Number Of Metastases Research Articles

Survival Outcomes of Stereotactic Radiotherapy for Ten or More Brain Metastases

Abstract AIMS Discrepancies exist in the use of stereotactic radiotherapy (SRT) for patients with 10 or more brain metastases. Concerns include multiple metastases being associated with poor survival and the lack of prospective data. We analysed survival outcomes of these patients in a multi-centre cohort. METHOD We performed a retrospective cohort study of 511 consecutive patients from three SRT centres treated for brain metastases between January 2010 - August 2021, censored in January 2022. We assessed survival post-SRT of patients with ≥10 metastases against a matched group of 5-9 and 1-4 metastases using the logrank test for statistical testing. We used a multivariate Cox model to assess the relationship between overall survival and: number of metastases; total volume; primary malignancy; use of systemic anti-cancer therapies with intracranial penetrance; controlled extracranial disease. Results with p-values <0.05 were considered significant. RESULTS Survival data was available for all patients, and for 85-100% of factors in multivariate analysis. 63 patients had ≥10 metastases (median 19). Median survival was 13.3 months, compared with 15.1 and 19.0 months for the 5-9 and 1-4 metastasis groups respectively. Differences were not statistically significant (p-value 0.14). Increasing volume of disease (HR 1.05 [1.01-1.09], p-value: 0.01), non-small cell lung cancer (HR 3.5 [1.35-9.09] p-value: 0.01) and use of systemic anti-cancer therapy with intracranial penetrance (HR 0.239 [0.105-0.547] p-value: <0.01) had a statistically significant effect on survival in multivariate analysis. CONCLUSION Carefully selected patients with multiple metastases have acceptable survival outcomes following SRT and this approach should be more widely considered.

Radiotherapy improves the outcomes of immunotherapy with Sintilimab in non-small-cell lung cancer: A real-world analysis.

IntroductionRadiotherapy may augment systemic antitumor responses to immunotherapy. We did a retrospective study to infer whether radiotherapy improves outcomes to immunotherapy in patients with stage III and IV non-small-cell lung cancer (NSCLC).MethodsThis retrospective study conducted at Enze Medical Center enrolled 259 patients with histopathology confirmed NSCLC from December 2018 to December 31, 2021. All were treated with Sintilimab, some patients received radiotherapy at an appropriate time point. Radiation type includes conventional radiotherapy and stereotactic body radiotherapy. The progression-free survival (PFS), and overall survival (OS) were the primary endpoint.ResultsA retrospective analysis was performed on 259 patients, of whom 140 had been treated with immunotherapy lonely and 119 had been remedied with immunotherapy plus radiotherapy. Baseline variables were well balanced between the two groups, including gender, age, smoking status, TNM staging, number of metastases, ECOG score, pathological type and lines of previous systemic therapy. The median PFS in the immunotherapy alone group was 5.00 months (95%CI 4.38-5.62) versus immunotherapy plus radiotherapy was 9.00 months (5.95-12.05; p<0.001). The median OS in the immunotherapy alone group was 16.00 months (12.59-19.42) versus immunotherapy plus radiotherapy was 30.00 months (20.75-39.25; p=0.027). PFS was finer in the radiotherapy plus immunotherapy group than the immunotherapy group alone in both stage III(P=0.0069) and Stage IV(P=0.006) patients. In the univariate analysis, radiotherapy, male, ECOG=0 and <2 lines of previous systemic therapy were connected with an observably better PFS (P<0.001; P=0.03; P=0.002;P=0.021). In a multivariate analysis, radiotherapy, ECOG=0 and <2 lines of previous systemic therapy were independent prognostic factors with a markedly better PFS (P<0.001; P=0.006;P=0.009). An univariate analysis, radiotherapy, male, stage III, non-metastasis, ECOG=0 and squamous carcinoma were associated with a significantly better OS (P=0.032, P=0.036,P=0.002,P<0.001,P=0.002,P=0.025). A multivariate analysis, non-metastasis was a standalone prognostic indicator with a significantly better OS (P=0.006). However, radiotherapy was a tendency indicator with a better OS (HR0.70 95% CI 0.47-1.06). There were also no obvious increases in adverse events in the combination group.ConclusionsRadiotherapy with addition of immunotherapy was observably linked to a better outcome in patients with III and IV staging NSCLC.

Radiotherapy for bone metastases of hepatocellular carcinoma: a hybrid systematic review with meta-analyses

Introduction External beam radiation therapy (EBRT) is commonly used as a palliative treatment for bone metastases of hepatocellular carcinoma (HCC). We planned a hybrid systematic review that meta-analyzed the efficacy and feasibility of EBRT and reviewed the literature to answer specific clinical questions. Methods The PubMed, Medline, Embase, and Cochrane Library databases were searched through 1 December 2021. Primary endpoints were overall survival (OS) and response rate (RR). Secondary endpoints were comparative data, including treatment response and survival related to dose escalation, number of metastases, and fractionation scheme. Formal pooled analyses were performed on the primary endpoints, and the secondary endpoints were systematically reviewed. Complications were also reviewed. Results Nineteen studies involving 1613 patients with HCC and bone metastases were included. The median OS was 6 months (range: 3–13 months). The pooled one-year OS was 23.1% (95% confidence interval [CI]: 18.4–28.6); pooled pain RR was 81.5% (95% CI: 76.4–85.7) and of pain complete remission was 26.5% (95% CI: 21.7–32.0). Pain response might be related to dose escalation, considering the moderate consistency of results and plausibility, with a low-quality grade of evidence†. Considering the indeterminate results, we cannot suggest that dose escalation is correlated with OS. The oligometastasis status might be related to better OS, considering the high consistency of results and plausibility with low to moderate quality of evidence. Hypofractionated EBRT might yield comparable efficacy to conventional EBRT, with a low-quality grade of evidence. There were few complications of grade ≥3, except for hematologic complications, which ranged from 11.5to 34%. Conclusion EBRT is an efficient and feasible palliative option. Clinical consideration of hematologic complications is necessary. Future studies are needed to increase the quality of evidence for actual clinical questions. †Reference to a system of the American Society for Radiation Oncology primary liver cancer clinical guidelines.

Role of metastasectomy in the management of renal cell carcinoma.

Treatment of metastatic renal cell carcinoma (mRCC) has evolved with the development of a variety of systemic agents; however, these therapies alone rarely lead to a complete response. Complete consolidative surgery with surgical metastasectomy has been associated with improved survival outcomes in well-selected patients in previous reports. No randomized control trial exists to determine the effectiveness of metastasectomy. Therefore, reviewing observational studies is important to best determine which patients are most appropriate for metastasectomy for mRCC and if such treatment continues to be effective with the development of new systemic therapies such as immunotherapy. In this narrative review, we discuss the indications for metastasectomies, outcomes, factors associated with improved survival, and special considerations such as location of metastasis, number of metastases, synchronous metastases, and use of systemic therapy. Additionally, alternative treatment options and trials involving metastasectomy will be reviewed.

Individualized Selection Criteria Based on Tumor Burden in Future Remnant Liver for Staged Hepatectomy of Advanced CRLM: Conventional TSH or ALPPS.

Simple SummaryCurrently, two established staged hepatectomy techniques are used for curative resection of advanced colorectal liver metastasis (CRLM) as well as preventing inadequate future remnant liver (FRL). However, the selection of staged hepatectomy between the conventional two-stage hepatectomy (cTSH) and the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) remains under debate. Therefore, the present study proposed a selection criterion based on tumor burden related to the size and number of metastases within the FRL for decision making when utilizing staged hepatectomy for advanced CRLM. Accordingly, metastatic tumors within the FRL should not exceed three nodules and none of the nodules should measure larger than 3 cm for ALPPS. By contrast, cTSH would be considered in patients whose tumor burdens within the FRL beyond the aforementioned criteria. The individualized selection criteria appear to be promising and can be used to select a more effective staged hepatectomy approach for patients with advanced CRLM.Staged hepatectomy is a promising strategy for curative resection of advanced colorectal liver metastasis (CRLM) to prevent inadequate future remnant liver (FRL). However, the selection criteria for conventional two-stage hepatectomy (cTSH) and associating liver partitioning and portal vein ligation for staged hepatectomy (ALPPS) remain unclear. This study aimed to propose a selection criterion for determining the optimal staged hepatectomy for patients with advanced CRLM. A selection criterion based on the degree of metastatic tumors within the FRL was established to determine staged hepatectomy approaches. Generally, ALPPS is recommended for patients with ≤3 metastatic nodules and whose nodules do not measure >3 cm in the FRL. cTSH is performed for patients whose tumor burden in FRL beyond the selection criteria. Data of 37 patients who underwent staged hepatectomy and curative intent of CRLM were analyzed. The clinical characteristics and outcomes of the two approaches were compared. Overall, cTSH and ALPPS were performed for 27 (73.0%) and 10 (27.0%) patients, respectively. Of those, 20 patients in the cTSH group and all patients in the ALPPS group had completed staged hepatectomy. The 1-, 3-, and 5-year survival rates were 91.6%, 62.4%, and 45.4% for all patients, respectively. The outcomes of patients who had successfully completed the staged hepatectomy were significantly better than those of other patients who failed to achieve staged hepatectomy. However, no significant difference was observed in the overall survival of patients who underwent staged hepatectomy between the two groups, but those in the ALPPS group had 100% survival at the end of this study. The individualized selection criteria based on tumor burden in the FRL that could balance the operative risk and oncologic outcome appear to be a promising strategy for achieving complete staged hepatectomy in patients with advanced CRLM.

Risk factors of extraneural spreading in astrocytomas and oligodendrogliomas in donors with gliomas: A systematic review.

BACKGROUNDPatients with a history of primary brain tumors can be eligible for organ donation under extended criteria. The risk assessment of tumor transmission via organ transplant in primary brain tumors is primarily based on the assessment of tumor histotype and grade. Previous surgeries, chemo-/radiotherapy, and ventriculo-peritoneal shunt placement can lead to a disruption of the blood-brain barrier, concurring to an increase in the transmission risk.AIMTo investigate the role of tumor transmission risk factors in donors with oligodendrogliomas and astrocytomas.METHODSWe searched PubMed and EMBASE databases for studies reporting extraneural spreading of oligodendrogliomas and astrocytomas and extracted clinical-pathological data on the primary tumor histotype and grade, the elapsed time from the diagnosis to the onset of metastases, sites and number of metastases, prior surgeries, prior radiotherapy and/or chemotherapy, ventriculo-atrial or ventriculo-peritoneal shunt placement, and the presence of isocitrate dehydrogenase 1/2 mutation and 1p/19q codeletion. Statistical analysis was performed using R software. Statistical correlation between chemotherapy or radiotherapy and the presence of multiple extra-central nervous system metastases was analyzed using χ2 and Fischer exact test. The Kaplan-Meier method was used to evaluate the presence of a correlation between the metastasis-free time and: (1) Localization of metastases; (2) The occurrence of intracranial recurrences; and (3) The occurrence of multiple metastases.RESULTSData on a total of 157 patients were retrieved. The time from the initial diagnosis to metastatic spread ranged from 0 to 325 mo in patients with oligodendrogliomas and 0 to 267 mo in those with astrocytomas. Respectively, 19% and 39% of patients with oligodendroglioma and astrocytoma did not receive any adjuvant therapy. The most frequent metastatic sites were bone, bone marrow, and lymph nodes. The lungs and the liver were the most commonly involved visceral sites. There was no significant correlation between the occurrence of multiple metastases and the administration of adjuvant chemo-/radiotherapy. Patients who developed intracranial recurrences/metastases had a significantly longer extraneural metastasis-free time compared to those who developed extraneural metastases in the absence of any intra- central nervous system spread.CONCLUSIONA long follow-up time does not exclude the presence of extraneural metastases. Therefore, targeted imaging of bones and cervical lymph nodes may improve safety in the management of these donors.

Progression time of de novo metastases in relation to castration resistant prostate cancer at a tertiary care hospital in Southern Thailand

Objective: Androgen deprivation therapy (ADT) is often the treatment of choice in metastatic prostate cancer patients. However, there is currently an insufficiency of biomarker-related data that can be used in order to predict how the disease would respond to ADT. In this study we evaluated the clinical response to ADT, including factors which are affecting the progression of the disease into castration-resistant prostate cancer (CRPC) in patients with de novo metastatic prostate cancer. Materials and Methods: This retrospective study incorporated patients with metastatic prostate cancer who received ADT at our center from January 2008 to December 2019. Baseline characteristics, mode of ADT, prostate-specific antigen (PSA), blood chemistry, Gleason score (GS) grade group, location, and the number of metastases were analyzed. The risk factors affecting the progression of the disease were identified. Results: Data from 125 patients were included in the study. One hundred patients (80%) were classified as suffering from high volume metastatic prostate cancer and six patients (6%) with visceral metastasis. Baseline PSA in high volume and low volume metastatic prostate cancer were defined as 500 ng/ml and 215.1 ng/ ml respectively. Eighty-one patients (64.8%) received a gonadotrophin-releasing hormone (GnRH) agonist while 42 patients (33.6%) underwent bilateral orchi- ectomy. Time to CRPC in high and low volume metastasis was 12 months and 23 months respectively. Patients with Alkaline Phosphatase (ALP) ≥350 U/L had 8.5 months to CRPC while patients with ALP &lt;350 U/L had 15 months. High GS grade group (3-5), short time to PSA nadir (&lt;6 months), PSA nadir level (≥ 2 ng/ ml), and serum ALP ≥350 U/L were independent factors associated with shorter time to CRPC. Conclusion: The clinical management of metastatic prostate cancer is challenging; the main aims of treatment are to prolong overall survival whilst maintaining quality of life. Patients with aggressive tumors, high volume metastasis, short time to nadir (TTN), high PSA nadir level, and high ALP level were independent factors associated with shorter time to CRPC.

Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study

Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P= 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P= 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.

Abstract 6279: Combination of metformin and local irradiation efficiently provokes abscopal effects in a murine rectal cancer model

Abstract Introduction; Neoadjuvant chemoradiation therapy (CRT) for locally advanced rectal cancer is effective for the reduction of local recurrence and improvement of postoperative QOL. However, CRT has little effects for metastatic lesions in distant organs and does not prolong the prognosis. Abscopal effect refers to a phenomenon of tumor regression at a distant tumor away from the irradiated primary tumor, presumably through the host immune system. Metformin, a widely used drug for the treatment of type 2 Diabetes Mellitus, has been shown to elicit anti-cancer effects partly through the activation of host immunity. However, how metformin modulates the abscopal effects of local radiation (RT) and metformin has not been well investigated. Method; Mice were subcutaneous inoculated by 1x106 cells of LuM1, a highly murine lung metastatic subclone of colon 26, at right flank of 7 weeks female BALB/c mice which were treated with metformin and/or RT. In RT groups, 4Gy X-ray was selectively given to subcutaneous tumors using lead shield under general anesthesia at day 13 and 15. Metformin hydrochloride (1mg/ml) were orally administrated from day13 continuously. At 28 days, mice were sacrificed, and we evaluated the weight of primary subcutaneous (s.c) tumor and the number of lung metastases. The phenotypes of splenocytes and blood were examined by flowcytometric analysis. Results: Local RT (4Gy x 2) suppressed the growth of s.c tumor to approximately half of control group although not statistically significantly (p=0.067). Metformin alone did not significantly suppress the tumor growth. However, when combined with RT, tumor weight at day28 was markedly reduced as compared with control group (p&amp;lt;0.01). Many lung metastases developed in all control group mice (Median (M)=120, 22-188) which was not changed by the treatment of metformin alone. The number of metastases tended to be reduced in RT group, although not significant (M=34, 3-78, p=0.12). In comparison, when metformin was combined to RT, the number of lung metastasis was markedly decreased (M=13, 0-70, p&amp;lt;0.01) with no metastases detected in 3 in 10 mice. The ratios of CD4(+) or CD8(+) T cells tended to be reduced in mice treated with RT alone, while increased in mice treated with RT and Metformin. CD49b(+)CD335(+) activated natural killer (NK) cells was significantly increase in combination group (1.1%±0.19% vs 2.6%±1.0%, p&amp;lt;0.05). The ratios PD-1(+) cells tended to be reduced, whereas those of IFN-γ (+) cells in T cell subpopulations after stimulation were significantly increased in mice treated with RT and metformin as compared with those in control group (CD4; 6.8±2.4% vs 10.4%±1.3%, p&amp;lt;0.05; CD8; 24.1±3.6% vs 40.4%±7.2%, p&amp;lt;0.01) Conclusion;Metformin restores T cell exhaustion and increase the number of activated NK cells in irradiated mice which may suppress the growth of lung metastases as abscopal effects. Citation Format: Mineyuki Tojo, Hideyo Miyato, Koji Koinuma, Hisanaga Horie, Hidenori Tsukui, Akira Saito, Yuki Kimura, Yuki Kaneko, Hideyuki Ohzawa, Hironori Yamaguchi, Alan Kawarai Lefor, Naohiro Sata, Joji Kitayama. Combination of metformin and local irradiation efficiently provokes abscopal effects in a murine rectal cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6279.

Abstract 5811: Ovarian cancer cell fate is regulated by the balance between saturated and unsaturated fatty acids

Abstract Background: Fat represents an important source of energy for ovarian cancer (OC) cells and is supplied either through import from the tumor milieu or via de novo lipogenesis. During fast tumor growth, when nutrients are scarce, lipogenesis becomes the primary source of fatty acids. Stearoyl-CoA desaturase (SCD), a rate-limiting enzyme in this pathway converts saturated (SFAs) into unsaturated fatty acids (UFAs) and is highly expressed in OC. The goal of this study was to determine how the balance between SFAs and UFAs tightly controlled by SCD, regulates OC cell survival and tumorigenicity. Methods: SCD was knocked down by shRNA or inhibited by using the small molecule CAY10566 and global effects on the lipidome and transcriptome were examined by targeted and untargeted lipidomics, stimulated Raman spectroscopy (SRS), and RNA sequencing. In OC cells in which SCD was blocked or knocked down, the effects of exogenous SFAs and UFAs on cell survival and endoplasmic reticulum (ER) stress pathway were assessed by using annexin V staining, XBP1 splicing assay and Western blotting of PERK/eIF2α/ATF4. Tumorigenicity was assessed by using an intraperitoneal (i.p.) xenograft model in nude mice. Results: RNA-seq analysis of SCD knockdown cells cultured under low serum conditions revealed activation of ER stress response pathways. Targeted lipidomics and SRS microscopy showed downregulation of UFAs vs. SFAs, while untargeted lipidomics discovered decreased fatty acyl chain plasticity among phosphatidylcholines. Activation of IRE1α/XBP1 and PERK/eIF2α/ATF4 axes was observed in cells accumulating SFAs. Stiff and disorganized ER membrane was detected by electron microscopy and Raman spectroscopy. Annexin V staining demonstrated apoptosis of OC cells under long-term mild ER stress or short-time severe ER stress induced by increased levels of SFAs. ER stress and apoptosis were rescued by addition of UFAs. In vivo SCD knockdown suppressed tumor growth and treatment with the SCD inhibitor CAY10566 reduced the number of metastases and the volume of ascites in mice fed with SFA enriched diet, but not in mice fed a balanced diet. Conclusion: Our data support that OC cells are highly susceptible to unbalanced intracellular SFAs/UFAs, undergoing ER stress and apoptosis in the presence of excessive intracellular SFAs. SCD inhibition coupled with a diet rich in saturated fats decreased cancer progression in vivo. These results support SCD as a key regulator of cancer cell fate during metabolic stress in growing tumors and point to new treatment strategies targeting lipid metabolism. Citation Format: Guangyuan Zhao, Yuying Tan, Horacio Cardenas, David Vayngart, Yinu Wang, Christina Ferreira, Ji-Xin Cheng, Daniela Matei. Ovarian cancer cell fate is regulated by the balance between saturated and unsaturated fatty acids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5811.

Abstract 3565: Viroimmunotherapy for solid tumors results in local and abscopal anti-cancer effects and the remodeling of tumor microenvironment

Abstract Oncolytic viruses are a promising experimental treatment for solid tumors. Recently, several phase 1 clinical trials have reported encouraging therapeutic effects of oncolytic viruses in adult and pediatric patients with malignant gliomas. To further improve the therapeutic outcome of viroimmunotherapy, we have developed Delta-24-RGDOX (DNX-2440), a replication competent adenovirus encompassing the T-cell activator OX40L in the genetic backbone of Delta-24-RGD. We have previously reported the effect of Delta-24-RGDOX in murine brain tumors supporting the translation of this new agent to treat patients with recurrent malignant gliomas (NCT03714334). In the work presented here, we have tested the therapeutic effect of Delta-24-RGDOX in murine syngeneic models of breast (4T1), gastric (M12) and lung cancer (LLC and CMT 167). We found that Delta-24-RGDOX infected all cancer cell lines efficiently. In addition, infection of cells was followed by the expression of the ectopic ligand in vitro and in vivo. Because the elicitation of an anti-tumor immunity is part of the mechanisms underlying the therapeutic effect of oncolytic viruses, we examined whether infection of tumors led to the reshaping of the tumor microenvironment. We observed that Delta-24-RGDOX infection was followed by increased frequencies of tumor infiltrating lymphocytes, particularly CD8+ T cells and NK cells. In addition, the CD8+/CD4+ ratio was increased in Delta-24-RGDOX-treated tumor versus PBS-treated tumors. Interestingly, abscopal modifications were observed in breast cancer brain metastases with increased frequency of CD8+ T cells at the distal, untreated site. Delta-24-RGDOX treatment induced an anti-cancer effect in orthotopically implanted breast cancer and subcutaneously implanted lung and gastric tumors, as well as in metastatic niches. In summary, our data showed that treatment of solid tumors with Delta-24-RGDOX induces robust remodeling of the tumor microenvironment and produces anti-tumor effects leading to decrease in tumor volume, along with a delay in the development and in the reduction of the number of metastases. These data suggest that Delta-24-RGDOX should be tested in the clinical setting in patients with metastatic breast, gastric and lung cancers. Citation Format: Arie C. Van Wieren, Sagar Sahoni, Teresa Nguyen, Ashley Ossimetha, Yisel Rivera-Molina, Hong Jiang, Dong Ho Shin, Debora Kim, Xuejun Fan, Yanhua Yi, Natalie M. Melendez-Vazquez, Filipa Godoy-Vitorino, Joy Gumin, Frederick F. Lang, Marta M. Alonso, Juan Fueyo, Candelaria Gomez-Manzano. Viroimmunotherapy for solid tumors results in local and abscopal anti-cancer effects and the remodeling of tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3565.

Analysis of the Clinical Value of Delphian Lymph Node Metastasis in Papillary Thyroid Carcinoma.

Purpose Delphian lymph node (DLN) is often involved in metastasis of malignant head and neck tumors. This study evaluates the predictive utility of the DLN and the clinicopathological factors related to DLN metastasis in individuals suffering from papillary thyroid carcinoma (PTC). Patients and Methods. A retrospective analysis was made on 969 PTC patients enrolled from 2017 to 2021. Among these patients, 522 PTC patients are DLN positive and 447 are negative. Comparisons of clinicopathological characteristics between the DLN-positive and DLN-negative patients were made. Results The DLN was detected in 53.9% (522/969) cases, and DLN metastasis occurred in 20.3% (106/522) cases. The independent predictors of DLN metastasis (DLNM) include tumor size >1 cm, tumor located in the upper third thyroid or isthmus, central lymph node metastasis (CLNM), and lateral lymph node metastasis (LLNM). DLN-positive individuals exhibited a higher incidence and the number of CLNM, contralateral CLNM (CCLNM), and LLNM as compared to DLN-negative patients. Whether it is cN0 or cN+, the CLNM incidence was increased among DLN-positive patients as compared to that of DLN-negative patients. Conclusions Positive DLN indicated an increased rate and number of metastases in the cervical lymph nodes. Intraoperative rapid freezing is recommended to assess the status of the DLN, and careful assessment of cervical lymph nodes is warranted when the DLN is involved to implement an appropriate surgical approach.

Long-term outcomes following percutaneous microwave ablation for colorectal cancer liver metastases

Purpose To evaluate the overall survival (OS), local progression-free survival (PFS) and prognostic factors of patients with colorectal cancer liver metastases (CRLM) undergoing microwave ablation (MWA). Method A total of 132 patients were retrospectively enrolled who had been treated between 2010 and 2018. For the evaluation of survival rates, all patients were divided according to their indications (curative n = 57 and debulking (patients with additional non-target extrahepatic metastases) n = 75). In total, 257 ablations were evaluated for prognostic factors: number of liver metastases, primary tumor origin (PTO), diameter and volume of metastases, duration and energy of ablation. Results The OS was 32.1 months with 93.2% of patients free from recurrence at 28.3 months (median follow-up time). The one- year and three-year OS were 82.72% and 41.66%, respectively. The OS and recurrence-free survival of the curative group were statistically significantly higher than the debulking group (p < .001). Statistically significant prognostic factors for OS included the location of the primary tumor (p < .038) and the number of metastases (all p < .017). Metastasis diameter and volume and ablation duration and energy had no significant correlation with survival (p > .05). Conclusions Satisfactory OS and local tumor PFS can be achieved in patients with CRLM using MWA with the number of metastases and the location of the primary tumor influencing the outcome of patients. The metastasis’s size and the duration and energy used for ablation were not of significant prognostic value.

Significant survival improvements for patients with melanoma brain metastases: can we reach cure in the current era?

New therapies for melanoma have been associated with increasing survival expectations, as opposed to the dismal outcomes of only a decade ago. Using a prospective registry, we aimed to define current survival goals for melanoma patients with brain metastases (BM), based on state-of-the-art multimodality care. We reviewed 171 melanoma patients with BM receiving stereotactic radiosurgery (SRS) who were followed with point-of-care data collection between 2012 and 2020. Clinical, molecular and imaging data were collected, including systemic treatment and radiosurgical parameters. Mean age was 63 ± 15years, 39% were female and 29% had BRAF-mutated tumors. Median overall survival after radiosurgery was 15.7months (95% Confidence Interval 11.4-27.7) and 25months in patients managed since 2015. Thirty-two patients survived [Formula: see text] 5years from their initial SRS. BRAF mutation-targeted therapies showed a survival advantage in comparison to chemotherapy (p = 0.009), but not to immunotherapy (p = 0.09). In a multivariable analysis, both immunotherapy and the number of metastases at 1st SRS were predictors of long-term survival ([Formula: see text] 5years) from initial SRS (p = 0.023 and p = 0.018, respectively). Five patients (16%) of the long-term survivors required no active treatment for [Formula: see text] 5years. Long-term survival in patients with melanoma BM is achievable in the current era of SRS combined with immunotherapies. For those alive [Formula: see text] 5years after first SRS, 16% had been also off systemic or local brain therapy for over 5years. Given late recurrences of melanoma, caution is warranted, however prolonged survival off active treatment in a subset of our patients raises the potential for cure.

Predicting Lapatinib Dose Regimen Using Machine Learning and Deep Learning Techniques Based on a Real-World Study.

Lapatinib is used for the treatment of metastatic HER2(+) breast cancer. We aim to establish a prediction model for lapatinib dose using machine learning and deep learning techniques based on a real-world study. There were 149 breast cancer patients enrolled from July 2016 to June 2017 at Fudan University Shanghai Cancer Center. The sequential forward selection algorithm based on random forest was applied for variable selection. Twelve machine learning and deep learning algorithms were compared in terms of their predictive abilities (logistic regression, SVM, random forest, Adaboost, XGBoost, GBDT, LightGBM, CatBoost, TabNet, ANN, Super TML, and Wide&Deep). As a result, TabNet was chosen to construct the prediction model with the best performance (accuracy = 0.82 and AUC = 0.83). Afterward, four variables that strongly correlated with lapatinib dose were ranked via importance score as follows: treatment protocols, weight, number of chemotherapy treatments, and number of metastases. Finally, the confusion matrix was used to validate the model for a dose regimen of 1,250 mg lapatinib (precision = 81% and recall = 95%), and for a dose regimen of 1,000 mg lapatinib (precision = 87% and recall = 64%). To conclude, we established a deep learning model to predict lapatinib dose based on important influencing variables selected from real-world evidence, to achieve an optimal individualized dose regimen with good predictive performance.

Intratumor heterogeneity of positive lymph nodes provide a promising prognostic stratification factor for stage III colorectal cancer.

e15554 Background: Stage III colorectal cancer (CRC) is defined as patients with regional positive lymph nodes (pLN) but without distant metastasis, including stage IIIA, IIIB, IIIC. The prognosis of patients with stage III CRC varies dramatically, with 5-year survival rates ranging from 80 percent to 30 percent form stage IIIA to IIIC CRC, that does not exactly to be fully explained by the difference in the number of pLN. Therefore, other prognostic indicators need to be identified to improve and personalize prognosis prediction for patients with stage III CRC. Intratumor heterogeneity (ITH) widely exists between primary and metastatic lesions of CRC, however, there have been few studies focused on ITH of pLN. Therefore, this study aims to explore whether ITH of pLN could serve as a novel prognostic stratification factor for stage III CRC. Methods: We retrospectively analyzed the Poly-G genotype to reconstruct high-confidence phylogenetic trees for 20 CRC patients using 317 accurately scraped biopsy (134 primary tumors, 66 lymph node metastases and 37 normal samples). Root diversity score (RDS) index was used to reflect ITH of pLN. The association among Poly-G mutation rates, RDS index and clinical pathological data was analyzed. The area under the receiver operating characteristic (ROC) curves were calculated and the cut-off valve was confirmed. Results: Poly-G mutations accumulate in the occurrence and development of CRC. Poly-G mutation rate was correlated with tumor grade, N stage and microsatellite state (all P &lt; 0.05), and had a certain correlation trend with age (P = 0.066). The results of multivariate Cox regression analysis showed that ITH of pLN was an independent risk factor for recurrence and metastasis which lead to a poor progression free survival (PFS). The area under the curve (AUC) was 76%, and the cut-off valve of RDS index was 0.25. We also found ITH of pLN was not associated with substages of stage III CRC, which indicated that ITH of pLN and the number of metastases are two different dimensions. Conclusions: ITH of pLN may provide a promising prognostic stratification factor for the patients with stage III CRC. A higher ITH of pLN indicates that subclones with distant metastasis potential might more likely to exist in the primary tumors, which lead to a poor PFS including recurrence and distant metastasis. In addition, ITH of pLN is not related to the number of lymph node metastases in stage III CRC, suggesting that ITH of pLN is promising to serve as a supplementary strategy of TNM staging for patients with Stage III CRC.

Predictive factors of toxicity of immune checkpoint inhibitors (ICI) in older patients with lung cancer: The ToxImmune study.

12048 Background: Immunotherapy (Im) improved the survival of patients with lung cancer. It may be responsible for adverse events impacting these patients' quality of life. We have few data on the tolerance of older cancer patients (OP) to immunotherapy. The Toximmune study aims to describe the safety of older lung cancer patients to Im and identify clinical, biological and radiological markers that can help to predict immune-related adverse events for OP. Methods: All patients aged 60 years and older who had received at least one dose of ICI between June 2015 and December 2020 and diagnosed with lung cancer were included. We collected patients' baseline demographic characteristics, biological blood markers and imaging by PET-scanner. All adverse events (AEs) and immune-related AEs (irAEs) were recorded (CTCAE V.5.0). Results: 49 patients were included, median age was 71 (range 61-97). The incidence of grade 2 and grade 3-4 was 34% and 6% respectively. The main irAEs reported were: asthenia in 51% patients after 13.5 months median delay (grade ≥2 in 22%),musculoskeletal disorders in 45% after 21 months median delay (grade ≥2 in 10%), pneumonitis in 37% after 21 months median delay (grade ≥2 in 10%), and colitis in 35% after 21 months median delay (grade ≥2 in 6%). Female sex, primitive tumor SUV max &lt; 5, number of metastases ≥ 3, prior systemic therapy &gt; 1, PLR &lt; 250 were significantly associated with a risk of toxicity in univariate analysis (p &lt; 0.05) We developed the ToxImmune score (0, 1, or ≥2) to predict the risk of having a grade ≥2 adverse event by adding the following risk factors: Primitive Tumor SUV &lt; 5 = 1, Number of metastases ≥3 = 1, And L1 = 0 vs &gt; L1 = 1. The incidence of grade ≥2 adverse events was 31%, 35% and 86% with ToxImmune scores 0, 1 and 2 respectively (p = 0.032). Median overall survival times (OS) &amp; progression-free survival (PFS) were 21.8 &amp; 21 months, 15.1 &amp; 6.6 months, and 9.8 &amp; 2.1 months for ToxImmune scores 0, 1 and ≥ 2 respectively (p = 0.06 &amp; p = 0.001). There was significant association between the ToxImmune score and the risk of "progressive disease" at the first assessment of the disease: 16% for score = 0, 48% for score = 1, and 71% for score = 2, (p = 0.01). Conclusions: The quality of life is our goal for OP care. The ToxImmune score, which is based on objective clinical parameters, identifies OP with a significant higher risk of severe adverse events. Also, this score was significantly associated with patients’ PFS risk of developing rapid tumor progression. It could be used in clinical practice to personalize toxicity surveillance in OP treated for lung cancer with immunotherapy. This score will be validated in larger prospective cohorts.

Predictive value of MAOB gene expression for targeted therapy in patients (pts) with metastatic colorectal cancer (mCRC) enrolled in CALGB (Alliance)/SWOG 80405.

3580 Background: Monoamine oxidases (MAOs), including MAOA and MAOB, are mitochondrial enzymes responsible for catalyzing monoamine oxidation. Increased expression of MAOs were found in several cancer types and high MAOB was associated with worse disease stage and poorer survival in CRC. Positive and negative correlations of MAOB expression with mesenchymal type and epithelial type gene expressions, respectively, have been reported. Hence, we investigated whether MAOB expression is predictive for targeted therapies in mCRC. Methods: 430 mCRC pts treated with either bevacizumab (BEV, n = 224) or cetuximab (CET, n = 206) in combination with first-line chemotherapy within the CALGB/SWOG 80405 trial were included in the analysis. MAOB RNA was isolated from FFPE tumor samples and sequenced on the HiSeq 2500 (Illumina). Overall survival (OS) and progression-free survival (PFS) were compared between groups of pts categorized by tertiles of MAOB expression into high (H), medium (M) and low (L). Hazard ratios (HR) and 95% confidence intervals (CI) were computed from multivariable Cox proportional hazards model, adjusting for age, sex, location, number of metastases, KRAS, MSI status, and treatment with FOLFOX or FOLFIRI. Sensitivity analyses were conducted after stratifying by sex. Logrank P-values describe differences without adjustment for patient characteristics. Results: In CET-treated pts, MAOB-L showed significantly longer OS (median 39.2 vs 30.9 vs 15.9 months, logrank P = 4.7E-05, L vs H (as reference) adjusted HR 0.42, 95% CI [0.27, 0.65]) and PFS (median 13.2 vs 11.8 vs 7.6 months, logrank P = 0.006, L vs H adjusted HR 0.59 [0.40, 0.88]) compared to MAOB-M and MAOB-H, respectively. Similar results were observed when evaluating MAOB expression as a continuous variable. In BEV-treated pts, no significant differences were observed when comparing MAOB expression tertiles; however, pts with lower MAOB expression had significantly better OS, but not PFS, when evaluating MAOB as a continuous variable (Cox LRT P = 0.015, covariate adjusted). In CET-treated pts, the effect of MAOB expression was observed in male but not female pts (OS: median 40.3 vs 30.9 vs 16.1 months by MAOB-L, M, H, respectively, logrank P = 6.8E-05, L vs H adjusted HR 0.33 [0.19, 0.59]; PFS: median 13.8 vs 12.6 vs 7.9 months, logrank P = 0.001, L vs H adjusted HR 0.46 [0.28, 0.79]). A significant interaction was observed between MAOB expression and treatment for OS ( P = 0.010) in males and females combined, but only in males ( P = 0.018) when stratified by sex. Conclusions: Our results suggest that pts with MAOB-L tumors may have greater benefit from CET-based treatment and that targeting MAOB may be a promising strategy to improve patient outcomes. Further validation studies are warranted to develop a novel personalized approach based on MAOB expression in mCRC pts. Clinical trial information: NCT00265850.

Intraperitoneal administration of dihydrobromide-2-(3,4-dihydroxyphenyl)-9-diethylaminoethylimidazo-[1,2-a]benzimidazole has an antitumor effect against syngeneic tumors of melanoma and lung.

e21568 Background: Despite the wide range of modern drugs for cancer drug therapy, there is still a problem of their high toxicity, which leads to the search for antitumor agents that selectively suppress or inhibit the growth of neoplastic cells. Over the past decades, many benzimidazole derivatives have been reported with potent antitumor activity due to its structural similarity to naturally occurring nucleotides. The aim is to study the effect of dihydrobromide-2-(3,4-dihydroxyphenyl)-9-diethylaminoethylimidazo-[1,2-a]benzimidazole on the growth and metastasis of transplantable experimental tumors after intraperitoneal administration. Methods: Melanoma B16 and Lewis lung carcinoma (LLC) were inoculated subcutaneously into 96 female C57/Bl6j mice (weighing 18–20 g). Intraperitoneal (0.3 ml/day) administration of the drug was carried out 48 hours after tumor inoculation 1 time per day for 10 days in single doses of 6.15 (1st), 30.75 (2nd) and 61.5 (3 -i) mg/kg. The control group of animals was injected with saline. The increase in life expectancy (T/C,%), the degree of tumor growth inhibition (TGI,%) and the metastasis inhibition index (MII,%) were calculated. Results: With intraperitoneal administration of 2-(3,4-dihydroxyphenyl)-9-diethylaminoethylimidazo[1,2-a]benzimidazole at a dose of 30.75 mg/kg, it increased the lifespan of animals with B16 (T/C = 151.3%). On the 7th day after the end of treatment in the 1st (6.15 mg/kg) and 2nd groups (30.75 mg/kg) a slight decrease in the volume of the primary tumor B16 was found, which remained by the 14th day only in 2 -th group (TGI = 23.6%). Also for LLC in the 30.75 mg/kg dose group, the T/C index was 171.6%. The volume of the primary subcutaneous tumor node was already 2.3 times lower on the 1st day after the end of treatment compared to the control (p &lt; 0.05) and this effect persisted up to the 14th day (the tumor volume was reduced by 2. 1 and 1.9 times on the 7th and 14th days, respectively, at p &lt; 0.05). In groups with B16, the use of the substance reduced the number of metastases in the 1st and 2nd groups by 2.5 and 3.0 times, respectively (p &lt; 0.05), relative to the control. The frequency of metastasis was in the 1st group B16 -60.4%, and in the 2nd - 74.5%. Similar results of antimetastatic activity were shown for LLC: the number of metastases in the 1st and 2nd groups was reduced by 2.1 and 2.6 times, respectively (p &lt; 0.05) compared with the control. MII was higher for LLC compared to B16 and amounted to 63.1 and 79.6 in groups for groups 1 and 2, respectively. Conclusions: When administered intraperitoneally, 2-(3,4-dihydroxyphenyl)-9-diethylaminoethylimidazo[1,2-a]benzimidazole dihydrobromide showed an antitumor effect against primary Lewis lung carcinoma and its lung metastases, as well as against lung metastases for melanoma B16 mice.

A phase I study of ADXS-504, a cancer type specific immunotherapy, for patients with biochemically recurrent prostate cancer.

TPS5115 Background: Roughly 20%-30% of prostate cancer patients experience biochemical recurrence (BCR), rising prostate-specific antigen (PSA) levels, after definitive therapy with radical prostatectomy (RP) or radiation therapy (RT). The optimal therapy and timing of treatment for BCR is unknown, however, for patients who are not eligible for salvage radiation, androgen deprivation therapy (ADT) is the standard first-line treatment. ADT is an effective therapy but has many acute and long-term toxicities. Novel strategies to reduce ADT exposure and prolong disease control are needed. ADXS-504 is a live attenuated Listeria monocytogenes (Lm)-based immunotherapy consisting of a truncated nonhemolytic fragment of listeriolysin O (tLLO) fused to a total of 24 tumor associated antigens (TAA). ADXS-504 was designed so that nearly 20% of patients with BCR cancer will express at least one of the targeted hotspot mutation peptide antigens and that &gt;90% will express at least one of the TAAs targeted by the sequence-optimized TAA peptide antigens. By combining these shared, commonly expressed antigen targets into a single Lm-based immunotherapy, ADXS-504 provides the potential for a potent, disease-specific approach to treating patients with prostate cancer. In addition to the generation of antigen-specific T cell responses, treatment with Lm-based immunotherapies has been shown to reprogram the tumor microenvironment (TME), by reducing the frequencies and function of immunosuppressive regulatory T cells and myeloid-derived suppressor cells within the TME. A pre-clinical murine model showed that a proto-type Lm-construct could reduce the number of metastases after removal of the primary tumor by eliminating residual tumor cells. We hypothesize that ADXS-504 is safe and promotes anti-tumor immune responses that may delay or prevent the use of ADT in castration sensitive prostate cancer. Methods: This is an open-label dose-escalation phase I trial of ADXS-504 in patients with BCR of prostate cancer previously treated with RP or RT. The study will enroll up to 18 subjects with BCR with a PSA ≥ 0.3 and a PSADT ≥ 4 months without evidence of metastatic disease on traditional CT imaging and bone scans. ADXS-504 will be given by IV every 4 weeks level for 6 study treatments, followed by maintenance therapy given every 12 weeks for 4 doses for overall total of 10 doses of study treatment. DLTs will be evaluated over the first 28 days of treatment. PSA response, PSADT, and adverse events will be summarized. The Kaplan- Meier method will be used to estimate time to PSA progression and rPFS. Immunologic activity will be evaluated by ELISpot analysis, flow cytometry, and multiplex assays and blood samples will be collected for gene sequencing analysis. The study is currently open to enrollment. Clinical trial information: NCT05077098.