High Risk Of Disease Recurrence Research Articles

XRay Vision: A phase 3 study of xevinapant plus radiotherapy (RT) for high-risk, cisplatin-ineligible patients with resected, locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).

TPS6101 Background: The current standard of care for patients with resected LA SCCHN who are at high-risk of disease recurrence and are cisplatin eligible is chemoradiotherapy (CRT; cisplatin + RT). For patients at high risk of disease recurrence who cannot receive cisplatin, treatment options are limited, and there is currently no treatment specifically recommended by international guidelines. Xevinapant is a first-in-class, small-molecule IAP (inhibitor of apoptosis protein) inhibitor that has been shown to restore cancer cell sensitivity to apoptosis, thereby enhancing the effects of chemotherapy and RT. In a randomized phase 2 study in patients with unresected LA SCCHN, treatment with xevinapant + CRT was associated with a 53% lower risk of death after 5 years of follow-up and reduced the risk of death or disease progression by 67% after 3 years of follow-up vs placebo + CRT. In preclinical SCCHN models, xevinapant + RT alone also demonstrated antitumor activity. These promising clinical and preclinical data provide a strong rationale for combining xevinapant and RT in cisplatin-ineligible patients with LA SCCHN. Methods: XRay Vision (NCT05386550) is a randomized, double-blind, placebo-controlled, phase 3 study comparing xevinapant or placebo in combination with intensity-modulated RT (IMRT) in patients with resected LA SCCHN who are ineligible for cisplatin and have a high risk of relapse. Eligible patients must have histologically confirmed cancer of the oral cavity, oropharynx, hypopharynx, or larynx; undergone surgery with curative intent 4 to 8 weeks before the start of treatment; high risk of relapse; no residual disease by computed tomography scan; and ineligible for cisplatin (meeting ≥1 of the following criteria: estimated glomerular filtration rate <60 mL/min/1.73 m2; hearing loss [grade ≥2 audiometric hearing loss or grade ≥2 tinnitus]; grade ≥2 peripheral neuropathy; and if aged ≥70 years old, unfit according to the G8 questionnaire [score ≤14]). Other eligibility criteria include ECOG performance status of 0 or 1 and adequate hematologic and hepatic function. Approximately 700 eligible patients will be randomized to oral xevinapant (200 mg/day on days 1-14 of a 3-week cycle) or placebo for 3 cycles + standard fractionation IMRT (66 Gy in 33 fractions, 2 Gy per fraction, 5 days per week) followed by 3 cycles of xevinapant or placebo. The primary endpoint is disease-free survival. Secondary endpoints include overall survival, time to subsequent cancer treatments, safety, and health-related quality of life. Patients will be followed up for a minimum of 60 months. Enrollment is planned in 27 countries, including the US, and countries in South America, Europe, and Asia. The study started in October 2022, and recruitment is ongoing. Clinical trial information: NCT05386550 .

GS-011 - IMbrave050: Efficacy, safety and patient-reported outcomes (PROs) for adjuvant atezolizumab (atezo) + bevacizumab (bev) vs active surveillance in hepatocellular carcinoma (HCC) patients at high risk of disease recurrence after resection or ablation

GS-011 - IMbrave050: Efficacy, safety and patient-reported outcomes (PROs) for adjuvant atezolizumab (atezo) + bevacizumab (bev) vs active surveillance in hepatocellular carcinoma (HCC) patients at high risk of disease recurrence after resection or ablation

Circulating tumor DNA detection as a prognostic tool in patients with localized colon cancer: A systematic review and meta-analysis.

e15629 Background: Current modalities for postoperative risk stratification in localized colon cancer are still suboptimal in guiding adjuvant chemotherapy (ACT) administration. In recent years, circulating tumor DNA (ctDNA) has emerged as a novel biomarker to identify patients at high-risk for recurrence following R0 tumor resection. In this meta-analysis, we aimed to assess the prognostic value of ctDNA detection on postoperative recurrence risk that in the future, with further study, may help guide ACT treatment. Methods: Electronic databases Pubmed, Google Scholar, and Embase were searched up to 31 January 2023. Patient data were extracted using the following inclusion criteria: stage I to III colon cancers, R0 resection, sufficient ctDNA data following surgery, and no other concurrent malignancy. Pooled relative risk (RR) and 95% confidence interval (CI) were estimated to assess ctDNA positivity on the risk of recurrence in patients having surgery only, patients having surgery followed by ACT, and all patients combined. Random effects model was implemented to account for inter-study variation. Study heterogeneity was detected using χ2 test and I2 coefficient, with I2 more than 50% indicating significant heterogeneity. All analyses were completed using RevMan 5, with p < 0.05 being statistically significance. Results: Fifteen studies with a total of 3411 patients (64.4±10.7 years old) were evaluated. In patients undergoing surgery only without ACT treatment, postoperative ctDNA-positive patients were at higher risk of recurrence compared to those with negative ctDNA (RR = 7.73, 95% CI: 5.73-10.42, p < 0.01, I2= 0%). In patients having surgery followed by ACT, postoperative/pre-ACT ctDNA-positive patients were at higher risk of recurrence compared to ctDNA-negative ones (RR = 5.25, 95% CI: 3.67-7.50, p < 0.01, I2= 19%); post-ACT ctDNA-positive patients were also at higher risk of recurrence (RR = 6.34, 95% CI: 4.12-9.78, p < 0.01, I2= 29%). When combining the two populations (surgery only and surgery followed by ACT), postoperative ctDNA-positive patients again have higher risk of recurrence (RR = 3.86, 95% CI: 2.63-5.67, p < 0.01, I2= 87%); after completing all treatments, ctDNA-positive patients continue to have higher risk of recurrence (RR = 7.02, 95% CI: 3.40-14.51, p < 0.01, I2= 94%). Conclusions: This meta-analysis shows that the presence of ctDNA post-surgery correlates with higher risk of disease recurrence. In localized colon cancers, ctDNA detection can be a valuable tool to identify high-risk patients who, regardless of pathologic stage, may be the most likely to benefit from ACT treatment. Additionally, patients with persistently positive ctDNA after completing ACT are at very high risk for recurrence and should require closer follow-up than current guidelines, along with consideration of enrollment in clinical trials of newer treatment strategies.

Efficacy, safety and patient reported outcomes (PROs) from the phase III IMbrave050 trial of adjuvant atezolizumab (atezo) + bevacizumab (bev) vs active surveillance in patients with hepatocellular carcinoma (HCC) at high risk of disease recurrence following resection or ablation.

4002 Background: In IMbrave050, adjuvant atezo + bev demonstrated a statistically significant and clinically meaningful improvement in recurrence-free survival (RFS) vs active surveillance in patients (pts) at high risk of HCC recurrence following resection or ablation with curative intent. Further, the safety of atezo + bev was generally manageable. Here, we additionally report PRO data from IMbrave050. Methods: IMbrave050 (NCT04102098) enrolled HCC pts at high risk of recurrence following resection or ablation. Pts were randomized to Arm A (atezo + bev) or Arm B (active surveillance). Pts in Arm A received atezo 1200 mg + bev 15 mg/kg IV q3w for a period of one year (17 cycles). Pts in Arm B underwent active surveillance for one year and were eligible to crossover to atezo + bev following independent review facility (IRF) confirmation of recurrence. The primary endpoint was IRF-assessed RFS. Pre-specified exploratory analyses included change from baseline in global health status (GHS)/quality of life (QoL), physical functioning, role functioning, emotional functioning, and social functioning. Clinically meaningful deterioration was defined as a ≥ 10-point decrease. Pts completed the IL42–EORTC QLQ-C30 (reduced) questionnaire at baseline and then at every odd treatment/surveillance visit through Cycle 17. Results: The ITT population included 334 pts in both Arms A and B. With a median follow-up time of 17.4 mo (clinical cutoff date: 21 Oct 2022), IRF-RFS HR was 0.72 (95% CI: 0.56, 0.93; P = 0.0120). In the safety population, Grade 3 or 4 adverse events occurred in 41% of 332 Arm A pts and 13% of 330 Arm B pts. In ITT pts, IL42 completion rates remained ≥ 93% in both arms from baseline through treatment/surveillance Cycle 17. Mean scores at baseline in both arms were high and similar, as measured by the GHS/QoL and physical, role, emotional and social functioning scales. Mean changes from baseline were not considerable through Cycle 17 and were similar between arms as evidenced by overlapping 95% CIs. Pts’ GHS/QoL and functioning was maintained through Cycle 17, with no clinically meaningful deterioration observed at any time. Conclusions: Statistically significant and clinically meaningful improvement in RFS was seen in pts receiving atezo + bev vs active surveillance. Atezo + bev safety was generally manageable, and consistent with the established safety profiles of each therapeutic agent and with the underlying disease. PRO outcome analyses revealed similar overall health-related QoL (HRQoL) and functioning between atezo + bev and active surveillance, and that treating high-risk pts with HCC with adjuvant atezo + bev following procedures with curative intent did not result in a clinically meaningful deterioration in HRQoL or function. Clinical trial information: NCT04102098 .

Abstract CT003: IMbrave050: Phase 3 study of adjuvant atezolizumab + bevacizumab versus active surveillance in patients with hepatocellular carcinoma (HCC) at high risk of disease recurrence following resection or ablation

Abstract Background: The risk of HCC recurrence after liver resection or ablation with curative intent is 70-80% within 5 years, indicating an unmet need for effective adjuvant therapies. Atezolizumab (atezo) with bevacizumab (bev) is the standard of care for unresectable HCC based on the IMbrave150 study, which demonstrated statistically significant and clinically meaningful improvements in overall survival (OS), progression-free survival, and objective response rate versus sorafenib (Finn NEJM 2020, Cheng J Hepatol 2022). On the basis of the antitumor activity of atezo + bev and its capacity to positively modulate the tumor microenvironment, IMbrave050 was designed to evaluate the efficacy of adjuvant atezo + bev in delaying or preventing recurrence in patients (pts) with high-risk HCC. Methods: IMbrave050 (NCT04102098) enrolled pts with HCC at high risk of recurrence following resection or ablation. High-risk criteria were based on tumor burden (tumor size and number), vascular invasion, and tumor differentiation. Pts were randomized to Arm A (atezo + bev) or Arm B (active surveillance). Stratification factors included geographic region (Asia-Pacific excluding Japan vs rest of world) and a composite factor encompassing the number of high-risk features, curative procedure, and use of optional adjuvant TACE (allowed for one cycle following resection). Pts in Arm A received atezo 1200 mg + bev 15 mg/kg IV q3w for a period of one year or 17 cycles. Pts in Arm B underwent active surveillance for one year and were eligible to crossover to atezo + bev following independent review facility (IRF) confirmation of recurrence. The primary endpoint was IRF-assessed recurrence-free survival (RFS). Secondary efficacy endpoints included OS; investigator-assessed (INV) RFS; RFS and OS according to PD-L1 status; and time to extrahepatic spread and/or macrovascular invasion. Results: The ITT population included 334 pts each in Arms A and B. Baseline demographics were well balanced between arms. At interim analysis, with a median follow-up of 17.4 mo (cut off date: Oct 21, 2022), the primary endpoint was met with an IRF-RFS HR of 0.72 (95% CI, 0.56, 0.93; P=0.0120), and results were generally consistent across clinical subgroups. INV-RFS was similar (HR, 0.70; 95% CI, 0.54, 0.91). The safety of atezo + bev was generally manageable and consistent with the well-established safety profile of each therapeutic agent and with the underlying disease. Conclusions: Atezo + bev is the first adjuvant regimen to demonstrate a statistically significant and clinically meaningful improvement in RFS vs active surveillance in pts at high risk of disease recurrence following resection or ablation. The benefit:risk profile of atezo + bev favors the use of this regimen as an adjuvant therapy and has potential to set a new standard of care in adjuvant HCC. Citation Format: Pierce Chow, Minshan Chen, Ann-Lii Cheng, Ahmed O. Kaseb, Masatoshi Kudo, Han Chu Lee, Adam Yopp, Jian Zhou, Lu Wang, Xiaoyu Wen, Jeong Heo, Won Young Tak, Shinichiro Nakamura, Kazushi Numata, Thomas Uguen, David Hsiehchen, Edward Cha, Stephen P. Hack, Qinshu Lian, Jessica Spahn, Chun Wu, Shukui Qin. IMbrave050: Phase 3 study of adjuvant atezolizumab + bevacizumab versus active surveillance in patients with hepatocellular carcinoma (HCC) at high risk of disease recurrence following resection or ablation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT003.

Multifokal Papiller Tiroid Karsinomlu Hastalarda Total Tiroidektominin Sonuçları ve Patolojik Özellikleri

Aim: The incidence of thyroid cancer has increased dramatically in recent decades. Multifocality is considered a poor prognostic factor for papillary thyroid carcinoma (PTC). Patients with multifocal PTC (MPTC) are at high risk for local recurrence, as well as lymphatic and distal metastases. This study examined the features and outcomes of MPTC. Material and Methods: This retrospective study was conducted on 300 patients with PTC. Patients were classified into a multifocal group and a unifocal group. The pathological features of the PTC and the patients’ outcomes were analyzed and compared. Results: The multifocal group included 146 patients (48.7%), while the unifocal group included 154 patients (51.3%). The occurrence of multifocality was higher in females than in males (Odds ratio, OR: 2.37, 95% confidence interval, CI: 1.20-4.67, p=0.015). Tumor size of >1 cm in the multifocal group was larger than in the unifocal group (2.5 and 2.2 cm, respectively, p=0.021). Moreover, in multifocal group higher moderate risk of recurrence was detected than in the unifocal group (OR: 1.63, 95% CI: 1.01-2.60, p=0.044). At follow-up after treatment, MPTC patients had higher lymph node metastasis (OR: 2.89, 95% CI: 1.23-6.80, p=0.014). In addition, significantly higher thyroglobulin plasma levels (p=0.026) and disease recurrence (OR: 2.41, 95% CI: 1.05-5.52, p=0.037) were found in the multifocal group compared to the unifocal group. Conclusion: Patients with MPTC had a higher risk of disease recurrence, and multifocality was concluded to be an independent prognostic factor for overall disease recurrence.

Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence.

LRG1 could serve as a potential target and as a biomarker to identify patients with high risk for disease recurrence, and consequently benefit from additional therapies and intensive follow-up.

Abstract CT270: Immunogenicity of PGV_001 neoantigen vaccine in a Phase-I clinical trial, across various types of cancers in adjuvant setting

Abstract Introduction: Immunotherapies such as checkpoint blockade, have demonstrated remarkable clinical efficacy yet a large percentage of patients do not respond, potentially due to a paucity of pre-existing immune priming against neoantigens. We developed a personalized genome vaccine (PGV_001) platform to generate neoantigen vaccines targeting each patient’s unique mutanome. Primary objectives of the study were to determine 1) the safety and tolerability; 2) the feasibility of PGV_001 production and administration; and 3) the immunogenicity of PGV_001. Secondary objectives included immunophenotyping vaccine driven cellular and soluble immune milieu in peripheral blood. We previously reported on the clinical efficacy, and here we report, analysis of vaccine-driven immune responses in all treated patients. Methods: The study (Trial Registration NCT02721043) enrolled patients with resected malignancies, including Head and neck squamous cell carcinomas, breast cancer and bladder cancer, or, in the case of multiple myeloma treated with autologous stem cell transplant; all patients determined to have a high risk of disease recurrence (>30% over 5 years). Tumor-derived and germline RNA and DNA was sequenced to predict neoantigens utilizing our custom computation pipeline, OpenVax. Approximately 10 peptides were synthesized per patient, and a mixture of these peptides was administered as 10 subcutaneous and intradermal vaccines over 27 weeks in combination with poly-ICLC and helper Tetanus peptide as adjuvants. Immune responses were analyzed utilizing assays including IFN-gamma ELISPOT, antigen specific T cell expansion followed by flow cytometry, etc. Results: In total 148 neoantigen peptides were manufactured for 15 patients. Overall, 136 PGV_001 doses were administered to 13 patients. Vaccine-specific T cell immunity was observed against multiple vaccine neoepitopes in all 13 subjects. Of the peptides administered, 45% of vaccine antigens (57/126) induced de novo immunity, starting as early as Week8 and often sustaining past last vaccination. Notably, while the vaccine driven T cell immunity was CD4 T cell dominant, most evaluated subjects also displayed vaccine induced polyfunctional CD8-T cell responses. Additional studies are ongoing to define qualities of reactive T cells, evaluate vaccine-induced humoral responses and probe the circulating inflammatory immune milieu. These will be presented. Conclusions: We have established a platform for generating personalized neoantigen vaccines. 100% of the vaccinated patients developed an immune response specific to the vaccine neoantigens predicted by OpenVax. Subjects who received treatment experienced mild Grade 1 or 2 adverse reactions as per the CTEP v 4.0 NCI CTCAE. This vaccine trial reached the primary endpoint of safety, tolerability, feasibility and immunogenicity. Based on the PGV_001 platform two clinical trials, one in patients with glioblastoma multiforme (NCT03223103) in combination with TT fields and second in patients with urothelial carcinoma (NCT03359239) in combination with Atezolizumab have been performed. Data from these trials is under evaluation. Citation Format: Mansi Saxena, Thomas Marron, Julia Kodysh, Alex Rubinsteyn, John Finnigan, Ana Blasquez, Marcia Meseck, Tim O'Donnell, Daniela Delbeau, Mathew Galsky, Deborah Doroshow, Brett Miles, Krzysztof Misiukiewicz, Hanna Irie, Amy Tiersten, Samir Parekh, Marshall Posner, Andrea Wolf, John Mandeli, Rachel Brody, Sacha Gnjatic, Eric Schadt, Philip Friedlander, Nina Bhardwaj. Immunogenicity of PGV_001 neoantigen vaccine in a Phase-I clinical trial, across various types of cancers in adjuvant setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT270.

Abstract LB293: The evolution of MRD assays: Moving beyond the tumor-Informed bespoke NGS panel

Abstract The non-invasive detection of circulating tumor DNA (ctDNA) from plasma has been shown to have clinical value for detection of minimal residual disease (MRD), identification of emerging resistance to treatment, and predicting treatment response. The ability to detect MRD following curative treatment allows for the stratification of patients with higher risk of disease recurrence. Multiple studies, across hundreds of patients in different indications, including lung and colon cancer, have shown that tumor-informed personalized assays have high sensitivity to detect recurrence. The tumor-informed bespoke panels utilize sequencing of the tumor tissue to identify clonal somatic variants, which are then used to generate a personalized panel to track the variants in patient plasma. Next-generation MRD technologies are aiming to provide greater sensitivity by expanding methods beyond the small, personalized panels. Utilization of increased numbers of somatic variants is predicted to achieve a greater level of sensitivity for detection of MRD. Here we describe, C2I Genomics which provides a novel platform that exploits whole genome sequencing of the tumor tissue and plasma to define a somatic variant signature. An important difference of this method is that it develops a personalized bioinformatic signature rather than a personalized NGS panel. To understand the potential of this novel methodology, we utilized a set of 54 contrived clinical sample dilutions from three indications, with an expected (or engineered) VAF range of 0.2-0.002%, that have commutability to the intended use population. We found that C2I Genomics technology is highly sensitive, where for all returned samples, the assay routinely achieved detection down to the lowest dilution of 0.002% allelic frequency. Overall, the assay resulted in an average detection rate of 93% across all dilutions (n = 54). The aggregate detection rate of several tumor-informed assays, examining the same dilutions, yielded a detection rate of 68%. In summary, the C2I Genomics assay showed robust detection from contrived samples which are representative of clinical trial samples in both cfDNA yields and allele frequency. Citation Format: Paul Labrousse, Daniel Stetson, James Hadfield, Chris Abbosh, Ahmet Zehir, Carl Barrett, Brian Dougherty, Darren Hodgson. The evolution of MRD assays: Moving beyond the tumor-Informed bespoke NGS panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB293.

Abstract 3374: Circulating cell-free tumor DNA dynamics capture minimal residual disease with neoadjuvant immune checkpoint blockade plus chemoradiotherapy for patients with operable esophageal/gastroesophageal junction cancer

Abstract Introduction: There is a critical need to incorporate molecular assessments of minimal residual disease (MRD) during neoadjuvant immunotherapy, in order to identify individuals at high risk for disease recurrence based on analyses of circulating cell-free tumor DNA (ctDNA) landscapes. Here we employed longitudinal liquid biopsies to dynamically assess clinical outcomes with neoadjuvant immuno-chemoradiotherapy in patients with esophageal/gastroesophageal junction (E/GEJ) cancer. Methods: We utilized targeted error-correction sequencing to perform high-depth ctDNA next-generation sequencing for 141 serial plasma and 32 matched white blood cell (WBC) DNA samples from 32 patients with operable stage II/III E/GEJ cancer that received neoadjuvant immune checkpoint blockade (ICB) with chemoradiotherapy prior to surgery (NCT03044613). ctDNA analyses were performed at baseline, post-ICB induction, after completion of chemoradiotherapy (pre-op), and post-operatively (post-op). Using a tumor-agnostic WBC DNA-informed panel NGS approach we determined the cellular origin of plasma variants, filtering out germline and clonal hematopoiesis (CH) variants and evaluated ctDNA clonal dynamics over time. Molecular MRD was evaluated post-ICB, pre-op and post-op and correlated with recurrence-free (RFS) and overall survival (OS). Results: Twenty out of 32 patients had detectable ctDNA at any timepoint. Of the 12 patients with undetectable ctDNA, 9 had only CH- and/or germline-derived variants, while 3 patients had no detectable variants of any origin. ctDNA clearance post-ICB was correlated with tumor regression >80% at the time of resection (Fischer’s exact p=0.04). The subset of patients that did not attain complete pathologic response was heterogeneous with respect to ctDNA dynamics; such that ctDNA clearance pre-op identified patients with longer OS despite residual tumor of >0% at the time of resection (log rank p=0.06). Patients with undetectable ctDNA or ctDNA clearance pre-op had a longer RFS (log rank p=0.007) and OS (log rank p=0.03). Molecular MRD was associated with RFS and OS such that patients with ctDNA clearance post-op had longer RFS (log-rank p=0.007) and OS (log-rank p=0.017). Conclusion: ctDNA clearance post-ICB, pre-op and post-op reflects differential clinical outcomes for patients with E/GEJ cancer receiving neoadjuvant immuno-chemoradiotherapy. Understanding ctDNA dynamics and their relationship with pathological response and long-term outcomes can help identify patients at higher risk for recurrence and open a therapeutic window for future intervention. Citation Format: Blair V. Landon, Ronan J. Kelly, Ali H. Zaidi, Archana Balan, Jenna V. Canzoniero, Gavin Pereira, Zineb Belcaid, Russell K. Hales, K Ranh Voong, Richard J. Battafarano, Blair A. Jobe, Stephen C. Yang, Stephen Broderick, Jinny Ha, Kellie N. Smith, Elizabeth Thompson, Fyza Y. Shaikh, James R. White, Cynthia L. Sears, Eun J. Shin, Ali I. Amjad, Benny Weksler, Josephine L. Feliciano, Chen Hu, Vincent K. Lam, Valsamo Anagnostou. Circulating cell-free tumor DNA dynamics capture minimal residual disease with neoadjuvant immune checkpoint blockade plus chemoradiotherapy for patients with operable esophageal/gastroesophageal junction cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3374.

MP56-07 IMPACT OF SMOKING, CUMULATIVE EXPOSURE AND CESSATION ON ONCOLOGIC OUTCOMES AFTER RADICAL CYSTECTOMY AND ADJUVANT CHEMOTHERAPY FOR LOCALLY-ADVANCED BLADDER CANCER: A MULTICENTER STUDY

MP56-07 IMPACT OF SMOKING, CUMULATIVE EXPOSURE AND CESSATION ON ONCOLOGIC OUTCOMES AFTER RADICAL CYSTECTOMY AND ADJUVANT CHEMOTHERAPY FOR LOCALLY-ADVANCED BLADDER CANCER: A MULTICENTER STUDY

Laser interstitial thermal therapy of lung lesions near large vessels: a numerical study

Objective. Laser interstitial thermal therapy (LITT) is an evolving hyperthermia-based technology that may offer a minimally invasive alternative to inoperable lung cancer. LITT of perivascular targets is challenged by higher risk of disease recurrence due to vascular heat sinks, as well as risk of damage to these vascular structures. The objective of this work is to examine the impact of multiple vessel parameters on the efficacy of the treatment and the integrity of the vessel wall in perivascular LITT. Approach. A finite element model is used to examine the role of vessel proximity, flow rate, and wall thickness on the outcome of the treatment. Main result. The simulated work indicates that vessel proximity is the major factor in driving the magnitude of the heat sink effect. Vessels situated near the target volume may act as a protective measure for reducing healthy tissue damage. Vessels with thicker walls are more at risk of damage during treatment. Interventions to reduce the flow rate may reduce the vessel’s heat sink effect but may also result in increased risk of vascular wall damage. Lastly, even at reduced blood flow rates, the volume of blood reaching the threshold of irreversible damage (>43 °C) is negligible compared to the volume of blood flow throughout the treatment duration. Significance. This investigative simulation yields results that may help guide clinicians on treatment planning near large vessels.

Cribriform morphology is associated with higher risk of biochemical recurrence after radical prostatectomy in patients with Grade Group 5 prostate cancer.

Grade Group 5 (GG5) prostate cancer (PCa) is associated with a high risk of disease recurrence after radical prostatectomy (~75% at 5 years). However, this is a heterogeneous category that includes neoplasms with different combinations of Gleason pattern (GP) 4 and 5. Within GP4, large cribriform growth has been associated with adverse disease-specific outcomes in GG2-4 PCa. Less is known about the significance of cribriform morphology and the different histologic patterns of GP5 in GG5 PCa. In this study we evaluated the prognostic implications of cribriform morphology (either invasive or intraductal, henceforth "cribriform") and large solid growth or comedonecrosis (comedo/solid) in patients with GG5 PCa. One-hundred and thirty prostatectomies from a single institution were analysed. The presence of comedo/solid components was associated with a higher frequency of concurrent cribriform PCa (85.7% versus 45.9%, P <0.001), lymphovascular invasion (44.6% versus 27%, P=0.04), and biochemical recurrence (48.2% versus 28.4%, P=0.03). The presence of large cribriform growth was associated with a higher frequency of extraprostatic involvement (i.e. pT3a-b; 85.3% versus 68.7%, P=0.02), positive surgical margins (47.6% versus 29.2%, P=0.04) and biochemical recurrence (47.6% versus. 18.7%, P=0.001). Kaplan-Meier analysis demonstrated that GG5 PCa with cribriform or comedo/solid components had a higher probability of biochemical recurrence. Multivariable analysis showed that only cribriform components were an independent predictor of a higher risk of biochemical recurrence in this series. These findings highlight the importance of reporting the presence of cribriform components in GG5 PCa and suggest that cribriform morphology might help decide postsurgical management in these patients.

Prognostic Value of Combined Hematological/Biochemical Indexes and Tumor Clinicopathologic Features in Colorectal Cancer Patients-A Pilot Single Center Study.

Colorectal cancer (CRC) is a significant public health problem. There is increasing evidence that the host's immune response and nutritional status play a role in the development and progression of cancer. The aim of our study was to examine the prognostic value of clinical markers/indexes of inflammation, nutritional and pathohistological status in relation to overall survival and disease free-survival in CRC. The total number of CRC patients included in the study was 111 and they underwent laboratory analyses within a week before surgery. Detailed pathohistological analysis and laboratory parameters were part of the standard hospital pre-operative procedure. Medical data were collected from archived hospital data. Data on the exact date of death were obtained by inspecting the death registers for the territory of the Republic of Serbia. All parameters were analyzed in relation to the overall survival and survival period without disease relapse. The follow-up median was 42 (24-48) months. The patients with the III, IV and V degrees of the Clavien-Dindo classification had 2.609 (HR: 2.609; 95% CI: 1.437-4.737; p = 0.002) times higher risk of death. The modified Glasgow prognostic score (mGPS) 2 and higher lymph node ratio carried a 2.188 (HR: 2.188; 95% CI: 1.413-3.387; p < 0.001) and 6.862 (HR: 6.862; 95% CI: 1.635-28.808; p = 0.009) times higher risk of death in the postoperative period, respectively; the risk was 3.089 times higher (HR: 3.089; 95% CI: 1.447-6.593; p = 0.004) in patients with verified tumor deposits. The patients with tumor deposits had 1.888 (HR: 1.888; 95% CI: 1024-3481; p = 0.042) and 3.049 (HR: 3.049; 95% CI: 1.206-7.706; p = 0.018) times higher risk of disease recurrence, respectively. The emphasized peritumoral lymphocyte response reduced the risk of recurrence by 61% (HR: 0.391; 95% CI: 0.196-0.780; p = 0.005). Standard perioperative laboratory and pathohistological parameters, which do not present any additional cost for the health system, may provide information on the CRC patient outcome and lay the groundwork for a larger prospective examination.

Optical coherence tomography biomarkers for myopic choroidal neovascularization treated with anti-vascular endothelial growth factor.

In recent years, optical coherence tomography (OCT) biomarkers for specific retinal diseases have been found to be associated with treatment outcome and disease recurrence. The main purposes of this study were to identify OCT biomarkers for myopic choroidal neovascularization (mCNV) treated with intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF). OCT features in 43 eyes of 39 patients with mCNV treated with anti-VEGF with at least 1 year of follow-up were retrospectively analyzed. Eyes with subretinal hyperreflective material (SHM) in baseline spectral-domain OCT (SD-OCT) had significantly more visual improvement than eyes without SHM at month 6 (p=0.007) and had a trend of more visual improvement than eyes without SHM (p=0.058) at month 12. Eyes with subretinal fluid (SRF) at baseline had significantly more central retinal thickness (CRT) decrease than patients without SRF at month 6 and 12 (p=0.012 and 0.006 respectively). In univariate regression analysis, dome-shaped macula (DSM), SRF in baseline OCT image and fuzzy border of mCNV when entering pro re nata (PRN) injection protocol tended to have higher risk of disease recurrence in 1 year (odds ratio: 14.86 (p=0.003), 3.75 (p=0.049) and 22.92 (p < 0.001) respectively). However, they were not significant in multivariate regression analysis. OCT biomarkers at baseline could provide prognostic information for mCNV management.

The Prognostic Value of the Serum Level of C-Reactive Protein for Survival of Children with Ewing’s Sarcoma

The purpose of the present study was to evaluate the prognostic role of C-reactive protein (CRP) in children with Ewing's sarcoma. We conducted a retrospective study on 151 children undergoing multimodal treatment for Ewing's sarcoma in the appendicular skeleton from December 1997 to June 2020. Univariate Kaplan-Meier analyses of laboratory biomarkers and clinical parameters showed that CRP and metastatic disease at presentation were poor prognostic factors associated with overall survival and disease recurrence at 5 years (p < 0.05). A multivariate Cox regression model showed that pathological CRP (≥1.0 mg/dL) [HR of 3.67; 95% CI, 1.46 to 10.42] and metastatic disease [HR of 4.27; 95% CI, 1.58 to 11.47] were associated with a higher risk of death at 5 years (p < 0.05). In addition, pathological CRP (≥1.0 mg/dL) [HR of 2.66; 95% CI, 1.23 to 6.01] and metastatic disease [HR of 2.56; 95% CI, 1.13 to 5.55] were associated with a higher risk of disease recurrence at 5 years (p < 0.05). Our findings demonstrated that CRP was associated with the prognosis of children with Ewing's sarcoma. We recommend pre-treatment measurement of the CRP in order to recognize children with Ewing's sarcoma who are at greater risk of death or local recurrence.

Macrophage Biomarkers sCD163 and sSIRPα in Serum Predict Mortality in Sarcoma Patients

Most soft tissue sarcoma (STS) patients do not respond to traditional checkpoint inhibitor treatment, which may be due to infiltrating immunosuppressive tumour-associated macrophages. This study investigated the prognostic value of four serum macrophage biomarkers. Methods: Blood samples were taken from 152 patients with STS at the time of diagnosis; clinical data were prospectively collected. The concentrations of four macrophage biomarkers (sCD163, sCD206, sSIRPα, sLILRB1) were measured in serum, dichotomised based on median concentration, and evaluated either individually or when combined with established prognostic markers. Results: All macrophage biomarkers were prognostic of overall survival (OS). However, only sCD163 and sSIRPα were prognostic for recurrent disease (sCD163: hazard ratio (HR): 1.97 (95% CI: 1.10-3.51) and sSIRPα: HR: 2.09 (95% CI: 1.16-3.77)). A prognostic profile was made based on sCD163 and sSIRPα; it also included c-reactive protein and tumour grade. Patients with intermediate- or high-risk prognostic profiles (adjusted for age and tumour size) had a higher risk of recurrent disease compared to low-risk patients (HR: 2.64 (95% CI: 0.97-7.19)) and (HR 4.3 (95% CI: 1.62-11.47)), respectively. Conclusion: This study demonstrated that serum biomarkers of immunosuppressive macrophages were prognostic for OS; when combined with well-established markers of recurrence they allowed for a clinically relevant categorising of patients.

Practical Application of Circulating Tumor-Related DNA of Human Papillomavirus in Liquid Biopsy to Evaluate the Molecular Response in Patients with Oropharyngeal Cancer.

Recent findings have shown that human papillomavirus (HPV) DNA is present in the blood as a tumor-specific biomarker (circulating tumor-related HPV; ctHPV) in patients with HPV-related oropharyngeal cancer (HPV-related OPC). The molecular response (MR) in patients with HPV-related OPC can be defined as the change in the number of ctHPV copies in relation to its initial quantity. The optimal model for assessing the MR using a liquid biopsy (LB) should be based on the E6/E7 sequences of the viral genome. MR assessment can help to evaluate the intensity of ongoing treatments in relation to the tumor response. The evaluation of the residual disease at the end of therapy may also be performed by MR assessment. If a partial MR (pMR) is found, caution is indicated and a subsequent LB should be considered, due to the likelihood of disease progression. Complete radiological and clinical responses together with a complete MR (cMR) convincingly indicate a low risk of treatment failure. Moreover, molecular recurrence (Mrec) during a follow-up, confirmed in two consecutive assays, even despite the lack of any other clinical or radiological symptoms of progression, indicates patients at high risk of disease recurrence. In conclusion, MR by ctHPV assessment may hasten the early detection of disease progression, at any stage of the management of the patient with HPV-related OPC.

C-Reactive Protein and Lymphocyte-to-Monocyte Ratio Predict Recurrence in Stage III Melanoma Patients with Microscopic Sentinel Lymph Node Metastasis.

Although adjuvant therapies with immune checkpoint inhibitors (ICI) and BRAF/MEK inhibitors improve recurrence-free survival (RFS) in stage III melanoma patients significantly, prognostic factors are needed to identify patients with a high risk of disease recurrence. Therefore, the aim of our study was to investigate the prognostic potential of routinely collected blood parameters for stage III melanoma patients with microscopic sentinel lymph node (SLN) metastasis. Altogether, we retrospectively analyzed 138 stage III melanoma patients who were diagnosed with microscopic SLN metastasis at the skin cancer center of the University Hospital Cologne between 2011 and 2020 and who did not receive prior adjuvant therapy with ICI or BRAF/MEK-inhibitors. Univariate and multivariate Cox regression analyses, Kaplan-Meier survival analyses and receiver operating characteristic (ROC) curves were performed to assess the impact of preoperatively collected blood parameters and blood ratios on recurrence-free survival (RFS; primary endpoint) and overall survival (OS). A high neutrophil-to-lymphocyte ratio (NLR), low lymphocyte-to-monocyte ratio (LMR) and high C-reactive protein (CRP) value were significantly associated with shorter RFS in multivariate analysis. For LMR (cut-off 3.5) and for CRP (cut-off 3.0) this effect remained after dichotomization. CRP showed a stronger association with RFS than NLR or LMR, with the highest association being detected for the combination of low LMR and high CRP. Additionally, derived NLR ≥ 2.0 was significantly associated with shorter OS in multivariate analysis. In summary, our data suggest that CRP in combination with LMR should be considered as a marker for melanoma recurrence in stage III melanoma patients with microscopic SLN metastasis.

Identification of stage I/II melanoma patients at high risk for recurrence using a model combining clinicopathologic factors with gene expression profiling (CP-GEP)

PurposePatients with cutaneous melanoma stage I/IIA disease are currently not eligible for adjuvant therapy, despite their risk for relapses and death. This study validates the ability of a model combining clinicopathologic factors with gene expression profiling (CP-GEP) to identify patients at high risk for disease recurrence in stage I/II and subgroup stage I/IIA. Patients and methods543 patients with stage I/II primary cutaneous melanoma from the University of Tuebingen diagnosed between 2000 and 2017 were analysed. All patients received sentinel lymph node biopsy (SLNB). Analysis was conducted for a separate group of 80 patients who did not undergo SLNB. ResultsCP-GEP stratified 424 stage I/IIA patients (78% of the cohort) according to their risk for recurrence, with five-year relapse-free survival (RFS) rates of 77.8% and 93% for CP-GEP high risk (195 patients) and low risk (229 patients), respectively, and hazard ratio of 3.53 (p-value <0.001). In patients who did not receive SLNB biopsy, CP-GEP captured 6 out of 7 relapses. ConclusionCP-GEP can be used to identify primary cutaneous melanoma patients with a high risk for disease recurrence – especially for stage I/IIA, who are considered low risk by AJCC 8th. These patients may benefit from adjuvant therapy. Also, in the future, when SLNB may become irrelevant, CP-GEP may serve as a risk stratification tool.