OBJECTIVE:Chemotherapy treatment modifications can impact survival in patients with ovarian cancer, particularly when the relative dose intensity falls below 85%. Exercise and dietary interventions may benefit treatment tolerability. This study aimed to explore the effects of a combined exercise and dietary intervention on secondary outcomes of the Physical Activity and Dietary intervention in OVArian cancer (PADOVA) trial, specifically relative dose intensity and progression-free survival. METHODS:81 patients with ovarian cancer were randomized into a combined supervised exercise and dietary intervention during (neo)adjuvant chemotherapy or a usual care control group. Relative dose intensity was calculated as the ratio of delivered dose intensity (dose per actual time) to the standard dose for six chemotherapy cycles. The effect on relative dose intensity was analyzed using logistic regression and Bayesian posterior probability of correctly identifying the best study arm. The effect on progression-free survival was examined using Cox regression. RESULTS:The proportion of patients achieving a relative dose intensity ≥85% was 74.4% in the intervention group compared with 61.5% in the control group (OR 2.04, 95% CI 0.75 to 5.84). The Bayesian posterior probability that the intervention group had a higher proportion of patients with a relative dose intensity ≥85% was 88.4%. Intervention effect on progression- free survival was not statistically significant (HR 1.63, 95% CI 0.82 to 3.23). At 18 months, the proportion of patients without disease progression was 73% in the intervention group and 51% in the control group. CONCLUSION:The proportions of patients with ovarian cancer with a relative dose intensity ≥85% and an 18-month progression-free survival were numerically higher in the intervention group compared with the control group, but these differences were not statistically significant. The higher proportions and the 88.4% probability that intervention is superior to usual care for clinical outcomes support future studies on exercise and dietary interventions with a focus on clinical outcomes as primary endpoints. TRIAL REGISTRATION NUMBER:Registered in the Netherlands Trial Registry (NTR6300).

PURPOSE There is an increasing interest in studying the potential of mobile health (mHealth) technologies, such as smartphone apps and wearables, as monitoring tools for patients with cancer during or after their treatment. However, little research is dedicated to exploring the opinions and concerns of patients regarding the adoption of these technologies. This study aimed to gain insight into patients' perspectives and preferences for participating in mHealth-based monitoring in cancer care. METHODS A qualitative study comprising semistructured interviews was conducted in the Netherlands between April and June 2023. Participants were eligible if they were 18 years or older with a current or past diagnosis of cancer. The interview guide was developed on the basis of the technology acceptance model, with main themes being use, communication, trust, privacy, and expectations. RESULTS Thirteen participants with urologic primary cancer were interviewed. Most patients had already some familiarity with the use of digital monitoring devices or wearables. Main barriers included persistent reminders of the illness, receiving notifications deemed unnecessary or unwanted, and the acknowledgment that mHealth technology does not serve as a substitute for human doctors. Conversely, patients recognized the potential for time-savings through the utilization of mHealth, viewed active monitoring as nonburdensome, considered mHealth a tool for reducing the communication threshold with their doctor, and expressed willingness to adopt such a platform if they perceived personal or societal relevance. CONCLUSION This study has elucidated which factors are important for successful development of mHealth for patients with cancer. While both barriers and facilitators play a role, patients' attitudes were positive toward the implementation of remote digital monitoring, showing promising prospects for future research of mHealth in oncology.

PURPOSE:Patients with cancer are prone to frequent unplanned hospital visits because of disease or treatment complications. Smartphone-based passive sensing (SBPS) comprises data collection using smartphone sensors or device usage patterns, which may be an affordable and burdenless technique for remote monitoring of patients with cancer and timely detection of safety events. The aim of this article was to systematically review the published literature to identify the current state of SBPS in oncology care and research.METHODS:A literature search was done with cutoff date July 29, 2022, using six different databases. Articles were included if they reported original studies using SBPS in patients with cancer or cancer survivors. Data extracted from studies included type of sensors used, cancer type, study objectives, and main findings.RESULTS:Twelve studies were included, the oldest report being from 2017. The most frequent of the nine analyzed sensors and smartphone analytics was the accelerometer (eight studies) and geolocation (eight studies), followed by call logs (two studies). Breast cancer was the most studied cancer type (eight studies with 111 patients), followed by GI cancers (six studies with 133 patients). All studies aiming for feasibility concluded that SBPS in oncology was feasible (seven studies). SBPS was used as a monitoring tool, with passively sensed data being correlated with adverse events, symptom burden, cancer-related fatigue, decision conflict, recovery trends after surgery, or psychosocial impact. SBPS was also used in one study as a predictive tool for health deterioration.CONCLUSION:SBPS shows early promise in oncology, although it cannot yet replace traditional tools to monitor quality of life and clinical outcomes. For this, validation of SBPS will be required. Therefore, further research is warranted with this developing technique.

The real-world results of chimeric antigen receptor T-cell (CAR-T) therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) substantially differ across countries. In the Netherlands, the CAR-T tumorboard facilitates a unique nationwide infrastructure for referral, eligibility assessment and data collection. The aim of this study was to evaluate real-world outcomes of axicabtagene ciloleucel (axi-cel) in the Dutch population, including the thus-far underreported effects on health-related quality of life (HR-QoL). All patients with R/R LBCL after ≥2 lines of systemic therapy referred for axi-cel treatment between May 2020–May 2022 were included (N = 250). Of the 160 apheresed patients, 145 patients received an axi-cel infusion. The main reason for ineligibility was rapidly progressive disease. The outcomes are better or at least comparable to other studies (best overall response rate: 84% (complete response: 66%); 12-month progression-free-survival rate and overall survival rate: 48% and 62%, respectively). The 12-month NRM was 5%, mainly caused by infections. Clinically meaningful improvement in several HR-QoL domains was observed from Month 9 onwards. Expert-directed patient selection can support effective and sustainable application of CAR-T treatment. Matched comparisons between cohorts will help to understand the differences in outcomes across countries and select best practices. Despite the favorable results, for a considerable proportion of patients with R/R LBCL there still is an unmet medical need.

Background: The emerging study of wearable devices (WDs) in patients with cancer provides opportunities to harness real-time patient data for predicting clinical outcomes. We conducted a systematic review with best evidence synthesis to examine the association between WD metrics and clinical outcomes in patients with cancer.Methods: MEDLINE and Embase were searched from inception until June 2022. Risk of bias assessment and best evidence synthesis were performed and, If possible, meta-analysis was conducted.Results: A total of 34 studies was included. We found moderate-to-strong evidence for associations between circadian rest-activity metrics and OS. Disrupted I2.08; 95 %CI: 1.50-2.88). For most associations there was insufficient evidence due to lack of studies (n = 32) or inconsistent results (n = 14).Conclusion: Meta-analysis was greatly hampered due to heterogeneity and different methodology used between studies. Studies primarily designed to investigate the association between WD metrics and clinical outcomes are warranted.

PURPOSE Prompt recognition of acute chimeric antigen receptor T (CAR T)-cell-mediated toxicities is crucial because adequate and timely management can prevent or reverse potential life-threatening complications. In the outpatient setting, patients and informal caregivers have to recognize and report signs and symptoms marking these acute toxicities. This study provides a core set of patient- and caregiver-reported signs and symptoms (outcomes, P/CROs) and definitions of red flags warranting immediate action to include in a daily checklist for support at home, with the goal to make outpatient post-CAR T-cell care safer, optimize patient and caregiver support, and thereby facilitating an early discharge/hospital visit reduction strategy. METHODS We performed a systematic review of phase II/III trials of US Food and Drug Administration-approved CAR T-cell products and selected all common and severe adverse events that could be translated into a P/CRO for inclusion in a two-round modified Delphi procedure. Eleven CAR T-cell-dedicated hematologists from the Dutch CAR T-cell tumorboard representing all treating centers selected P/CROs for inclusion in the core set and defined red flags. The final core set was evaluated with patients and caregivers. RESULTS From nine clinical trials, 457 adverse events were identified of which 42 could be used as P/CRO. The final core set contains 28 items, including five signs for measurement via wearables and two signs for caregiver-performed assessments. CONCLUSION This study provides a core set of P/CROs that can serve as a framework for (eHealth) tools that aim to enable patients and caregivers to more effectively recognize and report signs and symptoms of acute toxicities after CAR T-cell therapy, which will enhance safe outpatient treatment monitoring.

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Prompt recognition of acute chimeric antigen receptor T (CAR T)-cell-mediated toxicity is crucial, because adequate and timely management can prevent or reverse potential life-threatening complications. A mobile health (mHealth) app was developed to support outpatient monitoring after CAR T-cell infusion and provide instructions on when to contact the hospital. It allows patients and informal caregivers to recognize, evaluate and report signs and symptoms marking potential acute toxicities using wearable measurements, symptom reporting, and caregiver-performed assessments. Aims: This study evaluates the usability and perceived usefulness of aforementioned app to determine whether mHealth development by physicians suits the end-users monitoring needs in the outpatient setting after CAR T-cell infusion. Methods: A total of 12 patient experts, who had undergone CAR T-cell treatment with axicabtagene ciloleucel or brexucabtagene autoleucel for Diffuse Large B-cell Lymphoma (DLBCL) and Mantle Cell lymphoma (MCL), respectively, were included. All participants were in complete metabolic response and participated in think aloud usability sessions in which they performed 9 tasks using the app on their own smartphone. Think aloud sessions were recorded, transcribed and analyzed. Usability problems were rated in accordance with the Nielsen severity scale. Moreover, participants were asked to rate the usability of the app by completing the eHealth UsaBility Benchmarking Instrument (HUBBI, 0-5 scale). Satisfaction was evaluated on a 0-10 scale and with the Net Promotor Score. Results: Median age of participants was 60 years (range 53-70) and 67% were male. Mean time after CAR T-cell infusion was 19.7 months (range 1.9-49.8). Used smartphone operating systems were iOS (50%) and Android (50%). Mean task completion rate was 84% (range 67%-100%). In total, 26 unique usability problems were identified, of which 10 had severity ³3. The main usability problems concerned the navigation through the app (mainly iOS) and unintuitive layout design. Furthermore, 83% of participants found and understood the instructions page in the app. HUBBI scores are depicted in Figure 1. iOS users gave lower usability scores in all categories. All participants rated the perceived usefulness of the app as very high and would have liked to use the app if it had been available after their CAR T-cell infusion. Satisfaction was rated high on HUBBI (4.33), Net Promotor Score (+83) and overall satisfaction (9.0). Summary/Conclusion: This think aloud usability study showed that the physician-developed mHealhth app was considered valuable by patient experts and could meet their needs. Perceived usefulness and satisfaction were rated high. Difficulties in navigating the app impacted the usability scores and will be addressed for redesign. The positive results of this usability study show promise in implementing this app for future CAR T-cell patients and enhancement of safe outpatient treatment monitoring.Figure 1. Results of HUBBI subcategories for all participants and subdivided between iOS and Android users. Keywords: CAR-T

e13610 Background: Wearable activity trackers offer possibilities to harness real-time patient data for predicting clinical outcomes in patients with cancer during treatment with immune checkpoint inhibitors (ICIs). As a first step towards this purpose, we aimed to assess the feasibility of using wearable activity trackers to objectively measure physical activity levels during the course of treatment. Methods: Patients with advanced melanoma, scheduled to receive treatment with ICIs were eligible to participate in the Comprehensive Ambulatory Monitoring Platform during ImmunoTherapy (CAMP-IT) trial. Participants were instructed to wear a Fitbit Versa 2.0 during waking hours for 12 weeks after start of immunotherapy. Feasibility of Fitbit use was assessed using predefined goals regarding compliance (> 75% participants with > 75% wear days) and acceptability (satisfaction score > 75%). Weekly averages of daily steps were calculated. A valid wear week was defined as a week with a minimum of 4 valid wear days (> 100 steps) including at least 1 weekend day. Linear mixed models were used to examine the changes in mean daily steps during 12 weeks after treatment initiation. We currently analyzed data of the first 30 of the 50 patients that will be included in the trial. Results: Of the 30 patients that were currently included 57% was female and mean age was 57,3 (SD 9,7). Forty percent had metastatic disease, and 30% received treatment with combination ICI therapy. Ninety-six percent of patients was compliant with Fitbit use. Moreover, Fitbit use was rated as satisfactory by 86% of patients. Mean steps per day in week 1 was 6728 (SD 3405). Mean daily steps per week did not change significantly over time during the observation period (b = -13,3 (95% CI: -85,7 - 59,1); p = 0.72). Conclusions: This is the first prospective study that reports on the use of consumer-grade wearable activity trackers to objectively measure physical activity in advanced melanoma patients during treatment with ICIs. Our results suggest that the use of wearable activity trackers in these patients is feasible and that treatment with ICI does not impact physical activity levels during the first 12 weeks. Future research should investigate whether our results hold true for specific subgroups (e.g., patients that receive combination ICI therapy). Clinical trial information: NL8827.

Background Multidisciplinary team meetings formulate guideline-based individual treatment plans based on patient and disease characteristics and motivate reasons for deviation. Clinical decision trees could support multidisciplinary teams to adhere more accurately to guidelines. Every clinical decision tree is tailored to a specific decision moment in a care pathway and is composed of patient and disease characteristics leading to a guideline recommendation. Objective This study investigated (1) the concordance between multidisciplinary team and clinical decision tree recommendations and (2) the completeness of patient and disease characteristics available during multidisciplinary team meetings to apply clinical decision trees such that it results in a guideline recommendation. Methods This prospective, multicenter, observational concordance study evaluated 17 selected clinical decision trees, based on the prevailing Dutch guidelines for breast, colorectal and prostate cancers. In cases with sufficient data, concordance between multidisciplinary team and clinical decision tree recommendations was classified as concordant, conditional concordant (multidisciplinary team specified a prerequisite for the recommendation) and non-concordant. Results Fifty-nine multidisciplinary team meetings were attended in 8 different hospitals, and 355 cases were included. For 296 cases (83.4%), all patient data were available for providing an unconditional clinical decision tree recommendation. In 59 cases (16.6%), insufficient data were available resulting in provisional clinical decision tree recommendations. From the 296 successfully generated clinical decision tree recommendations, the multidisciplinary team recommendations were concordant in 249 (84.1%) cases, conditional concordant in 24 (8.1%) cases and non-concordant in 23 (7.8%) cases of which in 7 (2.4%) cases the reason for deviation from the clinical decision tree generated guideline recommendation was not motivated. Conclusion The observed concordance of recommendations between multidisciplinary teams and clinical decision trees and data completeness during multidisciplinary team meetings in this study indicate a potential role for implementation of clinical decision trees to support multidisciplinary team decision-making.

Importance Pancreatic cancer is the third most common cause of cancer death; however, randomized clinical trials (RCTs) of survival in patients with resectable pancreatic cancer lack mandatory measures for reporting baseline and prognostic factors, which hampers comparisons between outcome measures. Objective To develop a consensus on baseline and prognostic factors to be used as mandatory measurements in RCTs of resectable and borderline resectable pancreatic cancer. Evidence Review We performed a systematic literature search of the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and Embase for RCTs on resectable and borderline resectable pancreatic cancer with overall survival as the primary outcome. We produced a systematic summary of all baseline and prognostic factors identified in the RCTs. A Delphi panel that included 13 experts was surveyed to reach a consensus on mandatory and recommended baseline and prognostic factors. Findings The 42 RCTs that met inclusion criteria reported a total of 60 baseline and 19 prognostic factors. After 2 Delphi rounds, agreement was reached on 50 mandatory baseline and 20 mandatory prognostic factors for future RCTs, with a distinction between studies of neoadjuvant vs adjuvant treatment. Conclusion and Relevance This findings of this systematic review and international expert consensus have produced this Consensus Statement on Mandatory Measurements in Pancreatic Cancer Trials for Resectable and Borderline Resectable Disease (COMM-PACT-RB). The baseline and prognostic factors comprising the mandatory measures will facilitate better comparison across RCTs and eventually will enable improved clinical practice among patients with resectable and borderline resectable pancreatic cancer.

A case of chronic relapsing pancreatitis with pleural effusion on the left side is presented. During an acute exacerbation marked eosinophilia was observed which appeared to be related to the activity of the inflammatory process. Eosinophilia of a mild-to-marked degree was found in sixteen other cases of definite pancreatitis but no obvious relationship between eosinophilia and degree of activity (including amylase values) was found. No mention of a similar relationship between eosinophilia and pancreatitis was found in the literature.

Due to the COVID-19 pandemic, multidisciplinary team (MDT) meetings have to switch from physical to digital meetings. However, the technology they currently use to facilitate these meetings can sometimes be lacking, therefore many software companies have developed new software to ease our new digital workspace. In this study, we propose a new method, a comparative participatory cognitive walkthrough, which can show mismatches in cognitive models. To test our method, we tested the compatibility of EPIC EMR (EPIC Care) and the NAVIFY Tumor Board for preparing MDT meetings. The identified mismatches are categorized in the HOT-fit model by Yusof et al, a common way to evaluate if a healthcare information system fits with the healthcare professionals and the organization. In total, 16 mismatches were identified. These mismatches were discussed in a feedback session with an implementation manager of the NAVIFY Tumor Board. The proposed method seems to be a fast and cheap method to gain useful insights in how well new software matches with the software currently in use, by comparing the cognitive models in place when performing tasks involved with specific scenarios. The identified aspects can be of use for the development and adaptation of the new software, as well as provide guidelines on which aspects to focus on when training healthcare professionals to use the new software to have a smooth transition of software.

TPS1589 Background: The emergence of immune checkpoint inhibitors has improved survival outcomes for patients with advanced melanoma. However, these treatment modalities are also associated with specific immune-related toxicities. These are often reversible after prompt recognition and initiation of appropriate management, but can result in severe morbidity and hamper health-related quality of life (HRQoL) if left undetected. Hence, accurate and regular monitoring of these patients is critical. Recent advances in mHealth technologies and the rapidly expanding armamentarium of wearable devices allow for real-time objective (vital signs and physical activity) data and patient-reported outcome measurement (PROMs) collection and, hence, serve this purpose. We hypothesize that collection of real-time objective data adds to the early detection of disease- and treatment-related adverse events. The primary objective of this study is to determine the feasibility of collecting real-time PROMs, vital signs, and physical activity data in advanced melanoma patients receiving immunotherapy using a comprehensive ambulatory monitoring platform (CAMP) that consists of a smartphone app, activity monitor, digital thermometer, and online dashboard for physicians. Methods: In this prospective multi-center trial, patients (n = 50) with advanced melanoma, scheduled to receive immunotherapy with immune checkpoint inhibitors, and with access to a smartphone are eligible for inclusion. Consenting patients will be asked to wear a FitBit Versa 2.0 during waking hours, collect daily temperature measurements using a Withings Smart Temporal thermometer, and answer weekly toxicity questionnaires (NCI PRO-CTCAE) using the smartphone app for the duration of the study (12 weeks). Primary outcome is feasibility in terms of (i) participation rates, (ii) wear-time, (iii) compliance rates with in-app questionnaires and temperature measurements, and (iv) satisfaction with the platform. Secondary exploratory outcomes include associations between CAMP-derived parameters and clinical outcomes: performance status (PS), HR-QoL scores (EORTC QLQ-C30 questionnaire), unplanned hospitalizations, physician-assessed adverse events, and 1-year survival outcomes. PS and HR-QoL will be rated at baseline, mid-study, and end-of-study. The occurrence of adverse events will be documented up to 12 months from baseline. Survival outcomes will be compared to a propensity score matched group from the Netherlands Cancer Registry. Accrual has started in February 2021. Clinical trial information: NL8827.

Background: There is no consensus on the optimal systemic conversion therapy in patients with unresectable colorectal cancer liver-only metastases (CRLM) to achieve a complete resection. Interpretation of trials is complicated by heterogeneity of patients caused by emerging prognostic and predictive characteristics, such as RAS/BRAF mutation status, lack of consensus on unresectability criteria and lack of data on clinical outcome of secondary resections. A systematic review was performed of characteristics of study populations and methodology of trials regarding patients with initially unresectable colorectal cancer liver-only metastases. Methods: Phase II/III randomised trials, published after 2008, regarding first-line systemic conversion therapy in patients or subgroups of patients with CRLM were included. Data on secondary resection outcomes were collected. Results: Overall, 20 trials were included for analysis: seven prospective trials in patients with unresectable CRLM and 13 trials in the overall population of unresectable metastatic colorectal cancer (mCRC) with retrospective subgroup analysis of CRLM patients. Fourteen trials did not provide unresectability criteria at baseline, and criteria differed among the remaining studies. Trials and study populations were heterogeneous in prognostic/predictive factors, use of primary end-points, and reporting on long-term clinical outcomes. R0-resection rates in CRLM patients varied between CRLM studies and mCRC studies, with rates of 22-57% and 11-38%, respectively. Conclusions: Cross-study comparison of (subgroups of) studies regarding first-line systemic treatment in patients with unresectable CRLM is hampered by heterogeneity in study populations, trial designs, use of (K)RAS/BRAF mutational tumour status, and differences/absence of unresectability criteria. No optimal conversion systemic regimen can be selected from available data. Prospective studies with well-defined criteria of these issues are warranted. (C) 2020 Elsevier Ltd. All rights reserved.

Photodynamic therapy (PDT) is a tumor treatment modality in which a tumorlocalized photosensitizer is excited with light, which results in local production of reactive oxygen species, destruction of tumor vasculature, tumor hypoxia, tumor cell death, and induction of an anti-tumor immune response. However, pre-existing tumor hypoxia may desensitize tumors to PDT by activating the hypoxia-inducible factor 1 (HIF-1) survival pathway. Therefore, we hypothesized that inhibition of HIF-1 with acriflavine (ACF) would exacerbate cell death in human epidermoid carcinoma (A431) cells. PDT of A431 tumor cells was performed using newly developed and optimized PEGylated cationic liposomes containing the photosensitizer zinc phthalocyanine (ZnPC). Molecular docking revealed that ACF binds to the dimerization domain of HIF-1α, and confocal microscopy confirmed translocation of ACF from the cytosol to the nucleus under hypoxia. HIF-1 was stabilized in hypoxic, but not normoxic, A431 cells following PDT. Inhibition of HIF-1 with ACF increased the extent of PDT-induced cell death under hypoxic conditions and reduced the expression of the HIF-1 target genes VEGF, PTGS2, and EDN1. Moreover, co-encapsulation of ACF in the aqueous core of ZnPC-containing liposomes yielded an adjuvant effect on PDT efficacy that was comparable to non-encapsulated ACF. In conclusion, HIF-1 contributes to A431 tumor cell survival following PDT with liposomal ZnPC. Inhibition of HIF-1 with free or liposomal ACF improves PDT efficacy.

Background: Hepatic ischemia and reperfusion (I/R) is common in liver surgery and transplantation and compromises postoperative liver function.Hepatic I/R injury is characterized by sterile inflammation that contributes to hepatocellular necrosis.Many immune cells and cytokines have been implicated in hepatic I/R injury.However, the role and relevance of IL-23 and IL-17A remains controversial in literature.Aim: To determine whether the IL-23/IL-17A signaling axis is activated in hepatic I/R using a triple-level experimental approach (in vitro, in vivo, and clinical).Methods: IL-23 and IL-17A were assayed by ELISA in the supernatant fractions of cultured murine (RAW 264.7) macrophages that were activated by supernatant fractions of necrotic cultured mouse (AML12) hepatocytes.Similarly, levels of these cytokines were determined in plasma samples and liver tissue of mice (N = 85) subjected to partial (70%) liver I/R.Finally, IL-23 and IL-17A were assayed in plasma samples obtained from a controlled cohort of liver resection patients who were either subjected to I/R (N = 27) or not (N = 13).Results: Activated macrophages did not produce IL-23 in response to supernatant of necrotic AML12 hepatocytes.IL-23 and IL-17A were not elevated in mice subjected hepatic I/R and were not elevated in serum from patients subjected to I/R during liver resection.Conclusion: IL-23 and IL-17A are not involved in hepatic I/R injury in mouse and man.Relevance for patients: If IL-23 and IL-17A were to mediate hepatocellular injury following I/R, these cytokines would constitute potential therapeutic targets.Since this study has revealed that IL-23 and IL-17A do not play a role in hepatic I/R, other pathways and therapeutic targets should be considered when developing modalities aimed at reducing hepatic I/R injury.

Although photodynamic therapy (PDT) yields very good outcomes in numerous types of superficial solid cancers, some tumors respond suboptimally to PDT. Novel treatment strategies are therefore needed to enhance the efficacy in these therapy-resistant tumors. One of these strategies is to combine PDT with inhibitors of PDT-induced survival pathways. In this respect, the transcription factor nuclear factor κB (NF-κB) has been identified as a potential pharmacological target, albeit inhibition of NF-κB may concurrently dampen the subsequent anti-tumor immune response required for complete tumor eradication and abscopal effects. In contrast to these postulations, this study demonstrated that siRNA knockdown of NF-κB in murine breast carcinoma (EMT-6) cells increased survival signaling in these cells and exacerbated the inflammatory response in murine RAW 264.7 macrophages. These results suggest a pro-death and immunosuppressive role of NF-κB in PDT-treated cells that concurs with a hyperstimulated immune response in innate immune cells.

BACKGROUND:Acetaminophen (APAP) hepatotoxicity is a major cause of acute liver failure in many countries. Mechanistic studies in mice and humans have implicated formation of a reactive metabolite, mitochondrial dysfunction and oxidant stress as critical events in the pathophysiology of APAP-induced liver cell death. It was recently suggested that ATP released from necrotic cells can directly cause cell death in mouse hepatocytes and in a hepatoma cell line (HepG2).AIM:To assess if ATP can directly cause cell toxicity in hepatocytes and evaluate their relevance in the human system.METHODS:Primary mouse hepatocytes, human HepG2 cells, the metabolically competent human HepaRG cell line and freshly isolated primary human hepatocytes were exposed to 10-100 µM ATP or ATγPin the presence or absence of 5-10 mM APAP for 9-24 h.RESULTS:ATP or ATγP was unable to directly cause cell toxicity in all 4 types of hepatocytes. In addition, ATP did not enhance APAP-induced cell death observed in primary mouse or human hepatocytes, or in HepaRG cells as measured by LDH release and by propidium iodide staining in primary mouse hepatocytes. Furthermore, addition of ATP did not cause mitochondrial dysfunction or enhance APAP-induced mitochondrial dysfunction in primary murine hepatocytes, although ATP did cause cell death in murine RAW macrophages.CONCLUSIONS:It is unlikely that ATP released from necrotic cells can significantly affect cell death in human or mouse liver during APAP hepatotoxicity.RELEVANCE FOR PATIENTS:Understanding the mechanisms of APAP-induced cell injury is critical for identifying novel therapeutic targets to prevent liver injury and acute liver failure in APAP overdose patients.

Contemporary photodynamic therapy (PDT) for the last-line treatment of refractory cancers such as nasopharyngeal carcinomas, superficial recurrent urothelial carcinomas, and non-resectable extrahepatic cholangiocarcinomas yields poor clinical outcomes and may be associated with adverse events. This is mainly attributable to three factors: (1) the currently employed photosensitizers exhibit suboptimal spectral properties, (2) the route of administration is associated with unfavorable photosensitizer pharmacokinetics, and (3) the upregulation of survival pathways in tumor cells may impede cell death after PDT. Consequently, there is a strong medical need to improve PDT of these recalcitrant cancers. An increase in PDT efficacy and reduction in clinical side-effects may be achieved by encapsulating second-generation photosensitizers into liposomes that selectively target to pharmacologically important tumor locations, namely tumor cells, tumor endothelium, and tumor interstitial spaces. In addition to addressing the drawbacks of clinically approved photosensitizers, this review addresses the most relevant pharmacological aspects that dictate clinical outcome, including photosensitizer biodistribution and intracellular localization in relation to PDT efficacy, the mechanisms of PDT-induced cell death, and PDT-induced antitumor immune responses. Also, a rationale is provided for the use of second-generation photosensitizers such as diamagnetic phthalocyanines (e.g., zinc or aluminum phthalocyanine), which exhibit superior photophysical and photochemical properties, in combination with a multi-targeted liposomal photosensitizer delivery system. The rationale for this PDT platform is corroborated by preliminary experimental data and proof-of-concept studies. Finally, a summary of the different nanoparticulate photosensitizer delivery systems is provided followed by a section on phototriggered release mechanisms in the context of liposomal photosensitizer delivery systems. (C) 2015 Elsevier B.V. All rights reserved.