Localized Solid Tumors Research Articles

Lipid Nanoparticles for Brain Tumor Theranostics: Challenges and Status.

Lipid nanoparticles have been recognized as a powerful weapon for delivering various imaging and therapeutic agents to the localized solid tumors, especially brain tumors individually or in combination. Promisingly, lipid-based nanosystems have been considered as safe delivery systems which are even approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). One recent spotlight of lipid nanoparticles as COVID-19 mRNA vaccines where lipid nanoparticles play an important role in effectively protecting and delivering mRNA to the desired cells. As of now, successive progress in lipid-based nanocarriers, viz., nanoliposomes, solid lipid nanoparticles, ionizable lipid nanostructures, etc., with better biochemical and biophysical stabilities, has been noticed and reported. Moreover, lipid nanostructures have been considered as versatile therapeutics platforms for a variety of diseases due to their biocompatibility, ability to protect and deliver therapeutics to the localized site, and better reproducibility and reliability. However, lipid nanoparticles still face morphological and biochemical changes upon their in vivo administration. These changes alter the specific biological and pathological response of lipid nanoparticles during their personalized brain tumor theranostics. Second, lipid nanomedicine still faces major challenges of zero premature leakage of loaded cargo, long-term colloidal stability, and off targeting. Herein, various lipid-based nanomedicines for brain tumor imaging and therapeutics "theranostics" have been reviewed and summarized considering major aspects of preclinical and clinical studies. On the other hand, engineering and biological challenges of lipid theranostics systems with relevant advantages and guidelines for clinical practice for different brain tumors have also been discussed. This review provides in-depth knowledge of lipid nanoparticle-based theranostics agents for brain tumor imaging and therapeutics.

From sutureless to standard: a comprehensive analysis of conversion rates in laparoscopic partial nephrectomy

ObjectiveTo assess the rate at which sutureless partial nephrectomy (SLPN) transitions to standard partial nephrectomy (SPN), focusing on preoperative factors that might prompt such conversions.Patients and methodsIn this retrospective study, we analyzed the efficacy of SLPN performed on adults at our institution from 2016 to 2023. The subjects were patients diagnosed with localized solid renal tumors. The primary technique employed was resection with scissors and argon beam coagulation for hemostasis, with suturing techniques used only when necessary. Predictive factors necessitating conversion to SPN were identified, and the associations among multiple variables were explored using various statistical analysis methods, including logistic regression, to identify key preoperative predictive factors.ResultsOur institution performed 353 SLPN, with 21 cases (5.9%) necessitating conversion to SPN. The conversion rates for the Laparoscopic Partial Nephrectomy (LPN) subgroup and the Robotic-assist Partial Nephrectomy (RPN) subgroup were 7.9% (17/215) and 2.9% (4/138), respectively, nearing statistical significance (P = .066). Significant differences were observed between the conversion group and the no conversion group in terms of preoperative estimated Glomerular Filtration Rate (eGFR), age at surgery, tumor size, and exophytic/endophytic characteristics. Multivariate analysis identified age at surgery, preoperative eGFR, radiological tumor size, and tumor exophytic/endophytic nature as significant predictors for conversion to SPN.ConclusionThis investigation highlights the efficacy and feasibility of SLPN while identifying critical factors influencing the necessity for conversion to SPN. The identified predictors, including younger surgical age, superior preoperative eGFR, and specific tumor characteristics, provide valuable insights for refining surgical strategies.

Dabrafenib protects from cisplatin-induced hearing loss in a clinically relevant mouse model.

The widely used chemotherapy cisplatin causes permanent hearing loss in 40%-60% of patients with cancer. One drug, sodium thiosulfate, is approved by the FDA for use in pediatric patients with localized solid tumors for preventing cisplatin-induced hearing loss, but more drugs are desperately needed. Here, we tested dabrafenib, an FDA-approved BRAF kinase inhibitor and anticancer drug, in a clinically relevant multidose cisplatin mouse model. The protective effects of dabrafenib, given orally twice daily with cisplatin, were determined by functional hearing tests and cochlear outer hair cell counts. Toxicity of the drug cotreatment was evaluated, and levels of phosphorylated ERK were measured. A dabrafenib dose of 3 mg/kg BW, twice daily, in mice, was determined to be the minimum effective dose, and it is equivalent to one-tenth of the daily FDA-approved dose for human cancer treatment. The levels of hearing protection acquired, 20-25 dB at the 3 frequencies tested, in both female and male mice, persisted for 4 months after completion of treatments. Moreover, dabrafenib exhibited a good in vivo therapeutic index (> 25), protected hearing in 2 mouse strains, and diminished cisplatin-induced weight loss. This study demonstrates that dabrafenib is a promising candidate drug for protection from cisplatin-induced hearing loss.

Home parenteral nutrition (HPN) using individually compounded PN via A 7/8/9-Multi-chamber system versus PN via 2/3-chamber bags in subjects with metastatic or localized solid tumors requiring HPN - The IKF-010 Pekannuss trial

Home parenteral nutrition (HPN) using individually compounded PN via A 7/8/9-Multi-chamber system versus PN via 2/3-chamber bags in subjects with metastatic or localized solid tumors requiring HPN - The IKF-010 Pekannuss trial

OTHR-08. MULTIDISCIPLINARY APPROACH TO PAEDIATRIC BRAIN CANCER BIO-BANKING IMPROVES ENROLLMENT, FACILITATES DISCOVERY RESEARCH, AND ENABLES BETTER ACCESS TO DIAGNOSTIC AND THERAPEUTIC STUDIES

Abstract Despite the significant progress made in the multi-modal treatment of childhood malignancies over the last four decades with a concomitantly increased cure rates, the benefit is still largely limited to patients with leukemias, lymphomas and localized non-CNS solid tumors, leaving patients with high-risk non-CNS solid tumours and most CNS malignancies with minimal advancements. More research is critical to understand what drives these cancers and to investigate the best ways to deliver curative therapies. Translational research relies on patient-derived tissue samples, animal models and cell-cultures to understand the biological, genetic, and molecular mechanisms of disease. To facilitate patient care and outcomes it is becoming increasingly important that paediatric clinical trials include tissue availability as part of eligibility criteria, making collection and storage of patient tissue a mandate of personalized medicine and a pillar of modern paediatric cancer medicine. Monash Children’s Cancer Biobank was established in 2011. Since 2017, a total of 64 patients were diagnosed with CNS malignancies across all grades, with an overall 69% of patients’ tissues being bio-banked at the time of initial diagnosis. Through the combination of an educational forum, regular multi-disciplinary meetings, and the early involvement of medical oncology and biobank staff, with our neurosurgical and clinical pathology colleagues, as part of patient management planning, the tissue acquisition for bio-banking increased from 44% to 82% over the course of 5 years. This consequently led to a 100% enrollment to tissue-enabling studies allowing for banking of both fresh-frozen tissue and living cell-line models, facilitating discovery research efforts as part of the Victorian Paediatric Cancer Consortium’s molecular analysis pipeline (https://vicpcc.org.au/dashboard). This significantly improves opportunities for identification of targetable pathways, access to targeted therapies, enrollment onto treatment clinical trials and identification of patients with cancer predisposition syndromes.

Home parenteral nutrition (HPN) using individually compounded PN administered via multi-chamber Eurotubes versus PN administered via 2/3-chamber bags in patients with metastatic or localized solid tumors requiring HPN: The randomized IKF-010 PEKANNUSS trial of AIO.

e24123 Background: Cancer patients (pts) often experience malnutrition and some of them require HPN. However, HPN is associated with challenges, including the need for nursing service to prepare PN bags and add supplements, severely limiting patient autonomy and flexibility. Moreover, HPN is a major risk factor for catheter-related infections (CRI). Eurotubes is a 7/8/9-multi-chamber system that offers fully individualized PN compounding without need for further line or bag manipulation outside GMP environment. This study evaluates whether HPN via Eurotubes improves patient autonomy compared with HPN via traditional 2/3-chamber bags. Methods: This is a randomized, multicenter, investigator-initiated, phase IV trial. Pts with metastatic/locally advanced tumors and need for HPN were stratified according to ECOG PS, the modified Glasgow Prognostic Score (mGPS) and concurrent systemic treatment and randomized 2:1 to receive HPN via Eurotubes (Arm A) or HPN via 2/3-chamber bags (Arm B). Primary endpoint was patient autonomy defined as the proportion of pts with ≥70% of HPN administrations done without nursing service assistance (self-administration or with help of relatives) as provided in pts diaries in the intent to treat population (ITT). A total of 192 pts were required to show a significant improvement in proportions of pt autonomy from 5 to 20% (80% power; 2-sided α < .05 [Fisher’s exact]). Secondary endpoints included CRI, safety, body weight and serum albumin. Results: Study was terminated for slow recruitment after enrollment of 142 pts of which 131 pts qualified for ITT. Baseline criteria were well balanced regarding ECOG PS, body weight, albumin, mGPS, and nutritional risk score, but more pts in Arm A had metastatic disease (78% vs 61%). In median, pts received HPN for 48 days (1 - 320 days) and median cumulative macronutrients of glucose, 3805g; amino acids, 2100g; and lipids, 2250g. Injections of additional supplements into PN bag at home were required in 11% v 96% of pts for Arm A vs B (p < .01). The primary endpoint was met, with patient autonomy being 52% vs 33% in Arm A vs B (p = .04) and the difference was more pronounced in pts with ECOG PS ≤1 (68% vs 42%). Relative changes in body weight and serum albumin favored the Arm A until visit 5. All grade adverse events related to HPN were lower in Arm A (27% vs 55%; p < .01) as were CRI rates (13% vs 22%; p = .22). Device deficiency (8% vs 7%) and PN related death (1% vs 2%), and median overall survival (6.6 vs 6.8 months) were similar. Conclusions: Eurotubes significantly improved patient autonomy, compared with 2/3-chamber bags and were associated with significantly less HPN-related adverse events. HPN via Eurotubes represents a treatment option that is safe and renders pts more able to self-manage their treatment. Clinical trial information: NCT04105777 .

The role of DWI MRI for differential diagnostic of solid renal tumors

Introduction. Currently, CT and MRI do not reliably differentiate oncocytoma, angiomyolipoma with minimal fat and renal cell carcinoma, and therefore most patients with localized solid renal tumors undergo surgical treatment. Identification of differential signs of benign formations according to imaging methods would make it possible to change the therapeutic tactics in more than a third of cases in patients with newly diagnosed small renal masses (less than 4 cm).Purpose. The aim of the study was to evaluate the diagnostic efficacy of diffusion-weighted MRI (DWI) in the differential diagnosis of solid renal masses.Materials and methods. А prospective study, which included 90 patients aged 34 to 79 years with primary solid renal masses who were examined and treated at the Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation was conducted in the period from February 2019 to October 2021. Before surgery, all patients underwent MRI of the retroperitoneal organs using DWI with b-factors of 0–800 s/mm2 and 0–1000 s/mm2. The diffusion coefficient was quantified on two ADC maps for renal masses of various histological types and the obtained values were compared with each other.Results. According to the results of the statistical analysis, the values of the diffusion coefficient for benign tumors were significantly higher than for RCC (p < 0.05). There was no statistically significant difference between clear cell, chromophobe and papillary types of RCC in terms of diffusion coefficient both at b-factors of 0–800 s/mm2 and at 0–1000 s/mm2.Conclusion. Using DWI we can suggest a benign genesis of a solid renal mass. Differential signs for RCC of various histological types according to diffusion-weighted images were not identified.

OTHR-30. Multidisciplinary approach to childhood cancer bio-banking improves enrollment and enables better access to diagnostic and therapeutic studies

Abstract Despite the significant progress made in the multi-modal treatment of childhood malignancies over the last four decades with a concomitantly increased cure rates, the benefit is still largely limited to patients with leukemias, lymphomas and localized non-CNS solid tumors, leaving patients with high-risk non-CNS solid tumours and most CNS malignancies with minimal advancements. More research is critical to understand what drives these cancers and to investigate the best ways to deliver curative therapies. Translational research relies on patient-derived tissue samples, animal models and cell-cultures to understand the biological, genetic, and molecular mechanisms of disease. To facilitate patient care and outcomes, it is becoming increasingly important that paediatric clinical trials include tissue availability as part of eligibility criteria, making collection and storage of patient tissue a mandate of personalised medicine and a pillar of modern paediatric cancer medicine. Monash Children’s Cancer Biobank was established in 2011. Since 2017, a total of 64 patients were diagnosed with CNS malignancies across all grades, with an overall 69% of patients’ tissues being biobanked at the time of initial diagnosis. A co-ordinated, multidisciplinary approach to biobanking is crucial to the success of tissue acquisition. Through the combination of an educational forum, regular neuro-surgical multi-disciplinary meetings, and the early involvement of medical oncology and biobank staff, with our neurosurgical and clinical pathology colleagues, as part of patient management planning, the tissue acquisition for biobanking increased from 44% to 82% over the course of 5 years. This consequently led to a 100% enrolment to tissue-enabling studies, significantly improving identification of targetable molecular lesions, enrolment onto treatment clinical trials and identification of patients with cancer predisposition syndromes.

Targeting Myeloid-Derived Suppressor Cells Derived From Surgical Stress: The Key to Prevent Post-surgical Metastasis.

Myeloid-derived suppressor cells (MDSCs) are known to play an essential part in tumor progression under chronic stress settings through their manipulation of adaptive and innate immune systems. Previous researches mainly focus on MDSC's role in the chronic tumor immune environment. In addition, surgery can also serve as a form of acute stress within the patient's internal environment. Nevertheless, the part that MDSCs play in post-surgical tumor development has not gained enough attention yet. Although surgery is known to be an effective definite treatment for most localized solid tumors, there are still plenty of cancer patients who experience recurrence or metastasis after radical resection of the primary tumor. It is believed that surgery has the paradoxical capability to enhance tumor growth. Many possible mechanisms exist for explaining post-surgical metastasis. We hypothesize that surgical resection of the primary tumor can also facilitate the expansion of MDSCs and their pro-tumor role since these surgery-induced MDSCs can prepare the pre-metastatic niche (the “soil”) and at the same time interact with circulating tumor cells (the “seeds”). This vicious, reciprocal mechanism is a crucial point in the emergence of post-surgical metastasis. According to our hypothesis, MDSCs can be the precise target to prevent cancer patients from post-surgical recurrence and metastasis during the perioperative phase to break the wretched cycle and provide better long-term survival for these patients. Future studies are needed to validate this hypothesis.

1758O Neoadjuvant pembrolizumab in localized/locally advanced solid tumors with mismatch repair deficiency

Pembrolizumab (pembro) significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors. This study evaluates pembro in the neoadjuvant space with the potential for an organ-sparing approach. This is a phase 2 open-label, single center trial of MSI-H/dMMR non-metastatic solid tumors with localized unresectable or high risk resectable (defined as ≥ 20% recurrence) with measurable disease. Treatment is Pembro 200mg every 3 wks for 8 cycles followed by surgical resection with option to continue therapy for 18 cycles followed by observation. First restaging is at 6 wks and includes baseline and 3-week 70-gene ctDNA assessment. To continue on study, patients are required to have PR/CR, SD with tumor shrinkage or SD with decline in ctDNA. The co-primary endpoints are safety and pathological complete response (pCR). Key secondary endpoints are response rate and organ-sparing at one year for patients who declined surgery. Between 10/2019 and 3/2021, 35 pts were enrolled and study has completed enrollment. Tumor types included 27 CRC and 8 non-CRC: endometrial, gastric, meningioma, 2 duodenal, ampullary and 2 pancreatic. Median follow-up was 9 months (range 0.1 - 17). Among 32 evaluable pts, best ORR was 75% (CR 25% , PR 50%), SD 22% and PD 3%. Luminal endoscopic response was seen in 17/19 (89%) pts. Among 8 (23%) pts who underwent surgery, pCR was seen in 4. At present non-operative approach was chosen by 8 (23%) pts with 1-year organ-sparing seen in 2/2 evaluable pts. Treatment-related grade 3/4 immune adverse events were seen in 3 (9%) pts (transaminitis, diarrhea and type 1 diabetes). Baseline ctDNA mutations were present in 20 (57%) pts and at 3 weeks declined in 15 (75%), unchanged in 1, no paired 3 week sample in 1, and increased in 3. Tumor microenvironment immune analysis is ongoing and will be presented. Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of radiographic and endoscopic response which has implications for organ-sparing strategies. Non-operative management of dMMR/MSI-H localized solid tumors should be further investigated.

Safety and efficacy of neoadjuvant pembrolizumab in mismatch repair deficient localized/locally advanced solid tumors.

2520 Background: Pembrolizumab (Pembro), anti-PD1 therapy, is FDA approved for refractory microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) advanced/metastatic solid tumors. The robust activity of anti-PD1 therapy in these tumors argues for a neoadjuvant organ-sparing approach. However, the role of anti-PD1 monotherapy in the neoadjuvant setting is unknown. Methods: This is a phase 2 open-label, single center trial (NCT04082572) of MSI-H/dMMR non-metastatic solid tumors with localized unresectable or high risk resectable (defined as ≥ 20% recurrence) with measurable disease per RECISTv1.1 and ECOG PS 0/1. Treatment is Pembro 200mg every 3 wks for 8 cycles (6 months) followed by surgical resection with option to continue therapy for 18 cycles (12 months) followed by observation. First restaging is at 6 wks and includes baseline and 3-week 70-gene ctDNA assessment. To continue on study, patients are required to have PR/CR, SD with tumor shrinkage or SD with decline in ctDNA [highest variant allele frequency (VAF) baseline mutation]. The co-primary endpoints are safety and pathological complete response (pCR). Key secondary endpoints are response rate and organ-sparing at one year for patients who declined surgery. Results: Between 12/2019 and 2/2021, 32 pts were enrolled and treated. Enrolment goal of 35 anticipated to be met by 4/2021. Baseline characteristics included 13 females, median age of 63 yrs (range 26 - 91), Lynch syndrome in 12 pts, BRAF V600E mutation in 11 pts. Tumor type included 24 CRC and 8 non-CRC (1 endometrial, 1 gastric, 1 meningeal, 2 duodenal, 1 ampullary, 2 pancreatic). At baseline disease was resectable in 23 (72%). Among 30 evaluable pts, best overall response rate was 77%: 30% CR (n = 9), 47% PR (n = 14), 20% SD (n = 6), 3% PD (n = 1). Only one pt progressed after initial SD of -18%. Median follow-up is 6.1 months (range 0.1 - 14). Among the 6 (20%) pts who underwent surgery, pCR was seen in 3 (50%). A non-operative approach (pembro for 12 months) has been chosen in 15 pts and 1-year organ-sparing was seen in 2/2 evaluable pts. Treatment-related grade 3/4 immune adverse events (TRAE) were seen in 3 (9%) pts: grade 3 immune hepatitis (2) and grade 3 type 1 diabetes (1). Baseline ctDNA was positive in 17 (53%) pts with a median of 4 mutations per pt (1 - 35) and median highest VAF of 0.9% (range 0.3% to 38.2%). Among 26 pts with successful tumor tissue testing, median tumor mutations were 10.5, range 1 to 21 (Oncomine 134 gene panel). ctDNA decline at 3 weeks was seen in 14/17 (82%) patients. Luminal disease was present in 24 pts with endoscopic response of: CR in 13 (54%), major response 1, pending follow-up evaluation 6, not evaluated 3, and no response in 1. Conclusions: Neoadjuvant pembrolizumab is safe with encouraging clinical activity and this data suggests that a non-operative management for dMMR/MSI-H localized solid tumors should receive further investigation. Clinical trial information: NCT04082572.

#53: High Burden of Serious Bacterial Infections in African Children Treated for Cancer

Abstract Background Infectious complications in children treated for cancer contribute to their morbidity and mortality. There is a paucity of studies on the incidence, microbiological etiology, risk factors, and outcome of serious bacterial infections in African children treated for cancer. Aim The aim of the study was to delineate the epidemiology of infectious morbidity and mortality in South African children with cancer. Methods This prospective, single-center, longitudinal-cohort study enrolled children one-19 years old hospitalized for cancer treatment at the Paediatric Oncology Unit, Chris Hani Baragwanath Academic Hospital, Soweto, South Africa. Children were investigated for infection as part of the standard of care. Results In total, 169 children were enrolled, 82 with hematological malignancy (HM), 87 with a solid tumor (ST), median age was 68.5 months and 10.7% were living with HIV. The incidence (per 100 child-years) of septic episodes (SE) and microbiologically confirmed SE (MSCE) was 101 (138 vs. 70, P < 0.001) and 70.9 (99.1 vs. 47.3; P < 0.001), respectively; higher in children with HM than ST. The incidence of MCSE in children with high-risk HM (137.7) was 4.32-fold greater compared with those with medium-risk HM (30.3; P < 0.001). Children with metastatic ST had a higher incidence (84.4) of MSCE than those with localized ST (33.6; aOR: 2.52; P < 0.001). The presence of an indwelling catheter was 3-fold (P < 0.001) more likely to be associated with MCSE compared with those without. There was no association for age group, nutritional status or HIV-status, and incidence of MCSE. The incidence of gram-positive (GPB) and gram-negative (GNB) SEs was 48.5 and 37.6, respectively, and higher in children with an HM. The most commonly identified GPB were Coagulase-negative Staphylococci, Streptococcus viridans and Enterococcus faecium; while the most common GNB were Escherichia coli, Acinetobacter baumannii, and Pseudomonas species. The median CRP was higher in children with MSCE compared with those with culture-negative SE (CNSE) (116.5 vs. 92; P < 0.001) in both HM (132.5 vs. 117; P < 0.001) and ST (87.5 vs. 46; P < 0.001). The procalcitonin was higher in those with MSCE compared with those with CNSE (2.30 vs. 1.40; P < 0.001) in both HM (2.95 vs. 1.60; P = 0.002) and ST (2.10 vs. 1.20; P < 0.001). The case fatality risk was 40.4%; 80% was attributed to sepsis. Of these, 35 (72.92%) had HM and 34 of the 35 (97.14%) had HR-HM. Children with HM had an overall sepsis CFR of 42.68%. Four (30.77%) of the 13 sepsis-related deaths in STs had metastatic disease and 8 (16.67%) of the total number of sepsis-related deaths were in children living with HIV. There was no association between malnutrition or HIV-positivity and death. The odds of dying from sepsis were higher in children with profound (aOR 3.96; P = 0.004) and prolonged (aOR 3.71; P = 0.011) neutropenia. Pneumonia (58.85% vs. 29.23%; aOR 2.38; P = 0.025) and tuberculosis (70.83% vs. 34.91%; aOR 4.3; P = 0.005) were independently associated with a higher CFR. Conclusion The current study emphasizes the high burden of sepsis in African children treated for cancer, and especially HM, and highlights the association of tuberculosis and pneumonia as independent predictors of death in children with cancer.

Red blood cell transfusions and the survival in patients with cancer undergoing curative surgery: a systematic review and meta-analysis.

Allogenic red blood cell transfusions exert a potential detrimental effect on the survival when delivered to cancer patients undergoing surgery with curative intent. We performed a systematic review and meta-analysis to assess the association between perioperative allogenic red blood cell transfusions and risk of death as well as relapse after surgery for localized solid tumors. PubMed, the Cochrane Library, and EMBASE were searched from inception to March 2019 for studies reporting the outcome of patients receiving transfusions during radical surgery for non-metastatic cancer. Risk of death and relapse were pooled to provide an adjusted hazard ratio with a 95% confidence interval [hazard ratio (HR) (95% confidence interval {CI})]. Mortality and relapse associated with perioperative transfusion due to cancer surgery were evaluated among participants (n = 123 studies). Overall, RBC transfusions were associated with an increased risk of death [HR = 1.50 (95% CI 1.42-1.57), p < 0.01] and relapse [HR = 1.36 (95% CI 1.26-1.46), p < 0.01]. The survival was reduced even in cancer at early stages [HR = 1.45 (1.36-1.55), p < 0.01]. In cancer patients undergoing surgery, red blood cell transfusions reduced the survival and increased the risk of relapse. Transfusions based on patients' blood management policy should be performed by applying a more restrictive policy, and the planned preoperative administration of iron, if necessary, should be pursued.

Abstract 4069: Selective ablation of solid tumors using a p53-targeted FAST-LNP gene therapy

Abstract While chemotherapy is a key treatment strategy for many solid tumors, it is rarely curative as patients will eventually become resistant. In this study, we sought to develop an effective suicide gene therapy approach for solid tumors that specifically exploits their unique transcriptional activation state. The tumor suppressor p53 is frequently mutated or dysregulated in cancer, and as a result the upstream signaling pathways activating p53 transcription are strongly upregulated. RNA-seq analysis has demonstrated that p53 transcription is significantly upregulated in almost all forms of cancer. Additionally, HCT116 cells lacking functional p53 display a 6-fold increase in p53 promoter activity when compared to its wild type p53 parent cell line. To exploit this, we have developed a Fusogenix FAST-LNP formulation to deliver a p53-driven inducible suicide gene, iCasp9, to solid tumors and destroy them upon activation with small molecule dimerizer, Rapamycin. To establish a proof-of-concept, plasmid encoding iCasp9 and luciferase under control of the p53 promoter was constructed and evaluated in a panel of cancer cell lines. While LNPs administered without Rapamycin or Rapamycin administered alone had no impact on cell viability, we observed greater than 90% apoptotic cell death when both were employed in a wide range of cancer cell lines with p53 deletions or mutations, as measured using cell viability assays, imaging assays, as well as Annexin V and TUNEL flow cytometry. Induction of iCasp9 protein expression and caspase-mediated apoptosis was confirmed using Western blot. No cell death was observed in cells with intact p53 such as human umbilical vein endothelial cells or the fibroblast cell line IMR-90. Next, we assessed the efficacy of FAST-LNPs containing p53-iCasp9 in xenograft PC-3 and H1299 models of human prostate cancer and lung cancer respectively. In some experiments, tumors were implanted subcutaneously in the flanks of 30 mice and allowed to grow to 500 mm3 before treatment by intravenous doses of 100 µg LNP twice per week during continuous low dosing of Rapamycin. We observed a rapid and dramatic reduction in tumor volume averaging 87% over the following 48 hours, with durable response. Tumors in control mice continued to grow exponentially. Overall survival of mice was extended 250% in the PC-3 cohort and 300% in the H1299 cohort. Optimization of number and concentration of LNP doses should allow for long term control of both localized and systemic disease. In conclusion, we describe a novel LNP gene therapy approach for the treatment of cancer with high selectivity for tumors with dysregulated p53 transcriptional activation. This approach has the potential to provide a highly efficacious alternative to current therapies for localized and advanced solid tumors. Citation Format: Douglas Wilson Brown, Arun Raturi, Prakash Bhandari, Deborah Sosnowski, Liliya Grin, Ping Wee, Hector Vega, Jennifer Gyoba, Maryam Hejazi, Jailal Ablack, Matthew Scholz, John D. Lewis. Selective ablation of solid tumors using a p53-targeted FAST-LNP gene therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4069.

Near-infrared stimulated hydrogel patch for photothermal therapeutics and thermoresponsive drug delivery

Nanotechnology driven cancer theranostics hold potential as promising future clinical modalities. Currently, there is a strong emphasis on the development of combinational modalities, especially for cancer treatment. In this study, we present a topical hydrogel patch for nanomaterial-assisted photothermal therapeutics as well as for on-demand drug delivery application. The patch was derived from interpenetrating networks (IPNs) of alginate (Alg) and polyacrylamide (PAAm) in weight ratio 8:1 by free radical polymerization. The patch interiors were composed of hybrid nanostructures derived from gold nanorods (AuNRs) anchored onto polyvinylpyrrolidone (PVP) functionalized graphene oxide (PVP-nGO) to form PVP-nGO@AuNRs hybrids. Field emission scanning electron microscopy (FE-SEM) images revealed the porous nature of the hybrid hydrogel patch with an average pore size of ~28.60 ± 3.10 μm. Besides, functional characteristics of the hybrid patch, such as mechanical strength, viscoelastic and swelling behavior, were investigated. Under near-infrared (NIR) radiation exposure, the hybrid patch exhibited photothermal properties such as surface temperature rise to 75.16 ± 0.32 °C, sufficient to ablate cancer cells thermally. Besides, the heat generated in the hybrid patch could be transmitted to an underlying hydrogel (mimicking skin tissue) when stacked together without much loss. Under cyclic photothermal heating, the patch could retain its photothermal stability for four cycles. Furthermore, the hybrid patch demonstrated NIR stimulated drug release, which was evaluated using methotrexate (MTX, water-insoluble anticancer drug) and rhodamine B (RhB, water-soluble dye). Taken together, this work provides a new dimension towards the development of externally placed hydrogel patches for thermal destruction of localized solid tumors and tunable delivery of chemotherapeutic drugs at the target site.

A Bioinformatic Approach for the Identification of Molecular Determinants of Resistance/Sensitivity to Cancer Thermotherapy.

Application of heat above 43°C and up to 47°C, the so-called “thermal ablation” range, leads to tumor cell destruction either by apoptosis or by necrosis. However, tumor cells have developed mechanisms of defense that render them thermoresistant. Of importance, the in situ application of heat for the treatment of localized solid tumors can also prime specific antitumor immunity. Herein, a bioinformatic approach was employed for the identification of molecular determinants implicated in thermoresistance and immunogenic cell death (ICD). To this end, both literature-derived (text mining) and microarray gene expression profile data were processed, followed by functional enrichment analysis. Two important functional gene modules were detected in hyperthermia resistance and ICD, the former including members of the heat shock protein (HSP) family of molecular chaperones and the latter including immune-related molecules, respectively. Of note, the molecules HSP90AA1 and HSPA4 were found common between thermoresistance and damage signaling molecules (damage-associated molecular patterns (DAMPs)) and ICD. In addition, the prognostic potential of HSP90AA1 and HSPA4 overexpression for cancer patients' overall survival was investigated. The results of this study could constitute the basis for the strategic development of more efficient and personalized therapeutic strategies against cancer by means of thermotherapy, by taking into consideration the genetic profile of each patient.

Preventive hypothermia as a neuroprotective strategy for paclitaxel-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe adverse effect that occurs secondary to anticancer treatments and has no known preventive or therapeutic strategy. Therapeutic hypothermia has been shown to be effective in protecting against central and peripheral nervous system injuries. However, the effects of therapeutic hypothermia on CIPN have rarely been explored. We induced lower back hypothermia (LBH) in an established paclitaxel-induced CIPN rat model and found that the paclitaxel-induced impairments observed in behavioral, electrophysiological, and histological impairments were inhibited by LBH when applied at an optimal setting of 24°C to the sciatic nerve and initiated 90 minutes before paclitaxel infusion. Lower back hypothermia also inhibited the paclitaxel-induced activation of astroglia and microglia in the spinal cord and macrophage infiltration into and neuronal injury in the dorsal root ganglia and sciatic nerves. Furthermore, LBH decreased the local blood flow and local tissue concentrations of paclitaxel. Finally, in NOD/SCID mice inoculated with cancer cells, the antiproliferative effect of paclitaxel was not affected by the distal application of LBH. In conclusion, our findings indicate that early exposure to regional hypothermia alleviates paclitaxel-induced peripheral neuropathy. Therapeutic hypothermia may therefore represent an economical and nonpharmaceutical preventive strategy for CIPN in patients with localized solid tumors.

Minimally invasive distal pancreatectomy for pancreatic cystic neoplams and localized solid tumors: variation in utilization and potential as a quality measure

Background: Minimally invasive distal pancreatectomy (MIDP) has been demonstrated to be a technically feasible and oncologically sound alternative to open distal pancreatectomy (ODP) for pancreatic cystic neoplasms and localized solid tumors, including pancreatic adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (PNET). However, it is unknown which patients are being selected for MIDP or the extent to which hospitals are adopting this approach. The objectives of this study were to (1) identify patient-level factors associated with utilization of MIDP, (2) describe hospital-level variation in utilization of MIDP, and (3) compare outcomes between ODP and MIDP for cystic lesions and early stage solid tumors. Methods: The American College of Surgeons National Surgical Quality Improvement Program Pancreas Targeted Data File was used to identify patients from 2014-2017 who underwent distal pancreatectomy for pancreatic cysts (serous cystadenomas, mucinous cystadenomas, and intraductal papillary mucinous neoplasms), Stage I PDAC, or Stage I PNET. Surgical approach was categorized as OPD or MIDP (laparoscopic or robotic). Outcomes of interest included unplanned conversion of MIDP to OPD, postoperative length of stay, and a composite outcome of death or serious morbidity (DSM). Associations between patient factors, surgical approach, and postoperative complications were assessed by risk-adjusted hierarchical multivariable logistic regression. Hospital-level utilization of MIDP was calculated to assess institutional variability in surgical approach. Results: Analysis identified 3,276 patients undergoing distal pancreatectomy at 141 hospitals. Overall, 55.1% of patients had pancreatic cysts, 12.0% had Stage I PDAC, and 32.9% had Stage I PNET. ODP was performed in 37.3% of cases (35.6% of cyst cases, 61.6% of PDAC cases, and 31.4% of PNET cases), while 62.7% were MIDP (of which 76.1% were laparoscopic and 23.9% were robotic). The rate of unplanned conversion to open during MIDP was 11.8% (12.1% laparoscopic, 10.8% robotic, p = 0.700). Patients were more likely to undergo MIDP if they were <55 years old (66.6% vs 56.4% if ≥75; aOR 1.34, 95%CI [1.08-1.67]) or had a BMI≥30 (67.1% vs 57.8%, aOR 1.34, 95%CI [1.11-1.62]). Patients were less likely to undergo MIDP if they had PDAC pathology (38.4% vs 66.0% for PNET; aOR 0.33, 95%CI [0.25-0.44]). There was significant variation in hospital-level MIDP utilization (range: 0% to 100% of cases, Figure). Only 36.9% of hospitals attempted MIPD on at least 75% of patients with localized neoplasms. Similar to previous studies, length of stay was significantly shorter following MIDP (5.4 vs 7.2 days, p<0.001), and patients were significantly less likely to experience DSM following MIDP (16.2% vs 20.1%; aOR 0.74, 95%CI [0.62-0.89]). There was no difference in DSM between cystic neoplasms (DSM 17.2%), PDAC (DSM 18.0%), and PNET (DSM 18.0%; p = 0.519). Conclusion: Despite being a safe alternative to ODP with fewer complications and shorter length of stay, MIDP is still underutilized even in cases of cystic neoplasms and localized solid pancreatic tumors. While some patient-level factors are associated with use of MIDP, hospital variation in adoption of MIPD appears to be the principal driver of utilization and should be the primary focus of strategies to increase its uptake. In addition to short-term and oncologic outcome measures, hospital-level MIPD rates in appropriate patients could be utilized as a measure of hospital quality to both improve patient outcomes and encourage adoption of minimally invasive techniques.

Local drug activation technology to make cytotoxics safer for localized solid tumors.

12082Background: Only 1-2% of systemic chemotherapies actually reaches a localized tumor while the rest can result in severe off-target effects. There is a critical need to safely deliver cytotoxic...

Tumor-Treating Fields: A Fourth Modality in Cancer Treatment.

Despite major advances in therapy, cancer continues to be a leading cause of mortality. In addition, toxicities of traditional therapies pose a significant challenge to tolerability and adherence. TTFields, a noninvasive anticancer treatment modality, utilizes alternating electric fields at specific frequencies and intensities to selectively disrupt mitosis in cancerous cells. TTFields target proteins crucial to the cell cycle, leading to mitotic arrest and apoptosis. TTFields also facilitate an antitumor immune response. Clinical trials of TTFields have proven safe and efficacious in patients with glioblastoma multiforme (GBM), and are FDA approved for use in newly diagnosed and recurrent GBM. Trials in other localized solid tumors are ongoing. Clin Cancer Res; 24(2); 266-75. ©2017 AACR.