Local Therapy Research Articles

Long-term follow-up results from KEYNOTE-041: Phase 1b study of pembrolizumab in Japanese patients with advanced melanoma.

Pembrolizumab demonstrated an acceptable safety profile and promising antitumor activity in Japanese patients with advanced melanoma in the phase 1b KEYNOTE-041 (Study of Pembrolizumab [MK-3475] in Participants With Advanced Melanoma) trial. To evaluate the long-term efficacy and safety of pembrolizumab in Japanese patients with advanced melanoma in KEYNOTE-041. The current analysis reports results of additional follow-up of approximately 12 months since the initial analysis. Eligible patients had locally advanced (unresectable stage III) or metastatic (stage IV) melanoma not amenable to local therapy and had received two or fewer prior systemic therapies. Pembrolizumab 2 mg/kg was given every 3 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points included safety, tolerability, and overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 by independent central review. The data cutoff for this analysis was August 30, 2017. Forty-two patients were followed up for a median of 22.3 months (range, 2.63-30.82 months). The ORR was 24.3% (nine of 37 evaluable patients [95% confidence interval (CI), 11.8%-41.2%]). Two patients with partial response at the time of the initial analysis achieved complete response. The median overall survival (OS) was 25.1 months (95% CI, 13.1-not reached] and the 30-month OS rate was 46.3% (95% CI, 29.8%-61.3%). The median duration of response was not reached. Treatment-related adverse events (TRAEs) were reported in 78.6% of patients; the incidence of grade 3 to 5 TRAEs was 23.8%. No additional treatment-related deaths occurred since the initial analysis. Pembrolizumab provided durable antitumor activity and an acceptable safety profile in Japanese patients with advanced melanoma.

The efficacy and safety of PD-1 inhibitor combined with TACE in the first-line treatment of unresectable hepatocellular carcinoma.

The application of immune checkpoint inhibitors (ICIs) has changed the treatment of advanced hepatocellular carcinoma. Transcatheter arterial chemoembolization (TACE) is a first-line treatment for intermediate hepatocellular carcinoma. Serving as a local treatment modality that can induce immunogenic cell death, the efficacy and safety of combined use with ICI have not been evaluated. Although there have been prospective studies aimed at evaluating the efficacy and safety of ICI combined with TACE in BCLC stage B HCC patients, there are few reports on the evaluation of BCLC stage C patients with distant metastasis or portal vein cancer thrombus. Data of unresectable hepatocellular carcinoma patients received PD-1 inhibitor and TACE were collected in Xijing Hospital from June 2019 to December 2022. The tumor response was evaluated according to the Solid Tumor Modified Response Evaluation Standard (mRECIST), including complete response (CR), partial response (PR), disease stability (SD), disease progression (PD), objective response rate (ORR), and disease control rate (DCR). The progression-free survival (PFS) and overall survival (OS) were used to estimate therapy efficacy. The treatment-related adverse events were evaluated based on National Cancer Institute Common Adverse Event Evaluation Criteria (CTCAE) version 5.0. A total of 42 patients with unresectable hepatocellular carcinoma were included in this study, including 34 males (80.5%) and 8 females (19.5%). The average age is 54.5years, ranging from 34 to 72. The median follow-up time was 12.3months, with an ORR of 42.9% and a DCR of 90.5% as of the follow-up time. The median PFS is 7.5months (95% CI: 5.76-9.23), and the median OS has not yet been reached; 6-month PFS was 62.2%. Safety analysis showed that 41 (97.6%) patients experienced treatment-related adverse reactions, mainly including elevated AST and ALT, fever, elevated bilirubin, hypothyroidism, nausea, abdominal pain, and rash. 40 patients had grade 1/2 adverse reactions, and only one patient had grade 3 adverse reactions, manifested as intolerable rash, nausea, and vomiting. Treatment is terminated when symptomatic treatment and drug suspension cannot be alleviated. In this study, thre patients with unresectable hepatocellular carcinoma were treated with PD-1 inhibitor combined with TACE to achieve good tumor reduction effect and underwent liver cancer resection surgery. For patients with unresectable hepatocellular carcinoma, whether in BCLC stage B or stage C, effective systemic therapy (PD-1 inhibitor) combined with local therapy (TACE) can achieve a high rate of tumor regression and objective response. Some patients may even pursue surgical treatment opportunities, and the treatment-related adverse reactions are controllable, which is expected to provide new options for extending the survival of unresectable hepatocellular carcinoma patients.

Adenovirus keratoconjunctivitis after LASIK as a complication of COVID-19 vaccination: a clinical case

During large-scale vaccination against coronavirus infection, studying possible side effects after the introduction of the vaccine is of great practical value. We present a rare clinical case of a complication of COVID-19 vaccine prophylaxis. A 40-year-old female patient was diagnosed with a bilateral adenoviral keratoconjunctivitis complicated by corneal erosion and iritis after a LASIK refractive intervention and a subsequent (after 5 days) immunoprophylaxis with the Gam-COVID-Vac vaccine followed by a displacement of the corneal flap due to involuntary friction of the left eye. The corneal flap was urgently repositioned; its adhesion and stabilization were achieved usinga bandage soft contact lens. The timely local and systemic anti-inflammatory and antiviral therapy allowed achieving a successful visual result (1.0). Ophthalmologists need to remain vigilant about possible adverse effects after immunoprophylaxis on the part of the eye, specifically the conjunctiva and cornea. A timely diagnosis and treatment are important to prevent complications such as persistent corneal opacities that reduce visual acuity, especially in patients who have undergone refractive surgery aimed at achieving the highest possible vision. In our opinion, it is advisable to perform vaccination at least 1 month after the refractive surgery.

Percutaneous microwave ablation: a viable local therapy for breast cancer involving the skin/nipple-areola complex?

BackgroundThis study aimed to evaluate the treatment feasibility and efficacy of ultrasound (US)-guided percutaneous microwave ablation (MWA) in patients with breast cancer involving the skin/ nipple-areola complex (NAC). Material and methodsA retrospective study was conducted on 15 patients diagnosed with breast cancer with skin/NAC involvement between December 2017 and April 2023. Throughout hospitalization and subsequent follow-up, regular clinical examinations and comprehensive breast imaging were performed to monitor and assess treatment outcomes. ResultsThe study included fifteen patients diagnosed with breast cancer involving the skin/NAC, with a mean patient age of 60 ± 14 years (range, 33 - 86 years). The mean tumor diameter involving the skin/NAC (n=16) was 5.4 ± 3.1cm (range, 1.0 - 13.0 cm). All patients achieved technique success and technique effectiveness, as confirmed by contrast-enhanced ultrasound combined with dynamic contrast-enhanced magnetic resonance imaging. Before MWA, four patients had breast cancer involving the skin, four had breast cancer involving NAC, and seven had both. Furthermore, five patients presented with skin ulceration/nipple loss. Following MWA, four patients developed both perilesional skin burn and nipple loss, while one patient experienced nipple loss. The median healing time was 3.7 months (range, 2 - 6 months). During a median follow-up of 33.5 months (range, 2 - 63 months), four patients experienced recurrence, and two patients died due to late-phase breast cancer and heart disease, respectively. ConclusionsUS-guided percutaneous MWA shows feasibility and efficacy for managing breast cancer involving the skin/NAC. This technique offers hope for improved therapeutic options and presents a potential alternative treatment approach for these challenging breast cancer patients.

Abstract 4570: Prostate-specific membrane antigen targeted chemo-photodynamic therapy for the treatment of prostate cancer

Abstract Introduction: Prostate cancer is the most prevalent cancer among men in the United States and is their second leading cause of cancer death. During initial screen, about 17-31% of patients are diagnosed with non-metastatic high-risk localized prostate cancer. These patients have an increased risk of treatment failure and oncological progression. The contemporary treatment paradigm of high risk localized prostate cancer is moving toward a multidisciplinary integrated approach of systemic and local therapy. In addition, incorporation of molecular biomarkers can also improve the risk stratification and treatment of prostate cancer. Among the biomarkers for prostate cancer, prostate specific membrane antigen (PSMA) has been proven to be an excellent target for diagnosis and treatment of prostate cancer. We have generated a PSMA-targeted photodynamic therapy (PDT) agent, PSMA-1-Pc413, and a PSMA-targeted chemotherapeutic agent, PSMA-1-MMAE. The objective of this study is to generate a new molecule that combines PDT and chemotherapy to achieve improved antitumor activity. Methods: Using a bifunctional PSMA ligand, a novel theranostic PSMA-targeting conjugate was synthesized, which integrated both the photosensitizer Pc413 and the microtubular inhibitor monomethyl auristatin E (MMAE) in one simple molecule, PSMA-1-MMAE-Pc413. This molecule was first tested for in vitro uptake and cytotoxicity studies using PSMA-positive PC3pip and PSMA-negative PC3flu cells. The conjugate was then tested for in vivo fluorescence imaging using mice bearing both PC3pip and PC3flu tumors. Finally, the antitumor activity of PSMA-1-MMAE-Pc413 was tested in mice with PC3pip tumors with and without light irradiation. Results: In in vitro uptake studies, the uptake of PSMA-1-MMAE-Pc413 in PC3pip tumor was about 3-fold higher than that in PC3flu cells. In in vitro cytotoxicity studies, when exposed to 5 J/cm2 of 672nm light, PSMA-1-MMAE-Pc413 demonstrated a synergistic effect leading to greater cytotoxicity for PC3pip cells (IC50=2.77nM) when compared to PSMA-1-Pc413 with light irradiation (IC50=372nM) or PSMA-1-MMAE-Pc413 without light irradiation (IC50=12.6nM). In in vivo imaging studies, PSMA-1-MMAE-Pc413 demonstrated selective uptake in PC3pip tumors. Further, antitumor activity studies showed that PSMA-1-MMAE-Pc413 with light irradiation significantly inhibited PC3pip tumor growth and prolonged survival time as compared to mice receiving equimolar amounts of PSMA-1-Pc413 with light irradiation or PSMA-1-MMAE-Pc413 without light irradiation. Conclusion: We have synthesized a new theranostic agent PSMA-1-MMAE-Pc413 that combines imaging, chemotherapy and PDT. The new molecule dramatically improves the treatment effect as compared to each single treatment alone. (The work is supported by NIH 1RO1CA255925-01A.) Citation Format: Xinning Wang, Aditi Shirke, Sriprada Chavali, Lifang Zhang, Ethan Walker, Gopolakrishnan Ramamurthy, James Basilion. Prostate-specific membrane antigen targeted chemo-photodynamic therapy for the treatment of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4570.

Abstract 3835: Clinicopathologic determinants of survival in malignant histiocytic neoplasms: Analysis of a pooled database

Abstract Background: Malignant histiocytosis, also known as the M-group per the Histiocyte Society classification, represents a rare, aggressive malignant group of histiocytic neoplasms. It includes histiocytic neoplasms that occur de novo (pMHN) and those that develop in association with other malignant diseases (aMHN). However, little is known about factors that impact MHN clinical outcomes. We conducted this pooled database analysis to delineate key clinicopathological characteristics, prognostic indicators, and treatment modalities that affect survival in these rare diseases. Methods: To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 281 cases of MHN. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS). Results: A total of 281 patients with confirmed MHN were identified, with 77% pMHN and 23% aMHN. The median age was 45, with bimodal peaks between 0-13 and 52-65. There was a male preponderance with M:F of 1.6. Primary sites of involvement were liver (15%), CNS and spleen (13% each), thoracic, GI, and soft tissues (12% each), bones (11%), skin (10%), H&N (8%), and breast, heart, gonads, pancreas, and kidney (1% each). Lymphadenopathy and bone marrow (BM) were involved in 28% and 18%, respectively. Constitutional symptoms occurred in 12% and hemophagocytic syndrome (HPS) in 6%. The median OS of the whole group was 12 months. BM involvement had a worse median OS (5 vs. 60 months, p=0.0002). Stage 1 disease had better median OS than higher stages (p=0.0008). Furthermore, unifocal had better median OS than multifocal/multicentric disease (60 vs. 7 months, p=0.0001). The presence of inflammatory background positively impacted OS (p=0.01). The occurrence of HPS adversely affected OS (p<0.0001). Compared to no treatment, localized therapies such as surgery (S) and/or radiation therapy (RT) and systemic combination chemotherapy (CT) were statistically superior, with a median OS of 3, 24, and 16 months, respectively (p=0.009). Among systemic therapies, SCT and BRAF/MEK inhibitors were superior to conventional chemotherapy (p=0.02). Having CNS or splenic-lymphatic primary involvement tended to have a numerical but non-significant worse median OS than soft tissue or visceral disease. While female sex, size<10cm, and pMHN seemed to have numerically better OS, they did not reach statistical significance. There was no difference in median OS for age. Conclusion: This study presents updated clinicopathologic data from a pooled cohort of patients with MHN. It identifies BM involvement, stage, extent of the disease, the inflammatory background status, occurrence of HPS, and treatment approach as critical determinants of OS. Citation Format: Philip A. Haddad, Dinesh Keerty. Clinicopathologic determinants of survival in malignant histiocytic neoplasms: Analysis of a pooled database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3835.

Abstract 2462: Live attenuated Salmonella ZH9 as novel microbial immunotherapy for the treatment of bladder cancer

Abstract Microbial immunotherapy with Bacillus Calmette-Guérin (BCG) has been the standard-of-care for non-muscle invasive bladder cancer (NMIBC) for over 30 years. Today, global demand for BCG exceeds supply, leaving many patients untreated. BCG is associated with high disease recurrence and presents high treatment burden for patients. There remains therefore significant unmet need for novel therapeutic approaches for NMIBC and we sought to establish the utility of the live-attenuated Salmonella enterica Typhi ZH9 as a more effective microbial immunotherapy. Efficacy of ZH9 was established in orthotopic, syngeneic, mouse MB49 tumor models in which animals were treated in the bladder via catheterization, with or without prior subcutaneous immune priming. Immune responses were measured by flow cytometry and Nanostring transcriptomic analyses of bladder tissues. An intravesical dose of ZH9 after orthotopic MB49 tumour inoculation demonstrated significant survival benefit compared to both vehicle control and equivalent colony forming unit (CFU) BCG treatments. Repeat, weekly dosing studies showed a single administration of ZH9 was sufficient for maximum efficacy. To explore the durability of protection, surviving intravesical ZH9 treated animals were rechallenged, demonstrating protection from both bladder and subcutaneous MB49 tumors suggestive of lasting local and systemic anti-tumor immunity. Flow cytometry analysis of bladders showed that intravesical ZH9 treatment resulted in cellular immune response characterised by recruitment of NK cells, CD4+ and CD8+ T cells, and dendritic cells with an activated, cross-presenting phenotype, in all cases of greater magnitude than after treatment with an equivalent dose of BCG. Based on observations that pre-existing immunity to BCG has been associated with improved outcomes to intravesical BCG therapy in NMIBC, we explored whether systemic priming with ZH9 benefits local bladder therapy. Systemic prime with ZH9 followed by a single intravesical dose of ZH9 showed a trend for improved survival and will be explored in the clinical setting. This systemic immune priming effect was associated with enhanced local bladder immune cell infiltrates and the upregulation of more than 150 immune response genes in the bladder compared to intravesical therapy alone. These data form the basis of preclinical package accepted by the FDA for a Phase 1/1b study evaluating the safety, pharmacology, and clinical effect of ZH9 treatment in patients with NMIBC, currently recruiting patients. The investigation includes thorough translational and biomarker studies to delve into the mechanism of action of ZH9 and explore patient stratification approaches. By easing the treatment burden on patients, lowering healthcare costs, and featuring a scalable manufacturing process, ZH9 has the potential to revolutionize the treatment paradigm in NMIBC and reshape the patient journey. Citation Format: Nicholas Glanville, Oluwatobiloba Oke, Claudia Prevosto, Alexandra Sevko, Andrew Scott, Sonia Domingos-Pereira, Lenka Polak, Denise Nardelli-Haefliger, Livija Deban. Live attenuated Salmonella ZH9 as novel microbial immunotherapy for the treatment of bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2462.

Backflow reduction in local injection therapy with gelatin formulations

The local injection of therapeutic drugs, including cells, oncolytic viruses and nucleic acids, into different organs is an administrative route used to achieve high drug exposure at the site of action. However, after local injection, material backflow and side effect reactions can occur. Hence, this study was carried out to investigate the effect of gelatin on backflow reduction in local injection. Gelatin particles (GPs) and hydrolyzed gelatin (HG) were injected into tissue models, including versatile training tissue (VTT), versatile training tissue tumor-in type (VTT-T), and broiler chicken muscles (BCM), using needle gauges between 23 G and 33 G. The backflow material fluid was collected with filter paper, and the backflow fluid rate was determined. The backflow rate was significantly reduced with 35 μm GPs (p value < .0001) at different concentrations up to 5% and with 75 μm GPs (p value < .01) up to 2% in the tissue models. The reduction in backflow with HG of different molecular weights showed that lower-molecular-weight HG required a higher-concentration dose (5% to 30%) and that higher-molecular-weight HG required a lower-concentration dose (7% to 8%). The backflow rate was significantly reduced with the gelatin-based formulation, in regard to the injection volumes, which varied from 10 μL to 100 μL with VTT or VTT-T and from 10 μL to 200 μL with BCM. The 35 μm GPs were injectable with needles of small gauges, which included 33 G, and the 75 μm GPs and HG were injectable with 27 G needles. The backflow rate was dependent on an optimal viscosity of the gelatin solutions. An optimal concentration of GPs or HG can prevent material backflow in local injection, and further studies with active drugs are necessary to investigate the applicability in tumor and organ injections.

Abstract 2396: Tumor treating fields (TTFields) for spinal metastasis: Clinical trial concept for use of conductive implants as waveguides to enhance TTFields strength

Abstract Tumor treating fields (TTFields) is a FDA-approved electric fields-based therapy for glioblastoma (GBM) and malignant pleural mesothelioma. We describe a novel approach to increase the strength and therapeutic effect of TTFields at vertebral tumor targets, using spinal implants as electrically-conductive waveguides. In vivo anti-cancer efficacy is achieved with TTFields strength &amp;gt;1 V/cm. If the tumor is surrounded by tissues of lower conductivity (e.g., the skull in the case of GBM), then the TTFields strength reaching the tumor is decreased. Surgical treatment of radiation-refractory spinal metastases is difficult and provides a short-term benefit at the expense of a lengthy recovery. Such resections require bone removal that disrupts the spinal stability, necessitating reconstruction with titanium (Ti) pedicle screw constructs that are electrically conductive. We theorize that astute placement of Ti hardware in the proximate spinal levels post-resection would have a waveguiding effect of electrical current from the surrounding muscle towards the tumor. This would in turn boost TTFields strength achieved around the resection cavity, decreasing the chances of tumor recurrence. Bomzon et al. described a computational model of the distribution of TTFields in a realistic human torso. The simulation demonstrated that a TTFields strength of 3 V/cm can be achieved, which is approximately 3-fold greater than what is achieved in the brain parenchyma in the context of TTFields for GBM. In a more generic simulation using a 0.5 × 100 mm waveguide targeting a tumor deeper in the torso (480 mA), we found 21.8 vs. 61.2 cm3 volumes achieving ≥ the 1.0 V/cm efficacy floor, without and with the waveguide, respectively, a 2.8-fold increase. At a higher amplitude (550 mA) and stronger TTFields strength threshold of ≥1.5 V/cm, a negligible volume was attained with no waveguide (0.1 cm3), whereas a volume of 17.6 cm3 was attained around the tip of the waveguide when present. Based on compelling pre-clinical data, a prospective clinical trial is being designed in which patients with radiation-refractory spinal metastasis from any number of primary sites will undergo resection. Next, primary cultures of their tumor cells will be made and evaluated for the TTFields frequency that maximizes cell death on a per-patient basis. Patients will then undergo postoperative local TTFields therapy ± systemic therapy. The primary endpoint will be safety and efficacy of such an approach, with future aims focusing on local control rates. The application of TTFields as an adjunct to surgery may offer a new therapeutic option for patients with spinal metastasis who would otherwise not be considered surgical candidates. Similarly, waveguides may be used throughout the head and body to increase TTFields efficacy. Citation Format: Claudio E. Tatsui, Kristen W. Carlson, Chirag B. Patel. Tumor treating fields (TTFields) for spinal metastasis: Clinical trial concept for use of conductive implants as waveguides to enhance TTFields strength [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2396.

Abstract 2564: Circulating monocytes decrease significantly following disease-directed therapy and may reflect disease expansion in Langerhans cell histiocytosis

Abstract Introduction: Langerhans Cell Histiocytosis (LCH) is a rare disorder characterized by clonal hematopoietic cell expansion forming eosinophilic granulomas. Treatment approaches vary based on disease severity. Despite established therapies, assessing treatment response, particularly regarding peripheral blood monocytes, lacks comprehensive markers. Methods: We studied 76 LCH patients, collecting data on demographics, diagnostic methods, and treatment responses. Peripheral blood absolute monocyte counts were analyzed at key time points, including disease onset, progression, and post-therapy reinstatement, using statistical tests for comparison. Results: Analyzing data from 76 patients (average age: 38), we found diverse disease presentations, with common imaging modalities being CT (37), PET (29), and MRI (22). Complete responses were observed in 17 of 49 patients, with 11 undergoing local therapy. Conversely, 5 patients with pulmonary LCH and chronic tobacco use showed persistent progression. Notably, peripheral blood monocyte counts did not differ between initial and latest assessments, but on disease progression, the mean count (0.94 K/µL) significantly exceeded that following therapy reinstatement (0.31, p=0.000794). Results: Analyzing data from 76 patients (average age: 38), we found diverse disease presentations, with common imaging modalities being CT (37), PET (29), and MRI (22). Complete responses were observed in 17 of 49 patients, with 11 undergoing local therapy. Conversely, 5 patients with pulmonary LCH and chronic tobacco use showed persistent progression. Notably, peripheral blood monocyte counts did not differ between initial and latest assessments, but on disease progression, the mean count (0.94 K/µL) significantly exceeded that following therapy reinstatement (0.31, p=0.000794). Discussion: LCH is proposed to result from dysregulated hematopoiesis, leading to sequential somatic mutations during monocyte differentiation leading to clonal expansion of CD1A and CD207+ histiocytes. Our finding of increased monocyte count during disease progression may suggest elevated circulating LCH or heightened monocyte production for subsequent differentiation, potentially contributing to MHC Class 1 upregulation. This phenomena mirrors published findings from our own group in patients with Rosai Dorfman and Erdheim Chester Disease. To further elucidate the molecular underpinnings of LCH and explore the etiology of this monocyte trend, genetic sequencing analysis is in progress. Ultimately, monitoring peripheral blood monocyte dynamics could offer valuable insights into LCH progression and treatment response. Citation Format: Haadi Ali, Sam Reynolds, Sabrina Wilcox, Naina Chipalkatti, Asra Ahmed. Circulating monocytes decrease significantly following disease-directed therapy and may reflect disease expansion in Langerhans cell histiocytosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2564.

Abstract 3673: Monitoring treatment response in patients with metastatic colorectal cancer using cfDNA fragmentomics testing: The DOLPHIN trial

Abstract Background: Accurate monitoring of treatment response in patients with metastatic colorectal cancer (mCRC) is important to decide when to adjust treatment regimen or to proceed to local therapy of metastases. At present, clinical response is determined by computed tomography (CT) imaging-based assessment of changes in tumor size. However, this monitoring approach is constrained by limited sensitivity in detecting lymph node and peritoneal metastases, as well as inter-reader variability. Detection of circulating tumor DNA (ctDNA) is indicative of the amount of neoplastic cells and may have added clinical value to CT imaging for assessment of treatment response and guidance in treatment decision making in mCRC patients. We recently developed a tumor mutation-independent ctDNA test that utilizes low-coverage whole genome sequencing to analyze the plasma cell-free DNA (cfDNA) fragmentome to measure the ctDNA tumor fraction: the DELFI-tumor fraction (DELFI-TF) score. Aim: The DOLPHIN study aims to investigate whether the DELFI-TF ctDNA assay can provide a sensitive, affordable and broadly applicable ctDNA test to monitor treatment response of mCRC patients. Methods: The prospective, observational, multi-center DOLPHIN study is a substudy of the Prospective Dutch ColoRectal Cancer cohort (PLCRC). Clinical data, images and blood samples from 400 patients receiving systemic therapy in 8-10 Dutch hospitals will be collected. Blood samples will be drawn longitudinally in conjunction with regularly scheduled CT imaging. Plasma cfDNA will be analyzed for tumor-specific fragmentation patterns using the DELFI-TF score. Droplet digital PCR ctDNA-testing of RAS/RAF hotspot mutations will be performed as reference, when feasible. Primary endpoint is the association between ctDNA changes and clinical response. Secondary endpoints are the association between ctDNA changes and radiological response according to RECIST and to serum carcinoembryonic antigen (CEA) at various time points during systemic treatment, lead time of ctDNA-testing compared to CT imaging to detect progressive disease, and the prognostic value of longitudinal ctDNA-testing. Results: Since the inclusion of the first patient in March 2023, 117 patients have been included in the DOLPHIN study (November 2023). Seven hospitals throughout the Netherlands are currently open for patient inclusion and more sites have been approached to participate. Discussion: The DOLPHIN study will assess the added clinical value of longitudinal ctDNA-testing in treatment response monitoring of mCRC patients and whether imaging can be complemented and/or partly replaced by ctDNA-testing. The results of this study may lead to novel strategies for monitoring treatment response and to ctDNA-guided treatment decision making in mCRC patients. Citation Format: Denise E. van Steijn, Remond J. Fijneman, Geraldine R. Vink, Jeanine M. Roodhart, Miriam Koopman, Max J. Lahaye, Manon N.G. Braat, Veerle M. Coupé, Daan A. van den Broek, Gerrit A. Meijer, Haoyue Wang, Marjolein J. Greuter, Birgit I. Lissenberg-Witte, Lorenzo Rinaldi, E Peters, Alissa Konicki, Nicholas C. Dracopoli, Niels F. Kok, Victor E. Velculescu. Monitoring treatment response in patients with metastatic colorectal cancer using cfDNA fragmentomics testing: The DOLPHIN trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3673.

Abstract 1396: Targeting immune suppressive myeloid cells in prostate cancer recurrence and metastasis

Abstract Metastatic prostate cancer is a leading cause of cancer-related deaths worldwide and therefore an urgent inadequately addressed clinical problem. We have approached this problem primarily by studying immune cells within the tumor microenvironment rather than the tumor cells themselves. One critical cell subset that seems to be contributing to the aggressive behavior of clinically significant prostate cancers is the immune suppressive myeloid cells (MDSC) within the tumor microenvironment. MDSC have been shown to promote tumor metastases by participating in the formation of pre-metastatic niche, promoting angiogenesis, tumor cell invasion, and mediating immune suppression. Understanding the heterogeneity and function of these myeloid cells is an essential step toward developing effective therapeutic strategies to target them and enhance anti-tumor immune responses that have thus far been so elusive. We utilized previously generated scRNAseq data and combined it with publicly available prostate cancer scRNAseq datasets. The analysis included a total of 96 samples at different disease stages, including healthy prostate tissue, adjacent-normal tissue, low-grade tumors, high-grade tumors, as well as local and bone metastatic tumors. In addition, GeoMx spatial profiling was performed on 24 high-grade prostate cancer patients to assess immune cell spatial infiltration. This meta-analysis provided comprehensive insights into the molecular characteristics of prostate cancer. We characterized multiple MDSC subpopulations and revealed the dynamics of tumor associated macrophages (TAMs) during tumor progression and metastasis. We found that a specific type of TAM, known as APOE+ SPP1+TAM, is significantly enriched in metastatic tumors. They are transcriptionally similar to the TAMs found in the bone metastasis niche of prostate cancer. Moreover, we found APOE+ SPP1+TAMs within primary/localized tumors tumors alone could predict prostate cancer recurrence despite curative-intent local therapy. We validated the accumulation of APOE+ SPP1+TAMs in a prostate cancer mice model. We are currently studying the role of the specific subset of TAMs in tumor metastases by focused analysis of the communication between these TAMs, T cells, and tumors. Additionally, we are exploring the therapeutic potential of blocking APOE+ SPP1+TAMs in a mice model of prostate cancer. Our analyses provide a comprehensive picture of myeloid cell linage across different prostate cancer stages, highlighting the potential for therapeutic targets that disrupt the metastatic process via their effects on tumor associated macrophages. Citation Format: Shenglin Mei, Hanyu Zhang, Taghreed Hirz, Nathan Elias Jeffries, Shulin Wu, Chin Lee Wu, Douglas M. Dahl, Philip J. Saylor, David B. Sykes. Targeting immune suppressive myeloid cells in prostate cancer recurrence and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1396.

Tumor treating fields suppress tumor cell growth and neurologic decline in models of spinal metastases.

Spinal metastases can result in severe neurologic compromise and decreased overall survival. Despite treatment advances, local disease progression is frequent, highlighting the need for novel therapies. Tumor treating fields (TTFields) impair tumor cell replication and are influenced by properties of surrounding tissue. We hypothesized that bone's dielectric properties will enhance TTFields-mediated suppression of tumor growth in spinal metastasis models. Computational modeling of TTFields intensity was performed following surgical resection of a spinal metastasis and demonstrated enhanced TTFields intensity within the resected vertebral body. Additionally, luciferase-tagged human KRIB osteosarcoma and A549 lung adenocarcinoma cell lines were cultured in demineralized bone grafts and exposed to TTFields. Following TTFields exposure, the bioluminescence imaging (BLI) signal decreased to 10%-80% of baseline, while control cultures displayed a 4.48- to 9.36-fold increase in signal. Lastly, TTFields were applied in an orthotopic murine model of spinal metastasis. After 21 days of treatment, control mice demonstrated a 5-fold increase in BLI signal compared with TTFields-treated mice. TTFields similarly prevented tumor invasion into the spinal canal and development of neurologic symptoms. Our data suggest that TTFields can be leveraged as a local therapy within minimally conductive bone of spinal metastases. This provides the groundwork for future studies investigating TTFields for patients with treatment-refractory spinal metastases.

Liposome-integrated hydrogel hybrids: Promising platforms for cancer therapy and tissue regeneration

Drug delivery platforms have gracefully emerged as an indispensable component of novel cancer chemotherapy, bestowing targeted drug distribution, elevating therapeutic effects, and reducing the burden of unwanted side effects. In this context, hybrid delivery systems artfully harnessing the virtues of liposomes and hydrogels bring remarkable benefits, especially for localized cancer therapy, including intensified stability, excellent amenability to hydrophobic and hydrophilic medications, controlled liberation behavior, and appropriate mucoadhesion to mucopenetration shift. Moreover, three-dimensional biocompatible liposome-integrated hydrogel networks have attracted unprecedented interest in tissue regeneration, given their tunable architecture and physicochemical properties, as well as enhanced mechanical support. This review elucidates and presents cutting-edge developments in recruiting liposome-integrated hydrogel systems for cancer treatment and tissue regeneration.

Efficacy of differentiated targeted interferon and immunomodulatory therapy focused on pathological immunophenotypes in patients with atypical chronic active herpesvirus infections

Objective: In a prospective cohort study to evaluate the clinical and immunological efficacy of differentiated targeted interferon and immunomodulatory therapies focused on identified pathological immunophenotropes and associated clinical manifestations in immunocompromised patients suffering from atypical chronic active herpes viral infections (ACA-HVI).Materials and methods: 335 patients suffering from mixed-AHA-HVI were examined. The study complex included: methods for detecting herpesviruses: serodiagnosis, PCR-RV; immunological methods: a research of subpopulation of blood lymphocytes (method of a flow cytometry), determination of the spontaneous and induced products of IFNα and IFNγ, levels of serum cytokines and immunoglobulins (IL-1β, IL-6, IL-17, TNFα and IFNα and IFNγ, Ig A, M, G) by ELISA. The study was approved by the ethics board and informed consent was obtained from all patients.Results: Integral formulas of disorders in the antiviral immune defense system were created, which made it possible to isolate 3 pathological immunophenotypes (PIF): PIF1: NG↓+ind.IFNα/IFNγ↓+CTL↓+EKK↓+IgM↑+hypecytokinemiya (IL-1β↑+IL-6↑+TNFα↑); PIF2: NG↓+ ind. IFNα/IFNγ↓ + EKK↓+ IgG↓+hypercytokinemiya (IL-1β↑+IL-6↑+TNFα↑) and PIF3: NG↓+ind.IFNα/IFNγ↓+hypercytokinemiya (IL-1β↑+IL- 6↑+TNFα↑). Taking into account the identified disorders, a program of targeted interferon and immunomodulatory therapy was developed for each PIF: local and systemic IFN therapy + hexapeptide was developed for PIF1; for PIF2- local and systemic IFN therapy + glucosaminimuramyldipeptide; for PIF3-local and systemic IFN therapy.Conclusions: High clinical efficacy was demonstrated in 100% of patients with three groups of ACA-HVI. Immunological effectiveness of targeted interferon and immunomodulatory therapy programs: 89.5% for PIF1; for PIF2-57.6% and for PIF3- 37.5% of cases.

In vitro evaluation and characterization of cisplatin loaded nanofibers for local chemotherapy

Cancer is a disease that affects the quality of life of the patients that are treated with Cisplatin (CDDP), which is needed for adjuvant therapy, however it leads to many secondary and adverse effects. In this study, we manufactured and characterized poly-(lactic acid) (PLA) non-woven fibers loaded with Cisplatin (CDDP) by electrospinning technique to evaluate their cytotoxicity in in vitro assays on HeLa cells (cervical carcinoma cell line). PLA–CDDP solutions with increasing concentrations of CDDP (0.5, 1 and 2% w/w) were used in a TL-01 electrospinning equipment with the same system parameters. We analyzed the chemical, thermal and morphological characteristics of PLA and PLA–CDDP fiber mats. Furthermore, hydrolytic degradation, hemolysis and toxicity in HeLa cells were evaluated. By adding the CDDP to the fibers, the degradation, glass transition and melting temperatures were modified; the 3 µm fiber diameter of pristine PLA fibers was decreased in half the size and the degradation time was extended over 5 months. However, the hemocompatibility of the material with and without CDDP was maintained, while cytotoxicity in HeLa cells increased in the three concentrations of fiber mats of PLA–CDDP compared to the intravenous drug at 24 h (p < 0.01). We concluded that the fiber mats PLA–CDDP could be used for localized therapy in the adjuvant treatment when resection panels are expose after a surgical extirpation of solid tumors.

Long-Term Survival in Patients with Oligometastatic Non-Small Cell Lung Cancer by a Multimodality Treatment-Comparison with Stage III Disease.

Background: In patients with oligometastatic NSCLC, a cT3-cT4 primary tumor or an cN2/cN3 lymph node status was reported to be associated with unfavorable outcome. The aim of this study was to assess the importance of definitive or neoadjuvant thoracic radiochemotherapy for long-term outcome of these patients in order to find more appropriate treatment schedules. Methods: Analysis of the West Cancer Centre (WTZ) institutional database from 08/2016 to 08/2020 was performed. Patients with primary synchronous OMD, all without actionable driver mutations, who received definitive thoracic radiochemotherapy (RCT) or neoadjuvant RCT followed by surgery (trimodality treatment) were included. Survival outcome is compared with stage III NSCLC. Results: Altogether, 272 patients received concurrent radiochemotherapy. Of those, 220 presented with stage III (158 with definitive RCT, 62 with trimodality approach). A total of 52 patients had OMD patients with cT3/cT4 or cN2/cN3 tumors. Overall survival (OS) at five years for OMD patients was 28.3% (95%-CI: 16.4-41.5%), which was not significantly different from OS of patients with stage III NSCLC treated with definitive or neoadjuvant RCT (34.9% (95%-CI: 27.4-42.8%)). However, the PFS of OMD patients at five years or last follow-up was significantly worse than that of stage III patients (13.0% vs. 24.3%, p = 0.0048). The latter was due to a higher cumulative incidence of distant metastases in OMD patients (50.2% vs. 20.4% at 48 months, p < 0.0001) in comparison to stage III patients. A cross-validated classifier that included severe comorbidity, ECOG performance status, gender and pre-treatment serum CRP level as the most important factors in the univariable analysis, was able to divide the OMD patient group into two equally sized groups with a four-year survival rate of 49.4% in the good prognosis group and 9.9% in the poor prognosis group (p = 0.0021). Laboratory chemistry and clinical parameters, in addition to imaging and high-precision therapies, can help to predict and improve prognosis. Conclusions: A multimodality treatment approach and local metastases-directed therapy in addition to chemoimmunotherapy can lead to good long-term survival in patients with cT3/cT4 or cN2/cN3 OMD NSCLC without severe comorbidities and in good performance status and is therefore recommended.

Factors Influencing the Outcome of Patients with Primary Ewing Sarcoma of the Sacrum.

Ewing sarcoma (EwS) is a rare and highly malignant bone tumor primarily affecting children, adolescents, and young adults. The pelvis, trunk, and lower extremities are the most common sites, while EwS of the sacrum as a primary site is very rare, and only few studies focusing on this location are published. Due to the anatomical condition, local treatment is challenging in sacral malignancies. We analyzed factors that might influence the outcome of patients suffering from sacral EwS. We retrospectively analyzed data of the GPOH EURO-E.W.I.N.G 99 trial and the EWING 2008 trial, with a cohort of 124 patients with localized or metastatic sacral EwS. The study endpoints were overall survival (OS) and event-free survival (EFS). OS and EFS were calculated using the Kaplan-Meier method, and univariate comparisons were estimated using the log-rank test. Hazard ratios (HRs) with respective 95% confidence intervals (CIs) were estimated in a multivariable Cox regression model. The presence of metastases (3y-EFS: 0.33 vs. 0.68; P < 0.001; HR = 3.4, 95% CI 1.7 to 6.6; 3y-OS: 0.48 vs. 0.85; P < 0.001; HR = 4.23, 95% CI 1.8 to 9.7), large tumor volume (≥200 ml) (3y-EFS: 0.36 vs. 0.69; P=0.02; HR = 2.1, 95% CI 1.1 to 4.0; 3y-OS: 0.42 vs. 0.73; P=0.04; HR = 2.1, 95% CI 1.03 to 4.5), and age ≥18 years (3y-EFS: 0.41 vs. 0.60; P=0.02; HR = 2.6, 95% CI 1.3 to 5.2; 3y-OS: 0.294 vs. 0.59; P=0.01; HR = 2.92, 95% CI 1.29 to 6.6) were revealed as adverse prognostic factors. Young age seems to positively influence patients` survival, especially in patients with primary metastatic disease. In this context, our results support other studies, stating that older age has a negative impact on survival. Tumor volume, metastases, and the type of local therapy modality have an impact on the outcome of sacral EwS. Level of evidence: Level 2. This trial is registered with NCT00020566 and NCT00987636.

A study of clinical profile of snake bite at a tertiary care centre

Because India has long been a land of exotic snakes, snakebite is a serious occupational and rural hazard. Physicians pay very little attention to this occupational hazard despite the high morbidity and death. To study the various clinical profiles and the time interval between bite and start of treatment. Patients were categorized based on the envenomation centred by patient history and definitive bite evidence and graded (I-IV) grounded on a series of manifestations observed in association with the onset of treatment time that distinguishes a venomous from a non-venomous snake attack. Patients were obligating local inflammation owing to tourniquet use besides local innate therapies. Of the 100 patients deliberated, it was evident that there existed a minimal difference between the bites instigated by the snake type. Higher abnormal clotting was perceived on the arrival of patients (78%). While envenomation was predominantly reported to prompt primary coagulation abnormalities (84.32 %), neurotoxin manifestation was also found to occur at a lower rate (11.76 %). Both symptoms were also observed at a minimal level (3.92 %). Higher rates of renal failure were also reported and the clotting time normalization depended largely on patient admission time post-attack. In this investigation, the time gap between the bite and the commencement of therapy was not associated with the time required to normalize the coagulation abnormalities or develop a complication. The study also proposes appropriate protective and awareness measures that could save humankind and these reptiles together.

Local Therapy in the Management of Mucosal Melanoma: An NCDB Analysis

Local Therapy in the Management of Mucosal Melanoma: An NCDB Analysis