Median Survival Rate Research Articles

Clinical outcomes of hepatic arterial infusion chemotherapy combined with tyrosine kinase inhibitors and anti-PD-1 immunotherapy for unresectable intrahepatic cholangiocarcinoma.

To compare the treatment efficacy and safety of tyrosine kinase inhibitors (TKIs) and anti-programmed cell death 1 (PD-1) immunotherapy combined with transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) for patients with unresectable intrahepatic cholangiocarcinoma (ICC). Patients with unresectable ICC received TKIs and anti-PD-1 immunotherapy combined with HAIC (HTP group) or TACE (TTP group)were included. The clinicopathological characteristics, treatment efficacy, and adverse events (AEs) were compared between the two groups. The factors associated with response rate to the treatments were evaluated. A total of 58 patients were enrolled, with 39 in the HTP group and 19 in the TTP group. Patients in the HTP group exhibited a better objective response rate (ORR; Response Evaluation Criteria in Solid Tumors [RECIST] 48.7% vs 15.8%, P=0.02; modified RECIST [mRECIST] 61.5% vs 21.1%, P=0.004) and disease control rate (DCR; 82.1% vs 36.8%, P=0.001) compared to the TTP group. The median progression-free survival (PFS) rate was not reached and the 1-year PFS rate was 61.9% in the HTP group, whereas the median PFS was 11.0months and the 1-year PFS rate was 31.6% in the TTP group. The type of treatment and tumor size were significant factors for the response rate. More patients in the HTP group presented rash, abdominal pain and hand-foot syndrome, but all AEs were relieved after symptomatic treatment, and no treatment-related death occurred. For unresectable ICC, treatment with a combination of HAIC with TKIs and anti-PD-1 immunotherapy was effective and safe. Tumor size might serve as a significant factor for the response rate following treatment for unresectable ICC.

Salvage PTBD With Chemotherapy Improves Survival in Patients With Unresectable Malignant Biliary Obstruction - A Single Center Retrospective Study.

Malignant biliary obstruction (MBO) is a life-threatening condition. We aimed to investigate the outcome of salvage percutaneous transhepatic biliary drainage (PTBD) in patients with unresectable MBO due to failure of management by endoscopic retrograde cholangiopancreatography (ERCP) and/or prior surgical bypass. Fifty-two consecutive patients (mean age, 69 years; 44.2% women) underwent salvage PTBD between 2013 and 2020. The median overall survival rate was 4.2 months, with a 95% confidence interval (CI) of 1.9-5.7. The median overall survival (OS) were 11.1 months and 1.9 months for patients who underwent chemotherapy (n=17) and best supportive care (n=35), respectively (p=0.0005). Independent factors predicting poor outcome were best supportive care, with a hazard ratio (HR) of 3.3 (95%CI=1.3-8.5), American Society of Anesthesiologists physical status classification (ASA) with a HR of 13.5 (95%CI=1.3-136.0) and Eastern Cooperative Oncology Group (ECOG) performance status of 4, with a HR of 3.3 (95%CI=1.0-6.2). Salvage PTBD with chemotherapy has the potential to achieve prolonged survival in patients with unresectable MBO, including those with failure of ERCP and/or surgical bypass.

VHL and DNA damage repair pathway alterations as potential clinical biomarkers for first-line TKIs in metastatic clear cell renal cell carcinomas

PurposeVascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) are being used for the first-line treatment of metastatic clear cell renal cell carcinoma (mccRCC). Here, we set out to explore associations between genomic statuses, gene expression clusters and clinical outcomes of mccRCCs upon the application of VEGFR-TKIs.MethodsA retrospective study of 56 patients with mccRCC who received first-line VEGFR-TKIs and who underwent genomic profiling and whole transcriptome sequencing was conducted. Survival analysis was carried out using log-rank tests and Cox regression analyses, and Kaplan–Meier curves were plotted. Clustering was performed using the K-means method.ResultsAmong the 56 patients tested, 17 harbored DNA Damage and Repair (DDR) pathway alterations and 35 VHL mutations. The median progression-free survival (PFS) rates for the DDR and VHL alteration groups were 18 and 18 months, respectively, compared with 14 and 10 months for the nonmutant groups. DDR mutations, VHL mutations and co-mutations were identified as prognostic biomarkers of a longer PFS (p = 0.017, 0.04, 0.014). K-means clustering of expressed transcripts revealed three clusters of 40 patients: C_1, C_2 and C_3. The C_1 cluster exhibited the best PFS and objective response rate (ORR) to TKI therapy, with the highest proportion of DDR and VHL mutations. Further analysis of the tumor immune environment revealed that the C_1 cluster was enriched in activated CD8 T cells and effector CD4 T cells, whereas the C_2 cluster was enriched in eosinophils, mast cells and DC cells and, thus, in immunosuppressive cells.ConclusionsWe found that patients with mccRCC harboring DDR and VHL alterations were more likely to benefit from first-line VEGF-TKI systemic therapy than patients with wild-type disease. In addition, we found that a three-cluster prognostic model based on gene expression can predict PFS and ORR, which was well-matched with activated TIL infiltration.

An assessment of disease occurrence and mortality in marine fish farming in Spain

Marine fish farming in Spain, as in most Mediterranean countries, focuses on the production of European seabass (Dicentrarchus labrax) and gilthead seabream (Sparus aurata). The sector has experienced performance problems that affect the industry’s competitiveness, and infectious and parasitic diseases have been described as being among the main causes of losses. Whereas companies are aware of the need to assess the impact and causes of such losses, the analysis of disease occurrence and mortality in seabass and seabream has received scarce attention from the sector and official administrations. Through information obtained from interviews and surveys, it has been possible to carry out an assessment of disease occurrence and mortality in marine fish farming in Spain. The median survival rate data for seabass and seabream was shown to be slightly higher in seabream, although no significant differences were found between species. It was not possible to further differentiate the causes of diseases or losses, as they were generally not standardized into categories and they also varied between companies. Nevertheless, the aim was to prompt producers and health management stakeholders into discussing how to improve the collection and analysis of data for relevant disease outbreaks and mortalities. Moreover, EU Regulation 2016/429 (the ‘Animal Health Law’) calls on Member States to implement disease surveillance programmes to investigate ‘increased mortality’ events in order to be alert for possible emerging diseases. Good knowledge of a disease situation and its impact on production represents a base mechanism for designing health surveillance. Therefore, the standardization of health data collection and its analysis will help countries in the implementation of surveillance programmes and rapid alert mechanisms in order to combat emerging diseases at an early stage.

Stereotactic radiofrequency ablation of tumors at the hepatic venous confluence.

Radiofrequency ablation (RFA) is subject to "heat-sink" effects, particularly for treatment of tumors adjacent to major vessels. In this retrospective study, 104 patients with 137 tumors (40 HCC, 10 ICC and 54 metastatic liver tumors) close to (≤1cm from) the hepatic venous confluence underwent stereotactic RFA (SRFA) between June 2003 and June 2018. Median tumor size was 3.7cm (1.4-8.5) for HCC, 6.4cm (0.5-11) for ICC and 3.8cm (0.5-13) for metastases. Endpoints comprised safety, local tumor control, overall and disease-free survival. The overall major complication rate was 16.0% (20/125 ablations), where 8 (40%) were successfully treated by the interventional radiologist in the same anesthetic session and did not prolong hospital stay. 134/137 (97.8%) tumors were successfully ablated at initial SRFA. Local recurrence (LR) developed in 19/137 tumors (13.9%). The median and overall survival (OS) rates at 1-, 3-, and 5- years from the date of the first SRFA were 51.5 months, 73.5%, 67.0%, and 49.7% for HCC, 14.6 months, 60.0%, 32.0% and 32.0% for ICC and 38.1 months, 91.4%, 56.5% and 27.9% for metastatic disease, respectively. SRFA represents a viable alternative to hepatic resection for challenging tumors at the hepatic venous confluence.

Understanding clinical decision-making in mesothelioma care: a mixed methods study

IntroductionMalignant pleural mesothelioma is a rare, incurable cancer arising from previous asbestos exposure; patients have a poor prognosis, with a median survival rate of 8–14 months. Variation in mesothelioma clinical...

64-Year-Old Woman With Aphasia and Troponin Elevation

64-Year-Old Woman With Aphasia and Troponin Elevation

P-472 Extended oocyte cryostorage period is not associated with decreased post-warm survival rate: a retrospective study of 5208 vitrified/warmed oocytes at a single centre

Abstract Study question Is extended oocyte cryostorage period associated with decreased post-warm survival rate? Summary answer There is a weak inverse correlation between oocyte cryostorage duration and post-warm survival (r = 0.09, p = 0.01). This equates clinically to a reduction of 0.0003% survival/day. What is known already It is widely reported that extended embryo storage is not associated with reduced post-warm survival rates, however there are no such studies in the literature relating to the effect of extended cryostorage duration on oocytes. Successful outcomes from oocyte vitrification are related to reduced patient age however UK government regulations only permit those with a medical indication to store and use their gametes over 10 years. With the intended extension of this 10-year limit, it is therefore fair for clinics to expect an increasing population of younger patients choosing to store their oocytes for longer periods. Study design, size, duration A retrospective audit of all vitrified/warmed oocyte cycles at a single centre from 2014-2021. A total of 5208 oocytes were included in the study, from 602 treatment cycles. Participants/materials, setting, methods Patients of all ages were included in the study. Data was obtained retrospectively from IDEAS V6.0 at CRGH, UK. All oocytes were vitrified/warmed according to the Irvine Scientific/Kitazato media protocols, with all other protocols excluded. Data was analysed using IBM® SPSS® Statistics V24. Kendall’s tau-b and Spearman’s Rho correlation coefficients measured the strength and direction of association between variables. A linear regression model was used to establish the effect of duration on survival per day. Main results and the role of chance The median age at oocyte vitrification was 31 years (range 18-45 years, LQR=25 years, UQR=37 years). There was a median of 8 oocytes thawed per case (LQR=6, UQR 11 oocytes) with a median of 6 oocytes surviving (LQR=3, UQR=9 oocytes). The median survival rate across all ages was 81% (LQR=58%, UQR=100%). There was no significant difference in oocyte survival rate between age categories (<35 years vs > 35 years; p = 0.137, n = 414 & 188 respectively). Increasing age was however, significantly correlated with fewer oocytes vitrified (r = 0.283, p = 0.001). There is a weak inverse correlation between oocyte cryostorage duration and post-warm survival (r = 0.09). This correlation reaches statistical significance (p = 0.01), however this equates clinically to a reduction of 0.0003% survival rate per day. No significant difference was observed in post-warm oocyte survival rate across duration of vitrification categories (≤3 years vs 4-5 years vs > 5 years; p = 0.154, n = 416, 141 & 45 cases respectively). The median duration for which oocytes remained in cryostorage was 565 days (1.6 years) (LQR & UQR=233 days (0.64 years) and 1390 days (3.8 years) respectively). Limitations, reasons for caution Although retrospective, the study benefits from many cycles, all of which were carried out at the same unit, using the same vitrification/warming media protocol. Limitations of this study include a relatively short median cryostorage duration time which could be masking the true effect of duration on post-warm oocyte survival. Wider implications of the findings Following a public consultation in 2020 regarding the 10-year storage limit for gametes and embryos, the UK Government proposed changes the current legislation which will allow patients to extend cryostorage beyond 10 years without a medical indication. To our knowledge, this is the first study to lend support this movement. Trial registration number IRB-001C03-01-22

Stages of stereotactic radiosurgery in the treatment of recurrent glioblastomas

Objective: to evaluate the effectiveness of stereotactic radiosurgery as a therapy method taking into account overall survival in patients with recurrent glioblastoma at all stages of treatment. Materials and methods. A sample of patients (66 ailments) who were treated in 2016-2021 with a molecularly confirmed diagnosis of wild-type glioblastoma was analyzed. Only patients, who, were treated in several stages and as a rule, underwent stereotaxic radiosurgery (SRS), or SRS alone after a biopsy, or SRS in case of relapse, after surgery and radiotherapy, or SRS for subsequent relapses were selected. When evaluating the results, the following were taken into account: 1) age at the diagnosis, 2) volume of surgical resection, 3) use of radiation therapy, 4) use of adjuvant chemotherapy after SRS and response evluation criteria in solid tumors. Overall survival (OS) was assessed after diagnosis and at the time of SRS. Results. Patients received SRS at an average 10 months after initial diagnosis. Median duration of follow-up was 8 months after SRS and 12 months after diagnosis, median OS for all patients was nine months (1 to 42 months) after SRS and 20 months (4 to 64 months) respectively. The median survival after SRS was 9 months (p=0.008; χ2=7.008). The median OS for younger patients (<50 years) was 32.5 months, for elderly patients (>50 years) was 14.8 months (p=0.04; χ2=3.870). The median overall survival rate was 32.2 months in patients who received SRS 10 months after the diagnosis was made, and 16 months in those who received SRS earlier than 10 months (p=0.004, χ2=8.145). Radiosurgical doses ≥15 Gy were correlated with a mean survival rate of nine months and seven months in patients treated at doses <15 Gy (p=0.01; χ2=6.756). In patients who received adjuvant therapy with bevacizumab and/or chemotherapy after SRS, the median OS was 12 months, in patients who did not receive additional therapy after SRS, it was 7 months (p=0.04, χ2=4.19). Conclusions. Stereotactic radiosurgery promotes the effectiveness of glioblastoma treatment due to the possibility of carrying out this method at various stages of treatment. The overall survival of our patients depended on the period of SRS after diagnosis, patient age, radiation dose, and adjuvant chemotherapy.

Merkel cell carcinoma: Epidemiology, disease presentation, and current clinical practice outcomes

Using the National Cancer Database, we introduce the findings of a retrospective investigation of the largest cohort of cases with Merkel cell carcinoma (N = 20,829). A decreasing proportion of stage I (P = .0004) and stage II (P = .0065) Merkel cell carcinoma among skin cancers was complemented by an increasing proportion of stage III disease (P < .0001). A predominance of non-Hispanic White (96.4%), male (62.6%) patients with a mean age of 74.5 ± 10.8 years and Medicare coverage (73.5%) was observed. Stage I was the most common presenting stage at diagnosis (29.2%), followed by stages II (12.7%), III (11.0%), and IV (3.8%). Most Merkel cell carcinoma tumors grew outside the head and neck (53.4%) and showed a nodular growth pattern (66.0%) but no extracapsular lymph node (90.5%) or lymphovascular involvement (63.8%). Narrow-margin excision and radiation therapy (RT) were used in 75.2% and 56.3% of tumors, respectively. Wide-margin excision lead to improved overall survival (P < .001) versus narrow-margin excision, particularly in stage III (difference in the median overall survival rate [ΔmOS], 23.7 months; P < .001). RT showed a significant OS benefit (P =.006), most pronounced in stage II (ΔmOS, 37.8 months) followed by stage I (ΔmOS, 16.1 months; P < .001). The survival benefit with primary-site RT (ΔmOS, 24.0 months) was higher than that with primary-site/lymph node RT (ΔmOS, 5.2 months; P < .001). Wide-margin excision independently predicted improved OS (hazard ratio, 0.577; 95% CI, 0.403-0.826; P = .003) versus narrow-margin excision and RT predicted better OS (hazard ratio, 0.608; 95% CI, 0.424-0.873; P = .007) versus no RT on multivariable analysis.

Post-operative Mortality and Survival Rate in the Patients With Esophageal Carcinoma

Background: Esophageal cancer is the eighth-most common cancer and the sixth-most common cause of cancer death worldwide. In Iran, its prevalence is high. Surgery is recommended for tumors in early stages. Objectives: This study aims to determine demographic data, therapeutic approaches, postoperative mortality, and survival rate in patients with esophageal cancer who were managed in a referral hospital. Methods: In a cohort study, the patients hospitalized during six-year period were evaluated. Demographic data, tumor characteristics, laboratory data, surgical approaches, and survival time were obtained. Statistical analysis was performed using life tables, proportional hazard Cox regression, and the Kaplan-Meier method by SPSS version 20 software. Survival curves were compared by log-rank analysis. Results: Over six years, 92 patients were admitted of which 54 (58.7%) were male. The average age was 63.08±12.03 years. Ten patients (10.8%) were below 50 years old. Squamous cell carcinoma (SCC) was the most common type (85.8%). Fifty-three patients (57.6%) were selected for the surgery. Postoperative mortality in 30 days occurred in 7 patients (13.2%). The median survival rate was 12.8±2.92 months. The survival rate for one, three and five years were 51.94%, 24.67% and 19.48%, respectively. Two factors that had significant statistical correlation with median survival time were metastasis (P=0.01) and vomiting (P=0.003). Conclusion: Esophageal cancer is a poor prognostic disease and esophagectomy is a morbid operation. To reduce postoperative mortality and increase the survival time, better patient selection and operations by expert surgeons must be considered.

Abstract 4056: ONC201 in combination with carboplatin and etoposide as a novel triple drug treatment for small cell lung cancer (SCLC)

Abstract Lung cancer is the leading cause of cancer death in both men and women according to the American Cancer Society, with more deaths than colon, breast, and prostate cancer combined. Small cell lung cancer (SCLC) comprises about 10 to 15 percent of all lung cancer diagnoses. Frequent loss of RB1 and mutations in p53 in SCLC make it rather difficult to develop targeted therapies. Many current therapies rely on toxic chemotherapy or immunotherapy to combat the aggressive nature of SCLC; however, even with the advent of new therapies, the median survival rate has remained relatively low at 12 to 16 months. SCLC is also characterized by a high mutation rate, resulting in patients becoming increasingly resistant to treatments. This calls for a novel combination to extend patient life expectancy. ONC201 is an imipridone that is currently in clinical trials for its proapoptotic effects in several cancer types. We propose that combining ONC201 with standard first-line chemotherapeutic agents etoposide and carboplatin will result in a synergistic effect and serve as a novel treatment plan for SCLC patients. SCLC cell lines H1048 and H1105 were treated with the novel triple drug combination ONC201, etoposide, and carboplatin. Cell-Titer Glo cell viability assays were conducted for 72 hours to see the additive and/or synergistic effect of novel triple drug treatment. Western blots were also run to evaluate the expression of proapoptotic protein cleaved PARP or expression of cellular metabolic stress protein ATF4 to explore the synergistic effect of triple drug treatments in SCLC cell lines. Cell viability after the triple drug treatment in both cell lines H1048 and H1105 may indicate a potential synergistic effect. Preliminary western results indicate that the triple drug treatment results in an increase in cPARP or ATF4 expression relative to the vehicle, suggesting a synergistic effect of the triple drug treatment. We are currently exploring the novel combination and potential underlying mechanisms behind the synergistic effects of the triple drug treatment. Future studies will evaluate this triple drug combination treatment in mouse models of SCLC. Citation Format: Young S. Lee, Lanlan Zhou, Christopher Azzoli, Wafik S. El-Deiry. ONC201 in combination with carboplatin and etoposide as a novel triple drug treatment for small cell lung cancer (SCLC) [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 4056.

Abstract 2770: Microbiota, mutational landscape and tumor sidedness of colorrectal cancer

Abstract Background: Colorectal cancer (CRC) is one of the most common cancers in the world, and it is one of the leading causes of cancer-related death. New biomarker candidates have emerged as an important prognostic and predictive factor and genetic profile approach has been used in the choice of targeted therapies and in the prediction of drug response. The aim of this study was performed a comprehensive genomic profile and intestinal microbiota characterization in peruvian CRC patients to define biomarkers for decision making. Methods: Patients with CRC diagnosed in 2019 and treated at INEN were included. Tumor samples were collected to assessed the presence of high-risk human papillomavirus (HPV) and Epstein-Bar virus (EBV) by qPCR, microsatellite instability (MSI) by IHC and somatic genomic alterations by next generation sequencing (NGS) using Ampliseq FOCUS panel (Illumina). Fecal samples were self-collected to performed V3-V4 region 16S ribosomal RNA metagenomics sequencing (Illumina). Results: The study included 40 CRC patients with a mean age at diagnosis of 56 (28-90) years, 59.2% were men. Clinical stages were distributed, in I-II (16.5%), III (37.5%), IV (27.5%). The remaining 12.5% had an unknown tumor stage at diagnosis. The 62.5% of patients underwent tumor surgical treatment. Most tumors (85%) were adenocarcinoma NOS and moderately differentiated (65%). Tumor location was rectum (RC; 27.5%), right side colon (RCC; 42.5%) and left side colon (LCC; 30%). Chemotherapy was administered in 30%. The median follow-up period was 11.1 months (2-28). MSI was high (20%), low (10%) and stable (70%). HPV and EBV DNA was detected in 42.5% and 82.5% of CRC patients respectively. The prevalence of genomic alterations was 77.5%. KRAS alterations were found in 47.5% patients. BRAF (5%), NRAS (2.5%), PIK3CA (12.5%), APC (2.5%), and AKT1 (2.5%). All PIK3CA and BRAF variants were found in RCC. No variants were found in the NTRK or HER2 amplifications. Patients with BRAF variant had a median survival rate only 5 months (3-7). MSI-high/low was present only in colon, showing dominance on the RCC (66.7%). Verrucomicrobia, Staphylococcus, Peptostreptococcus and Clostridium were present in both RCC and LCC. Clostridium and Peptostreptococcus were highly enriched in the LCC. Campylobacter and Spirochaeta were found only in the LCC. Surprisingly, Fusobacterium was found in RCC except one patient in LCC. Bifidobacterium and Acinetobacter were present only in LCC and RC. Elusimicrobia, Shigella and WPS-2 were found only in RC. Conclusion: The current pressure to select the best treatment has generated intense interest in the evaluation of CRC molecular alterations characteristic to define prognostic and predictive biomarkers of disease and treatment in our population. This study constitutes the first integrative biomarkers research in peruvian CRC patients showing a diferent molecular signatures between RCC, LCC and RC patients. Citation Format: Bruno A. Muñante Luna, Jhoysi Casas Goñas, Manuel Chumpitaz, Juan Pablo Cerapio, Marcos Santos Chavez, Mariela Huerta-Rosario, Franco Doimi Garcia, Juan F. Olivos Gonzales, Claudia Jiménez Orosco, Daniel Valdivia Leonardo, Luis F. Barreda Bolaños, Silvia Neciosup Delgado, Victor Castro Oliden, Paola Montenegro Beltran, Luis Mas Lopez, Eduardo Payet Meza, Carolina Belmar-López. Microbiota, mutational landscape and tumor sidedness of colorrectal cancer [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 2770.

Abstract 5360: Temozolomide-resistant glioblastoma cells are collaterally sensitive to ferroptosis through NRF2 high expression

Abstract Glioblastoma patients have a poor prognosis with a low median survival rate mainly due to temozolomide (TMZ) resistance. NRF2 is an important transcript factor involved in chemotherapy resistance due to its ability to regulate genes related to the antioxidant response and to prevent cell death processes, such as ferroptosis. However, the relation between NRF2 and iron-dependent cell death is contradictory and poorly understood. This study aimed to analyze the role of NRF2 in ferroptosis modulation in glioblastoma cells. To this end, it was analyzed two human glioblastoma cell lines (U251MG and T98G) after treatment with TMZ, ferroptosis inducers (Erastin, RSL3, and Sorafenib), and ferroptosis inhibitor (Ferrostatin-1). Also, we performed gene expression analysis of glioma patients. Our results demonstrated that T98G compared to the U251MG was more resistant to chemotherapy and showed elevated levels of NRF2 expression and its targets xCT, HMOX1, and ABCC1. Interestingly, T98G cells revealed higher sensitivity and lipoperoxidation levels after ferroptotic treatment. Next, we established T98G NRF2 silenced cells and we observed a significant reduction in cellular viability after TMZ treatment when compared to wild-type cells. On the other hand, T98G-shNRF2 was more resistant to ferroptosis induction, indicating that NRF2 plays a key role in the modulation of chemoresistance and ferroptosis. After, we showed that NRF2 controls levels of ABCC1/MRP1 in glioblastoma cells, and ABCC1 silencing promotes sensitivity to TMZ and resistance to Erastin. These results support a possible mechanism of ferroptosis modulation by NRF2 on TMZ-resistant gliomas through ABCC1, which has been recently associated with ferroptosis induction by promoting efflux of glutathione out of the cell. Furthermore, we confirmed that NRF2 has a positive correlation with ABCC1 in glioma patients, and higher ABCC1 expression was associated with tumor aggressiveness. Also, we validated ABCC1 as an independent prognostic factor for poor overall survival on glioma. Finally, we observed that T98G cells have sensitivity to the ferroptosis inducer FDA-approved, sorafenib. Altogether our data suggest that high levels of NRF2 may result in ferroptosis sensitivity on glioblastoma through the high levels of expression of its pro-ferroptotic target ABCC1, once the xCT system is blocked by Erastin. Thus, glioblastoma cell vulnerability to ferroptosis by NRF2 and ABCC1 high expression can be an Achilles’ heel to reverse drug resistance on glioblastoma through the treatment with ferroptosis inducers. Citation Format: Izadora de Souza, Linda Karolynne Monteiro, Camila Banca Guedes, Marcela Latancia, Marina Tomaz Andrade, Matheus Molina Silva, Bruna Contieri, Bruna Felício Milazzotto Ribeiro, Mariana Lazarini, Luciana Gomes, Clarissa Rocha. Temozolomide-resistant glioblastoma cells are collaterally sensitive to ferroptosis through NRF2 high expression [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 5360.

Impact of radiotherapy on survival in resected or unresectable anaplastic thyroid carcinomas, a Rare Cancer Network study

PurposeAnaplastic thyroid carcinomas (ATC) are a heterogenous group of tumors of overall dismal prognosis. We designed models to identify relevant prognostic factors of survival of irradiated ATC patients including radiotherapy modalities (field size, dose). Material and methodsBetween 2000 and 2017, 166 ATC patients’ treatments were divided into surgery and postoperative radiotherapy (poRT) or definitive radiotherapy (RT). Multiple imputation approach was used for missing data. Prognostic factors were identified using Lasso-penalized Cox modelling and predicted risk scores were built. ResultsPatients undergoing RT (n=70) had more adverse patient and disease characteristics than those undergoing poRT (n=96). Corresponding median survival rates were 5.4 and 12.1 months, respectively. PoRT patients undergoing poRT more likely received extended-field radiotherapy with prophylactic nodal irradiation, but rather received platinum- vs. adriamycin-based chemoradiotherapy. Radiotherapy was conventionally fractionated, delivered >60Gy in 51.9% and 61.7% and used extended fields in 88.5% and 71.2% of patients with poRT or RT. Radiotherapy interruption rates for toxicity were similar in the two groups. The best poRT-group model identified age>45yo, PS≥1, pathologic tumor stage≥pT4b,>N1 and R2 resection as poor prognostic factors. The best RT-group model (C-index of 0.72) identified PS≥3,>N1 and extended-field radiotherapy with prophylactic nodal irradiation (as opposed to tumour-bed irradiation only) as poor prognostic factors. ConclusionIn patients undergoing poRT, radiotherapy parameters had little influence over their survival irrespective of patient, disease characteristics, and quality of resection. In patients undergoing RT, extended-field radiotherapy improved survival in addition to PS and nodal stage.

Identification of hub pathways and drug candidates in gastric cancer through systems biology

Gastric cancer is the fourth cause of cancer death globally, and gastric adenocarcinoma is its most common type. Efforts for the treatment of gastric cancer have increased its median survival rate by only seven months. Due to the relatively low response of gastric cancer to surgery and adjuvant therapy, as well as the complex role of risk factors in its incidences, such as protein-pomp inhibitors (PPIs) and viral and bacterial infections, we aimed to study the pathological pathways involved in gastric cancer development and investigate possible medications by systems biology and bioinformatics tools. In this study, the protein–protein interaction network was analyzed based on microarray data, and possible effective compounds were discovered. Non-coding RNA versus coding RNA interaction network and gene-disease network were also reconstructed to better understand the underlying mechanisms. It was found that compounds such as amiloride, imatinib, omeprazole, troglitazone, pantoprazole, and fostamatinib might be effective in gastric cancer treatment. In a gene-disease network, it was indicated that diseases such as liver carcinoma, breast carcinoma, liver fibrosis, prostate cancer, ovarian carcinoma, and lung cancer were correlated with gastric adenocarcinoma through specific genes, including hgf, mt2a, mmp2, fbn1, col1a1, and col1a2. It was shown that signaling pathways such as cell cycle, cell division, and extracellular matrix organization were overexpressed, while digestion and ion transport pathways were underexpressed. Based on a multilevel systems biology analysis, hub genes in gastric adenocarcinoma showed participation in the pathways such as focal adhesion, platelet activation, gastric acid secretion, HPV infection, and cell cycle. PPIs are hypothesized to have a therapeutic effect on patients with gastric cancer. Fostamatinib seems a potential therapeutic drug in gastric cancer due to its inhibitory effect on two survival genes. However, these findings should be confirmed through experimental investigations.

Spine high-grade osteosarcoma in the era of radiotherapy with high-energy charged particles: A single institution retrospective analysis.

11532 Background: Limited are data on high-grade osteosarcoma occurring in the spine. Wide resection is recommended, but it is a difficult and high morbidity procedure in the spine. High-energy particle therapy has been recently used. The goal of this study was to examine treatment and outcome of patients with osteosarcoma in the mobile spine. Methods: Spine high grade osteosarcoma patients who underwent surgery at the Rizzoli Institute between 2009 and 2020 were identified. Treatment, outcome, and prognostic factors in patients treated in a single institution were examined. Results: Characteristics of the 20 patients (8 female; 12 male) included: median age, 39.7 years (range, 14-71 years), 5 (25%) with tumors in the cervical spine, 6 (30%) with tumors in the thoracic spine, and 9 with tumors in the lumbar spine (45%); 14 (70%) patients with localized disease and 6 (30%) with metastatic disease at the time of presentation. Nineteen patients (95%) underwent chemotherapy, the majority were treated with MAP (methotrexate, doxorubicin, cisplatin) regimen. In 12 patients undergoing preoperative chemotherapy (n = 11) or chemotherapy and radiotherapy (n = 1), the median tumor % necrosis was 20 (IQR 20 - 40), with none achieving a good histologic response (&gt; 90%). All patients underwent surgery. Adequate surgical margins were achieved in 5 patients (25%). In patients with positive margins, radiotherapy was administered to 8 (40%) patients. Four patients with positive margins after resection received photon neoadjuvant or adjuvant therapy. Four patients received high-energy particles as adjuvant therapy after planned gross total excision. The median overall survival rate was 10.5 months (IQR 5.8 - 15.0) for patients with metastatic disease and 25.5 months (IQR 8.3 - 46.0) for patients with localized disease (P =.0501). Patients treated with planned intralesional gross total resection followed by adjuvant high-energy particle therapy had a significant higher disease-specific survival than patients with positive margins after resection with or without additional conventional radiotherapy (P =.023). Conclusions: Metastatic disease, is a poor prognostic factor for high grade osteosarcoma of the spine. Post-operative high-energy particle therapy improved overall survival in patients undergoing a planned gross total resection compared to intralesional resection in this series. Chemotherapy induced necrosis was low underscoring the need of more aggressive multidisciplinary approaches for these patients.

Favourable outcomes in locally advanced and metastatic pancreatic cancer treated with modified FOLFIRINOX as second-line chemotherapy.

e16252 Background: Pancreatic cancer has one of the poorest prognoses of all solid tumours with median overall survival rate between 9 and 12 months worldwide. (1, 2) Treatment guidelines beyond first line chemotherapy are subsequently limited by a paucity of data. Modified oxaliplatin, irinotecan, 5-fluorouracil and leucovorin (mFOLFIRINOX) has been used historically as second line chemotherapy but is not yet standard of care. (3) Patients are often excluded from use of second line FOLFRINOX due to age or performance status. Previous studies have recognized safe use of mFOLFIRINOX in patients with ECOG 0-1 and age below 75 years but there is limited evidence for other patient populations. (4) We first reported successful use of mFOLFIRINOX for pancreatic cancer in 2014 and reviewed the outcomes from this centre in 2019. (4,5) A promising response was seen for second line mFOLFIRINOX in patients with an ECOG of 2 or less. (5) We aim to provide further evidence of the efficacy of mFOLFIRINOX in second line treatment of pancreatic cancer using a larger dataset. Methods: A retrospective review was completed of all patient records for those treated for pancreatic cancer in a single centre in Western Australia between 2008 and 2022. We identified 258 patients treated for pancreatic cancer, 110 of whom received mFOLFIRINOX as second line treatment. Kaplan Meier method was used for calculation of overall survival with 32 patients included as censored data. Results: We identified 110 patients with either locally advanced or metastatic pancreatic cancer aged between 34 and 82 years. A large number (n = 32) of patients were over the age of 70. The majority of patients had metastatic disease at presentation (56%). Almost all patients (n = 109) had gemcitabine with nab-paclitaxel as first line chemotherapy, nineteen of whom received it as part of a clinical trial combination. Median overall survival was 28 and 18 months for locally advanced and metastatic pancreatic cancer respectively. The overall survival for both groups was 20 months with a range of 4-81 months. One year survival was 82%, 3 year survival was 23% and 5 year survival was 5% for this group. Median time maintained on second line mFOLFIRINOX was 5 months with a range of 1 to 36 months. Almost half (n = 50) of the patients went on to have third line chemotherapy, nineteen of whom had third line gemcitabine/abraxane. The dose intensity of m-FOLFIRINOX was 65% for oxaliplatin, 68% for irinotecan, 18% for bolus 5-fluorouracil (5-FU) and 68% for infusional 5-FU. Conclusions: This study is the largest retrospective review of second line mFOLFIRINOX chemotherapy for pancreatic cancer reported. It provides further evidence of the efficacy of second line mFOLFIRINOX for suitable patients with advanced pancreatic cancer and suggests ECOG 2 should not be a barrier to effective treatment in this group.

Overall survival by IDH2 mutant allele (R140 or R172) in patients with late-stage mutant-IDH2 relapsed or refractory acute myeloid leukemia treated with enasidenib or conventional care regimens in the phase 3 IDHENTIFY trial.

7005 Background: IDH2 gene mutations (m IDH2) occur in up to ̃20% of patients (pts) with acute myeloid leukemia (AML), most commonly as R140Q (in ̃75% of cases) or R172K (̃25%) point mutations. The functional effects and prognostic relevance of m IDH2-R140 and m IDH2-R172 can vary (Papaemmanuil 2016). In the randomized, phase 3 IDHENTIFY trial, enasidenib (ENA), an oral mIDH2 inhibitor, did not significantly improve overall survival (OS) vs conventional care regimens (CCR) as salvage treatment (Tx) for older pts with m IDH2 relapsed/refractory (R/R) AML in ITT analysis, but a trend for improved OS with ENA was detected in pts with IDH2-R172 mutations. We further investigated OS and correlative biomarkers in IDHENTIFY pt subgroups defined by m IDH2 variant (R140/R172). Methods: This open-label trial (NCT02577406) enrolled pts ≥ 60 years of age who had received 2 or 3 prior AML Tx. Pts were preselected to a CCR (azacitidine, intermediate- or low-dose Ara-C, or supportive care), and were then randomized 1:1 to ENA 100 mg/d or CCR in 28d cycles. Co-occurring gene mutations were identified by targeted next-generation sequencing (37-gene panel) of bone marrow mononuclear cell (BMMC) DNA. Total 2-HG levels were determined by LC/MS. Results: Of 319 pts enrolled, 88 pts (28%; 43 ENA, 45 CCR) had m IDH2-R172 and 229 (72%; 115 ENA, 114 CCR) had m IDH2-R140. Median baseline (BL) 2-HG levels were similar between Tx arms and m IDH2 variant subgroups, as were IDH2 variant allele frequencies. Pts with m IDH2-R172 had fewer median BL co-mutations (4 [range 2–8]) than did pts with m IDH2-R140 (5 [1–11]) ( P &lt; 0.0001). The most frequently co-occurring mutations were SRSF2 and RUNX1 in the R140 cohort (59% each) and DNMT3A in the R172 cohort (57%). Compared with the R172 cohort, the R140 group was enriched with SRSF2, FLT3 (-ITD/-TKD), NPM1, RUNX1, and JAK2 mutations, whereas DNMT3A and TP53 mutations were more common in the R172 group. In Cox multivariate analysis including m IDH2 variant (R140/R172), DNMT3A mutation status, and number of gene mutations at BL, m IDH2-R172 was significantly ( P = 0.04) correlated with improved OS (vs. R140) in the ENA arm, whereas the number of BL gene mutations was significantly ( P &lt; 0.01) associated with OS in the CCR arm. Median OS in the R172 subgroup was 14.6 mo with ENA vs 7.8 mo with CCR (HR, 0.59 [95%CI 0.35-0.98]; P = 0.039) and 1-yr survival rates were 62% and 30%, respectively. In m IDH2-R140 pts, median OS was 5.7 mo in both Tx arms (0.93 [0.70-1.24]; P = 0.61), and 1-year survival rates were 29% and 25% with ENA and CCR, respectively. Conclusions: Mutational burden and co-mutational profiles differed between pts with m IDH2-R140 and m IDH2-R172 R/R AML. ENA improved survival outcomes for pts with IDH2-R172 mutations, with median OS and 1-year survival rate approximately double those in the CCR arm. Clinical trial information: NCT02577406.

Survival trends in hilar and extrahepatic cholangiocarcinoma based on Facility type: A National Cancer Database analysis.

e13536 Background: The diagnosis and treatment of Cholangiocarcinoma continues to pose a challenge. Due to their rarity, few studies have examined the impact of facility type on the survival of patients with extrahepatic cholangiocarcinoma. The hypothesis of this study was that differences in the outcome of patients at different facility types exist. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with hilar and extra-hepatic cholangiocarcinoma from 2004 to 2017 using ICD-O-3 histology codes. We used four different cohorts to assess survival amongst those at different facility types: academic/research programs, community cancer programs, comprehensive community center programs, and integrated network cancer programs. Data was analyzed and descriptive statistics and Kaplan Meier curves were produced using SPSS to measure survival in these patients with statistical significance set at α = 0.05. Results: Using the database, a total of 57,146 patients with hilar and extrahepatic cholangiocarcinoma were identified. Overall median survival in these patients was 11.2 months. Patients at Academic/research programs had a median survival of 14 months (95% CI 14.1-14.8 p &lt; 0.001). In comparison, median survival of 9.7 months (95%CI 9.3-10.2 p &lt; 0.001) and 8.7 months (95% CI 8.4-8.9 p &lt; 0.001) was noted in Integrated network and Comprehensive community cancer programs, respectively. Community cancer programs had the lowest median survival rate in patients with all extrahepatic biliary tract cancers included in our study was 6.9 months (95% CI 6.4-7.7 p &lt; 0.001). Specifically, patients with Klatskin tumors at Academic/Research programs had median survival of 10.3 months (95% CI 8.6-11.9 p &lt; 0.0010) compared to median survival of 3.6 months in patients treated at Community Cancer program. We also studied specific histology types such as papillary and mucinous adenocarcinomas. In papillary adenocarcinomas, there are no statistically significant differences in median survival in different facility types. In mucinous adenocarcinomas, median survival of 26.5 months was found in academic/research program patients compared to 16.2 months in Comprehensive Community Cancer program patients (p &lt; 0.001). Conclusions: Median overall survival in patients with hilar and extrahepatic cholangiocarcinoma was significantly higher in academic/research programs compared to other facility types. Further studies are needed to ascertain why academic/research programs have superior outcomes in these patients.