Furthermore, epitope-specific stimulation of TCR-transduced T cells by peptide- or whole tumor lysate-loaded DC was efficiently stimulated only by DC matured in the full maturation cocktail containing IFNγ and the three TLR ligands R848, poly I:C, and LPS. We suggest that this cocktail is used for future clinical trials of anti-cancer DC vaccines.

Immune checkpoints are a series of inhibitory pathways that are crucial for modulating the intensity and duration of immune response. Among these checkpoints, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) has been shown to be a key regulator of the early activation of naïve and memory T cells. Immune checkpoint blockade is emerging as one of the most promising therapeutic approaches directed toward the activation of the immune response against tumors. The first of these therapies that has been FDA approved is ipilimumab, a fully human monoclonal antibody that blocks CTLA-4. The in cis effects that CTLA-4 blockade has on T cells have been properly described, but there are still questions to be answered regarding the indirect or in trans effects. One of the alternative cellular populations that may play a role in the outcome of CTLA-4 blockade therapy is myeloid-derived suppressor cells (MDSCs), which have recently been associated with clinical outcome in advanced melanoma. In addition to this, MDSCs have been shown to be decreased in number and functional potential after treatment with ipilimumab. A better clarification of what effects CTLA-4 blockade may have on these cellular populations is likely to provide insights on possible predictive biomarkers for CTLA-4 blockade therapy.

Background/aim: Patients with human papillomavirus (HPV)-positive tonsillar and base of tongue cancer have a better outcome than those with corresponding HPV-negative tumors (80% vs. 40% 5-year disease free survival with conventional radiotherapy). They should not all need chemoradiotherapy, but before tapering treatment, more markers are needed to predict treatment response. In the present study, human leukocyte antigen (HLA) - HLA-A*02 was analyzed with HPV as a prognostic factor for tonsillar and base of tongue cancer., Patients and Methods: Pre-treatment biopsies, previously tested for HPV DNA, from 425 patients diagnosed with tonsillar and base of tongue cancer between 2000-2009 at the Karolinska University Hospital were examined for HLA-A*02., Results: HLA-A*02 was present in 144/305 (47.2%) of the HPV-positive and 63/120 (52.8%) of the HPV-negative tumours. Among 383 patients treated with curative intent, absence of HLA-A*02 was correlated with increased disease-free survival in the HPV-positive (p=0.016), but not in the HPV-negative group., Conclusion: Absence of HLA-A*02 correlated with better disease-free survival for patients with HPV-positive tonsillar and base of tongue cancer.

Objectives: Semiautomated external defibrillators (AEDs) should be considered as a means to facilitate in-hospital early defibrillation (IHED) in areas where advanced life support rescuers are not readily available. In this study, we aimed to develop a checklist and a measurement protocol to evaluate and compare AEDs by assessing factors that may affect IHED., Methods: A clinical and technical comparison of six AEDs was performed. Technical specifications were analyzed, while an emergency team evaluated ergonomics and appropriateness for IHED at Bambino Gesù Children's Hospital. A measurement protocol was implemented, which aimed to assess the ability of defibrillators to recognize shockable and nonshockable rhythms, accuracy of delivered energy, and charging time., Results: Designs of AEDs differed in several features which influence their appropriateness for IHED. Some units showed poor ergonomics and instructions/feedback for cardiopulmonary resuscitation. Differences between defibrillators in recognizing shockable and nonshockable rhythms emerged for polymorphic ventricular tachycardia waveforms and when the frequency and amplitude of input signals varied. Tests for accuracy revealed poor performances at low and high impedance levels for most AEDs. Notably, differences greater than 20 seconds were found in the time from power-on to "ready for discharge.", Conclusions: The approach we used to assess AEDs allowed us to evaluate their appropriateness with respect to the organizational context, to measure their parameters, and to compare models. Results showed that ergonomics and/or performances (timing and accuracy) could be improved in each device.

Tumors can suppress the host immune system by employing a variety of cellular immune modulators, such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells (MDSC). In the peripheral blood of patients with advanced stage melanoma, there is an accumulation of CD14(+)HLA-DR(lo/-) MDSC that suppress autologous T cells ex vivo in a STAT-3-dependent manner. However, a precise mechanistic basis underlying this effect is unclear, particularly with regard to whether the MDSC induction mechanism relies on cell-cell contact of melanoma cells with CD14(+) cells. Here, we show that early-passage human melanoma cells induce phenotypic changes in CD14(+) monocytes, leading them to resemble MDSCs characterized in patients with advanced stage melanoma. These MDSC-like cells potently suppress autologous T-cell proliferation and IFN-γ production. Notably, induction of myeloid-suppressive functions requires contact or close proximity between monocytes and tumor cells. Further, this induction is largely dependent on production of cyclooxygenase-2 (COX-2) because its inhibition in these MDSC-like cells limits their ability to suppress T-cell function. We confirmed our findings with CD14(+) cells isolated from patients with advanced stage melanoma, which inhibited autologous T cells in a manner relying up prostaglandin E2 (PGE2), STAT-3, and superoxide. Indeed, PGE2 was sufficient to confer to monocytes the ability to suppress proliferation and IFN-γ production by autologous T cells ex vivo. In summary, our results reveal how immune suppression by MDSC can be initiated in the tumor microenvironment of human melanoma., (©2013 AACR.)