Median Survival Of Patients Research Articles

Abstract 3452: TNG908, a brain-penetrant MTA-cooperative PRMT5 inhibitor, is efficacious in preclinical glioblastoma models

Abstract Glioblastoma multiforme (GBM) is one of the most aggressive primary malignant brain tumors in adults. The median overall survival (OS) of GBM patients is poor (1-2 years) on standard of care therapies, which include surgery, radiotherapy, and the alkylating agent temozolomide. Therefore, developing new treatments for GBM is an urgent unmet medical need. TNG908 is a clinical stage MTA-cooperative PRMT5 inhibitor that inhibits PRMT5 activity selectively in MTAP-null cells leveraging a synthetic lethal interaction. Approximately 40% of GBM tumors are homozygous null for MTAP [1, 2]. In preclinical in vitro studies, the antiproliferation activity of TNG908 was 15 times more potent in MTAP-null cancer cell lines than in MTAP WT cells. TNG908 has high passive permeability and is not a substrate for P-glycoprotein nor Breast Cancer Resistant Protein efflux transporters, attributes which are favorable for crossing the blood-brain barrier. TNG908 demonstrated in vivo brain penetration in multiple preclinical studies, including non-human primates and mice, suggesting that TNG908 may fulfill the significant unmet need in the treatment of GBM. Pharmacodynamic activity of TNG908 to inhibit PRMT5 was demonstrated by decreased SDMA-modified protein levels in a dose-dependent manner in a GBM xenograft model. TNG908 demonstrated dose-dependent antitumor activity in multiple hyper- and hypomethylated GBM subcutaneous models, including cell lines and patient-derived xenograft models. Despite reduced Kpuu in rodents compared to primates, oral administration of TNG908 drove near tumor stasis and increased median survival by 3-fold in a highly aggressive murine GBM orthotopic model. In summary, TNG908 is a potent, brain-penetrant small molecule PRMT5 inhibitor that is selective for MTAP-null tumor cells with good drug-like properties and strong antitumor activity in preclinical models of GBM. As such, TNG908 may provide a novel treatment strategy for MTAP-deleted GBM patients. *MZ and AT contributed equally to the work. Reference: 1.Cerami et al., Cell, 2013. 2.Gao et al., Sci Signal, 2013 Citation Format: Minjie Zhang, Alice Tsai, Kevin M. Cottrell, Brian B. Haines, Erik Wilker, Heather DiBenedetto, Ron Weitzman, Alan Huang, Charles B. Davis, John P. Maxwell, Kimberly J. Briggs. TNG908, a brain-penetrant MTA-cooperative PRMT5 inhibitor, is efficacious in preclinical glioblastoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3452.

Five-Year Outcomes and Predictors of Mortality following Sepsis in a Large Cohort of Patients in a General Medical Ward: A Cohort Study from South India

Background: Although sepsis is a well-known cause of in-hospital mortality, data on long term outcomes are scarce. Aim: This study aims to estimate the cumulative 5-year mortality among patients with infection requiring admission. Methods: This was a cohort study done in tertiary care center in South India, with recruitment of those admitted with an infection between January 1st, 2009 and July 31st, 2014 in a medical unit. The patients were followed up by telephonic call or case record review. Kaplan–Meier survival curve was plotted and Cox-proportional hazard model was used as multivariable analysis to identify the independent risk factors of long-term mortality. Results: One thousand four hundred and fifty three patients were followed up in this cohort study. The mean survival by Kaplan–Meier survival analysis was 3.78 years (95% confidence interval [CI] 3.33, 4.22) in quick sepsis-related organ failure assessment (qSOFA) score positive patients and 6.07 years (95% CI 5.73, 6.41) in qSOFA negative patients which was statistically significant by the log-rank test. The cumulative 1-year mortality was 44.9% and 21.8% for qSOFA score of 2 or more and nonsepsis patients, respectively. The median survival of qSOFA score of 2 or more patients was 0.75 years (95% CI 0–2.1 years). The mortality among sepsis patients at discharge, 1 year, 5 and 8 years was 38.2%, 44.9%, 47.4%, and 47.8%, respectively. Cox regression analysis showed age hazard ratio (HR) 1.02 (1.01, 1.04), male gender 1.45 (1.03, 2.04), >qSOFA score HR 1.89 (1.32, 2.72), Charlson Comorbidity Index HR 1.29 (1.14, 1.46), respiratory tract infection HR 1.81 (1.10, 2.95), and inotrope requirement HR 3.24 (1.98, 5.29) were the independent predictors of long-term mortality. Conclusions: The median survival of patients with possible infection with qSOFA score of 2 or more patients was 0.75 years (95% CI 0–2.1 years). Older age, male gender, qSOFA score of 2 or more, Charlson Comorbidity Index, respiratory tract infection, and inotrope requirement HR 3.24 were the independent predictors of long-term mortality.

Retrospective Evaluation of the Efficacy of Gemcitabine-Based Therapies After FOLFIRINOX Failure in Advanced Pancreatic Cancer, Multi-Center Real-Life Data.

Combination therapies such as FOLFIRINOX or gemcitabine-nanoparticle albumin-bound paclitaxel (GnP) are recommended for the first-line treatment of patients with advanced pancreatic cancer. The purpose of this study was to evaluate the efficacy of gemcitabine-based second-line therapies in patients whose disease progressed on FOLFIRINOX. Patients diagnosed with advanced pancreatic cancer in 7 tertiary hospitals in Turkey were included. Patients were divided into 3 different groups according to their treatment regimens: GnP, gemcitabine doublet (gemcitabine-cisplatin or gemcitabine-capecitabine), and gemcitabine monotherapy. A total of 144 patients were included in the study. In the second-line treatment, 65% of patients were given GnP, 20% were given gemcitabine doublet, and 15% were given gemcitabine monotherapy. The median exposure of the patients to gemcitabine-based therapy was 3 cycles, whereas the median progression-free survival was calculated as 3.4 months. The median overall survival for patients who received GnP was 4.6 months, 6.4 months for patients who received gemcitabine doublet therapy, and 3.7 months for patients who received gemcitabine monotherapy ( P = 0.248). In conclusion, it has been shown that gemcitabine-based second-line treatments contribute to survival in patients with advanced pancreatic cancer. In addition, there was no difference in efficacy between gemcitabine monotherapy or combination treatments.

Outcomes and Prognostic Factors of Patients with Platinum- Resistant or Refractory Epithelial Ovarian Cancer, Fallopian Tube Cancer and Peritoneal Cancer.

To determine the survival outcomes and prognostic factors of the patients with recurrent platinumresistant and refractory epithelial ovarian cancer (EOC), tubal, and peritoneal cancer. Women with recurrent platinum-resistant and refractory EOC, tubal and peritoneal cancer who received treatment at the HRH Princess Maha Chakri Sirindhorn Medical Center (MSMC) between January 2010 and December 2019 were included. Demographic data, serum marker, surgical factors, pathological factors and response of treatment were reviewed. Kaplan-Meier was used to calculate survival outcome. Forty patients were recruited in this study (platinum-resistant 24 patients and refractory 16 patients). The median survival times were 19 and 21 months in and platinum-resistant and platinumrefractory patients, respectively. There were no significant differences in overall survival according to age, comorbidity, tumor grading, primary treatment, and secondary surgery. However, histology of clear cell carcinoma may associate with increased risk of death. The median overall survival of patients with clear cell carcinoma, serous carcinoma, and others were 14.4, 22.9, and 32.2, respectively (p = 0.003). Almost 10 years, the survival rate of the patients in these group has not increased despite new treatments option. Novel strategies should be considered in National policy of the treatment for ovarian cancer in our country.

884 Frailty and Socioeconomic Status Predict Outcome in Newly Diagnosed Glioblastoma Patients

INTRODUCTION: Identification of molecular markers of glioblastoma (GBM) prognosis has not often led to meaningful intervention. Individual patient and socioeconomic factors are underexplored prognostic factors. Frailty, a measure of physiological vulnerability, and area deprivation, a measure of socioeconomic status, are easily obtained during the preoperative evaluation. Moreover, both are amenable to intervention; the medical conditions that contribute to frailty can be optimized prior to surgery, while barriers to health care (physical, financial, and cultural) can be addressed for patients at risk socioeconomically. METHODS: This is a retrospective review of patients with newly diagnosed GBM undergoing surgery from 2015 through 2020. Demographic and tumor specific data were recorded. Additionally, the 5-factor modified frailty index (mFI-5) and national area deprivation index (ADI) were determined for each patient. RESULTS: There were 244 patients. Compared to patients in the “some or no” frailty category, patients with “significant” frailty had a shorter median survival: 273 days (95% CI 126-339) vs 393 days (95% CI 317-458), p = 0.008. The median survival for patients living in the most disadvantaged neighborhoods, 210 days (95% CI 134-334), is significantly lower than for those living in the least, 384 days (95% CI 239-484), p = 0.17. Twenty-five percent of patients living in the most disadvantaged neighborhoods did not receive postoperative chemoradiation compared to 11% of patients in the least disadvantaged neighborhoods, p=0.046. Similarly, patients of color were less likely to receive standard of care chemoradiation than white patients. CONCLUSIONS: Both increasing frailty and neighborhood disadvantage are associated with worse outcome in newly diagnosed GBM patients undergoing surgery. Patients living in the most deprived neighborhoods and patients of color are less likely to receive postoperative chemoradiation. Identification of non-traditional predictors of treatment and outcome will lead to mitigation strategies.

Experience of Using the INTRABEAM System to Determine the Safely Tolerated Dose During Intraoperative Irradiation of Malignant Gliomas

Glioblastoma is the most malignant primary brain tumor. For treatment uses a combined regimen that is currently available: surgery, radiation and chemotherapy. However, so far the median survival of patients does not exceed 14 months. In this connection, there is a constant search for effective methods. Improvement in radiation therapy has led to the possibility of its intraoperative, which is a practical and effective method aimed at getting rid of the remaining tumor cells, reducing the spread of the tumor and filling the therapeutic gap between surgery and subsequent chemotherapy and radiation therapy. Intraoperative radiation therapy (IORT) allows you to deliver the required tumoricidal dose exactly to the target, minimally affecting the surrounding healthy tissues.Goal: Establishment of the safety of intraoperative irradiation of patients with malignant gliomas with the INTRABEAM device (Carl ZEISS, Germany) with a dose of up to 40 Gy on the applicator.Material and methods: The study involved 15 patients, the average age of which was 51 years, the ratio of men and women was 4:6, the average Karnofsky index before surgery was 97. After surgical removal of the tumor, an express biopsy was performed. Next, intraoperative irradiation was performed with the INTRABEAM device (Carl ZEISS) at a dose of 40 Gy, followed by an assessment of the Karnofsky index, early postoperative and delayed possible complications.Results: In all patients operated on with intraoperative irradiation and subsequent adjuvant radiochemotherapy, the method was well tolerated, there were no wound healing features or identified complications, there were no cases of wound liquorrhea, wound inflammation.Conclusion: Intraoperative irradiation after surgical removal of the tumor can be recommended as a safe method for the treatment of malignant gliomas in addition to existing combination therapy.

Mechanical nanosurgery of chemoresistant glioblastoma using magnetically controlled carbon nanotubes.

Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Despite multimodal treatment including surgery, radiotherapy, and chemotherapy, median patient survival has remained at ~15 months for decades. This situation demands an outside-the-box treatment approach. Using magnetic carbon nanotubes (mCNTs) and precision magnetic field control, we report a mechanical approach to treat chemoresistant GBM. We show that GBM cells internalize mCNTs, the mobilization of which by rotating magnetic field results in cell death. Spatiotemporally controlled mobilization of intratumorally delivered mCNTs suppresses GBM growth in vivo. Functionalization of mCNTs with anti-CD44 antibody, which recognizes GBM cell surface-enriched antigen CD44, increases mCNT recognition of cancer cells, prolongs mCNT enrichment within the tumor, and enhances therapeutic efficacy. Using mouse models of GBM with upfront or therapy-induced resistance to temozolomide, we show that mCNT treatment is effective in treating chemoresistant GBM. Together, we establish mCNT-based mechanical nanosurgery as a treatment option for GBM.

Nomogram to predict the prognosis of patients with AFP-negative hepatocellular carcinoma undergoing chemotherapy: A SEER based study.

This study aimed to formulate reliable nomograms for predicting the outcomes of α-fetoprotein (AFP)-negative hepatocellular carcinoma (HCC) patients after chemotherapy. HCC patients with normal AFP expression who received chemotherapy were screened and evaluated from the surveillance, epidemiology, and end results database. The prognostic factors for predicting outcomes of HCC patients undergoing chemotherapy were chosen by analyzing the results of Cox analyses. Then, a nomogram integrating the prognostic factors was established. The discrimination ability of the nomogram was evaluated with computation of area under the curve (AUC) and calibration curve. A total of 2424 patients with AFP-negative HCC undergoing chemotherapy were identified. The median overall survival (OS) for HCC patients undergoing chemotherapy was 33 months. Age, race, pathologic grade, N stage, M stage, surgery, and lung metastases were significantly linked to OS. These relevant factors were incorporated into the nomogram. AUC values of the prognostic nomogram for 3- and 5-year OS were 0.696 and 0.706 in the training groups, which were superior to those of the tumor node metastasis (TNM) stage (0.641 and 0.671) in training groups. The calibration curves indicated a high consistency between the predicted probability of nomograms and the actual observation. The validation groups produced AUC values of 0.674 and 0.736 for 3- and 5-year OS, which were superior to those of the TNM stage (0.601 and 0.637) in validation groups. The results revealed significantly unfavorable OS in the high-risk group (P < .001). Nomograms to accurately predict the OS for AFP-negative HCC patients after chemotherapy were established and exhibited a more accurate predication than the conventional TNM staging system.

Ablation therapy for patients with colorectal liver metastases with and without extrahepatic metastases: evaluation of long-term outcomes and prognostic factors.

Ablation is a valuable treatment alternative to surgery for colorectal liver metastases. This study reports the long-term clinical outcomes in patients treated with ablation for colorectal liver metastases with or without extrahepatic metastases. Patients with colorectal liver metastases treated with ultrasound-guided ablation at Herlev Hospital, Denmark were included in this retrospective study. This study included 284 patients with 582 metastases. Complete ablation was obtained in 258 patients (91%) evaluated within 6 weeks. During follow-up, 94 patients (33%) developed local recurrence. The median survival for all patients was 31 months, with 1-, 3-, and 5-year survival rates of 82%, 45%, and 21%, respectively. The median survival for patients with extrahepatic metastases (n=49, 17%) was 24 months compared with 33 months for patients without (P=0.142). Propensity score-adjusted Cox regression showed that extrahepatic metastases were associated with increased mortality, with a hazard ratio (HR) of 1.45 (95% confidence interval [CI], 1.02 to 2.05; P=0.039). In multivariate Cox regression analysis for all patients, increased mortality risk was found for a diameter ≥2.6 cm (HR, 1.59; 95% CI, 1.23 to 2.05), >1 metastasis (HR, 1.66; 95% CI, 1.28 to 2.16), and extrahepatic metastases (HR, 1.45; 95% CI, 1.04 to 2.03). Male sex (HR, 0.75; 95% CI, 0.58 to 0.98) and receiving chemotherapy (HR, 0.69; 95% CI, 0.52 to 0.92) were associated with decreased mortality. Ablation for colorectal liver metastases offers acceptable survival rates, including for patients with extrahepatic metastases. In addition, chemotherapy was associated with improved survival for both patients with and without extrahepatic metastases.

Outcomes of Rural Men with Breast Cancer: A Multicenter Population Based Retrospective Cohort Study

Breast cancer is rare in men. This population-based study aimed to determine outcomes of male breast cancer in relation to residence and other variables. In this retrospective cohort study, men diagnosed with breast cancer in Saskatchewan during 2000-2019 were evaluated. Cox proportional multivariable regression analyses were performed to determine the correlation between survival and clinicopathological and contextual factors. One hundred-eight eligible patients with a median age of 69 years were identified. Of them, 16% had WHO performance status ≥ 2 and 61% were rural residents. The stage at diagnosis was as follows: stage 0, 7%; I, 31%; II, 42%; III, 11%; IV, 8%. Ninety-eight percent had hormone receptor-positive breast cancer. The median disease-free survival of urban patients was 97 (95% CI: 50-143) vs. 64 (46-82) months of rural patients (p = 0.29). The median OS of urban patients was 127 (94-159) vs. 93 (32-153) months for rural patients (p = 0.27). On multivariable analysis, performance status ≥ 2, hazard ratio (HR) 2.82 (1.14-6.94), lack of adjuvant systemic therapy, HR 2.47 (1.03-5.92), and node-positive disease, HR 2.32 (1.22-4.40) were significantly correlated with inferior disease-free survival in early-stage invasive breast cancer. Whereas stage IV disease, HR 7.8 (3.1-19.5), performance status ≥ 2, HR 3.25 (1.57-6.71), and age ≥ 65 years, HR 2.37 (1.13-5.0) were correlated with inferior overall survival in all stages. Although residence was not significantly correlated with outcomes, rural men had numerically inferior survival. Poor performance status, node-positive disease, and lack of adjuvant systemic therapy were correlated with inferior disease-free survival.

Fatostatin induces ferroptosis through inhibition of the AKT/mTORC1/GPX4 signaling pathway in glioblastoma

Glioblastoma multiforme (GBM) is the most common and fatal primary malignant central nervous system tumor in adults. Although there are multiple treatments, the median survival of GBM patients is unsatisfactory, which has prompted us to continuously investigate new therapeutic strategies, including new drugs and drug delivery approaches. Ferroptosis, a kind of regulated cell death (RCD), has been shown to be dysregulated in various tumors, including GBM. Fatostatin, a specific inhibitor of sterol regulatory element binding proteins (SREBPs), is involved in lipid and cholesterol synthesis and has antitumor effects in a variety of tumors. However, the effect of fatostatin has not been explored in the field of ferroptosis or GBM. In our study, through transcriptome sequencing, in vivo experiments, and in vitro experiments, we found that fatostatin induces ferroptosis by inhibiting the AKT/mTORC1/GPX4 signaling pathway in glioblastoma. In addition, fatostatin inhibits cell proliferation and the EMT process through the AKT/mTORC1 signaling pathway. We also designed a p28-functionalized PLGA nanoparticle loaded with fatostatin, which could better cross the blood-brain barrier (BBB) and be targeted to GBM. Our research identified the unprecedented effects of fatostatin in GBM and presented a novel drug-targeted delivery vehicle capable of penetrating the BBB in GBM.

Clinical Characteristics and Outcomes of Cyclin D1-Positive AL Amyloidosis.

To demonstrate the clinical features and prognostic impact of cyclin D1 positivity in patients with amyloid light chain amyloidosis (AL). We consecutively included 71 patients diagnosed with AL with cyclin D1 positivity between February 2008 and January 2022. t(11;14) was examined through interphase fluorescence in situ hybridization using bone marrow cells. The median age of the patients was 73 years, and 53.5% were male. The underlying diseases included symptomatic multiple myeloma, smoldering multiple myeloma, Waldenström macroglobulinemia, and monoclonal gammopathy of undetermined significance, representing 33.8%, 26.8%, 2.8%, and 36.6%, respectively. The prevalence of cyclin D1 and t(11;14) was 38.0% and 34.7%, respectively. Higher frequency of light chain paraprotein type was seen in cyclin D1-positive patients with AL than in cyclin D1-negative patients (70.4% vs 18.2%). The median overall survival (OS) of patients with AL with and without cyclin D1 expression was 18.9 months and 73.1 months, respectively (P = .019). Early death occurred in 44.4% of cyclin D1-positive patients and 31.8% of cyclin D1-negative patients. Moreover, 83.3% of cyclin D1-positive patients and 21.4% of cyclin D1-negative patients died of cardiac causes. Cyclin D1 immunohistochemistry accurately identified patients with t(11;14). Cyclin D1-positive patients had significantly inferior OS compared with cyclin D1-negative patients.

A Real-world Study on the Expression Characteristics of PD-L1 in Patients with Advanced EGFR Positive NSCLC and Its Relationship with the Therapeutic Efficacy of EGFR-TKIs

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is the first choice for first-line treatment of advanced patients with EGFR positive non-small cell lung cancer (NSCLC). For advanced NSCLC patients with negative drive gene and positive programmed cell death ligand 1 (PD-L1) or highly expressed NSCLC patients, the first-line treatment recommends immune checkpoint inhibitors (ICIs) monotherapy or ICIs combined chemotherapy. Therefore, the first-line treatment strategy for advanced NSCLC patients with EGFR positive at different PD-L1 expression levels is worth further exploring. Many previous studies have suggested that the expression of PD-L1 is obviously affected by EGFR mutation, and the expression of PD-L1 is likely to be related to the mechanism of EGFR-TKIs resistance. The purpose of this study was to analyze the expression characteristics of PD-L1 in patients with advanced EGFR positive NSCLC and its relationship with the efficacy of EGFR-TKIs. 159 patients with newly diagnosed advanced NSCLC with EGFR positive (including 141 patients with EGFR sensitive mutations) were enrolled to analyze the relationship between clinicopathological characteristics and PD-L1 expression. The factors affecting the therapeutic effect of EGFR-TKIs in 141 patients with EGFR sensitive mutations were also explored. The PD-L1 expression of the included patients was classified according to the tumor promotion score (TPS): negative (TPS<1%) accounted for 47.2%, low expression (1%≤TPS<50%) accounted for 32.1%, and high expression (TPS≥50%) accounted for 20.7%. Among them, patients with solid predominant cancer cell pathomorphology classification are more likely to have high expression of PD-L1, accounting for 52.9% (P<0.0001). The median progression-free survival (mPFS) of patients with PD-L1 negative expression, low expression and high expression who received first generation EGFR-TKIs treatment were 12.4 months, 10.5 months and 3.7 months, respectively, with significant statistical difference (P<0.0001). During the EGFR-TKIs treatment, patients with a history of radiotherapy for lung lesions have a longer PFS benefit than those without a history of radiotherapy (mPFS: 17.0 months vs 9.3 months, P<0.0001). The expression level of PD-L1 in advanced EGFR positive NSCLC patients was significantly correlated with the pathomorphology classification of cancer cells. The efficacy of EGFR-TKIs in patients with PD-L1 overexpression NSCLC was significantly poor. PFS can be significantly prolonged during targeted therapy combined with radiotherapy of lung lesions.

Planning for the Effect of the SC.24 Trial on Spine Stereotactic Body Radiation Therapy Utilization at a Tertiary Cancer Center

The goal of this study was to assess the potential real-world effect of the recently reported SC.24 trial on spine stereotactic body radiation therapy (SBRT) utilization. We estimated the proportion of patients treated with conventional radiation therapy (CRT) who would have been eligible for spine SBRT per trial inclusion criteria and analyzed the potential estimated increased costs to our institution. This was a retrospective review of patients who received spine CRT at our institution between August and October 2020. Data abstracted included demographics, SC.24 eligibility criteria, provider-reported pain response, and survival. A cost analysis and time survey was performed using institutional and provincial data. Of 73 patients reviewed, 24 patients (33%) were eligible. The most common exclusion factors included irradiation of ≥3 consecutive spinal segments (n=32, 44%), Eastern Cooperative Oncology Group performance status >2 (n=17, 23%), and symptomatic spinal cord compression (n=13, 18%). Of eligible patients, the mean age was 68.92 years, median spinal instability in neoplasia score was 8 (interquartile range, 7-9), and median Eastern Cooperative Oncology Group performance status was 2 (interquartile range, 1-2). The most common primary cancer types among eligible patients were lung (n=10) and breast (n=4). The median survival of eligible patients was 10 months (95% confidence interval, 4 months to not reached) with 58% surviving longer than 3 months. Of patients who had subjective pain documented after CRT, 54% had at least some response. The cost of spine SBRT was estimated at CA$4764.80 compared with $3589.10 for CRT, and tasks for spine SBRT took roughly 3 times as long as those for CRT. One-third of patients who received palliative spine CRT met eligibility criteria for SC.24. This possible expanded indication for spine SBRT can have a substantial effect on resource utilization. These data may be useful in guiding resource planning at institutions looking to commence a spine SBRT program.

Use of ramucirumab for various treatment lines in real-world practice of patients with advanced hepatocellular carcinoma

PurposeRamucirumab was shown to be effective as a second-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein levels > 400 ng/mL in a worldwide phase 3 trial. Ramucirumab is used in patients pretreated with various systemic therapies in clinical practice. We retrospectively examined the treatment outcomes of ramucirumab administered to advanced HCC patients after diverse systemic therapies.MethodsData were collected from patients with advanced HCC who received ramucirumab at three institutions in Japan. Radiological assessments were determined according to both Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and modified RECIST and the Common Terminology Criteria for Adverse Events version 5.0 was used to assess adverse events.ResultsA total of 37 patients treated with ramucirumab between June 2019 and March 2021 were included in the study. Ramucirumab was administered as second, third, fourth, and fifth-line treatment in 13 (35.1%), 14 (37.8%), eight (21.6%), and two (5.4%) patients, respectively. Most patients (29.7%) who received ramucirumab as a second-line therapy were pretreated with lenvatinib. We found grade 3 or higher adverse events only in seven patients and no significant changes in the albumin-bilirubin score during ramucirumab treatment in the present cohort. The median progression-free survival of patients treated with ramucirumab was 2.7 months (95% confidence interval, 1.6–7.3).ConclusionAlthough ramucirumab is used for various lines of treatment other than second-line immediately after sorafenib, its safety and effectiveness were not significantly different from the findings of the REACH-2 trial.

Impact of Postoperative Stereotactic Body Radiation Therapy on Survival of Patients with Spinal Metastases in the Context of Additional Systemic Adjuvant Therapy

Stereotactic body radiotherapy (SBRT) has been established as a safe and effective treatment modality for control of long-term pain and tumor growth. However, few studies have investigated the efficacy of postoperative SBRT versus conventional external beam radiation therapy (EBRT) in extending survival within the context of systemic therapy. A retrospective chart review of patients who underwent surgery for spinal metastasis at our institution was conducted. Demographic, treatment and outcome data were collected. SBRT was compared with EBRT and non-SBRT, and analyses were stratified by whether or not patients received systemic therapy. Survival analysis was conducted using propensity score matching. Bivariate analysis in the non-systemic therapy group revealed longer survival with SBRT compared to EBRT and non-SBRT. Further analysis also showed that primary cancer type and preoperative mRS significantly affected survival. Within patients who received systemic therapy, overall median survival for SBRT patients was 22.7 months (95% CI: 12.1 - 52.3) versus 16.1 months (95% CI: 12.7 - 44.0; p = 0.28) for EBRT patients and 16.1 months (95% CI: 12.2 - 21.9; p = 0.07) for non-SBRT patients. Within patients who did not receive systemic therapy, overall median survival for SBRT patients was 62.1 months (95% CI: 18.1 - unknown) versus 5.3 months (95% CI: 2.8 - unknown; p = 0.08) for EBRT patients and 6.9 months (95% CI: 5.0 - 45.6; p = 0.02) for non-SBRT patients. In patients who do not receive systemic therapy, treatment with postoperative SBRT may increase survival time compared to patients not receiving SBRT.

The First Report of Iranian Registry of Patients with Spinal Muscular Atrophy.

Insufficient amounts of survival motor neuron protein is leading to one of the most disabling neuromuscular diseases, spinal muscular atrophy (SMA). Before the current study, the detailed characteristics of Iranian patients with SMA had not been determined. To describe the key demographic, clinical, and genetic characteristics of patients with SMA registered in the Iranian Registry of SMA (IRSMA). IRSMA has been established since 2018, and the demographic, clinical, and genetic characteristics of patients with SMA were recorded according to the methods of treat neuromuscular disease (TREAT-NMD) project. By October 1, 2022, 781 patients with 5q SMA were registered. Of them, 164 patients died, the majority of them had SMA type 1 and died during the first 20 months of life. The median survival of patients with type 1 SMA was 23 months. The consanguinity rate in 617 alive patients was 52.4%, while merely 24.8% of them had a positive family history. The most common type of SMA in live patients was type 3. Morbidities were defined as having scoliosis (44.1%), wheelchair dependency (36.8%), tube feeding (8.1%), and requiring mechanical ventilation (9.9%). Most of the registered patients had a homozygous deletion of SMN1, while the frequency of patients with higher copy numbers of SMN2, was less in more severe types of the disease. Earlier onset of the disease was significantly seen in patients with lower copy numbers of SMN2. The neuronal apoptosis inhibitory protein (NAIP) gene deletion was associated with a higher incidence of more severe types of SMA, higher dependency on ventilators, tube feeding, and earlier onset of the disease. The IRSMA is the first established Iranian nationwide registry of patients with SMA. Using this registry, decision-makers, researchers, and practitioners can precisely understand the epidemiology, characteristics, and genetics of patients with SMA in Iran.

Surveillance for Pancreatic Cancer in High-Risk Individuals Leads to Improved Outcomes: A Propensity Score-Matched Analysis

Recent pancreatic cancer surveillance programs of high-risk individuals have reported improved outcomes. This study assessed to what extent outcomes of pancreatic ductal adenocarcinoma (PDAC) in patients with a CDKN2A/p16 pathogenic variant diagnosed under surveillance are better as compared with patients with PDAC diagnosed outside surveillance. In a propensity score matched cohort using data from the Netherlands Cancer Registry, we compared resectability, stage, and survival between patients diagnosed under surveillance with non-surveillance patients with PDAC. Survival analyses were adjusted for potential effects of lead time. Between January 2000 and December 2020, 43,762 patients with PDAC were identified from the Netherlands Cancer Registry. Thirty-one patients with PDAC under surveillance were matched in a 1:5 ratio with 155 non-surveillance patients based on age at diagnosis, sex, year of diagnosis, and tumor location. Outside surveillance, 5.8% of the patients had stage I cancer, as compared with 38.7% of surveillance patients with PDAC (odds ratio [OR], 0.09; 95% confidence interval [CI], 0.04-0.19). In total, 18.7% of non-surveillance patients vs 71.0% of surveillance patients underwent a surgical resection (OR, 10.62; 95% CI, 4.56-26.63). Patients in surveillance had a better prognosis, reflected by a 5-year survival of 32.4% and a median overall survival of 26.8 months vs 4.3% 5-year survival and 5.2 months median overall survival in non-surveillance patients (hazard ratio, 0.31; 95% CI 0.19-0.50). For all adjusted lead times, survival remained significantly longer in surveillance patients than in non-surveillance patients. Surveillance for PDAC in carriers of a CDKN2A/p16 pathogenic variant results in earlier detection, increased resectability, and improved survival as compared with non-surveillance patients with PDAC.

Efficacy of Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Patients Aged over 60 Years

Aim. To compare toxicity and efficacy of high-dose melphalan chemotherapy with subsequent autologous hematopoietic stem cell transplantation (auto-HSCT) in multiple myeloma (MM) patients aged under and over 60 years.&#x0D; Materials &amp; Methods. The retrospective analysis was conducted on the data of 107 MM patients, 78 of them were aged under 60 years (median 54 years), and 29 of them were aged 61 years and older (median 63 years). All patients received auto-HSCT in the period of 2017–2022. Single and tandem auto-HSCT were performed in 92 and 15 patients, respectively. Patients with tandem auto-HSCT (n = 15), lost to follow-up patients (n = 8), and patients who died during early post-transplant period (n = 4) were excluded from survival analysis. Survival rates were calculated based on the date of auto-HSCT.&#x0D; Results. A comparative evaluation of the results in two age groups showed a significant difference in the number of patients treated with ixazomib during the induction period (р = 0.019) and cyclophosphamide 3 g/m2 as part of auto-HSC mobilization (р = 0.014), as well as 200 or 140 mg/m2 melphalan as part of conditioning regimen (р = 0.039 and р = 0.009, respectively). With a follow-up median of 13 months (range 1–57 months), the median progression-free survival in the groups ≤ 60 years vs. &gt; 60 years was 32 and 47 months, respectively (hazard ratio [HR] 0.688; 95% confidence interval [95% CI] 0.270–1.754; p = 0.704). The median overall survival in patients aged under 60 years appeared to be 57 months, it was not reached in patients aged 61 years and older (HR 0.689; 95% CI 0.169–2.803; р = 0.577).&#x0D; Conclusion. The results of the study suggest that all newly diagnosed MM patients aged under 70 years should be regarded as being eligible for auto-HSCT.

Exploring Novel Therapeutic Opportunities for Glioblastoma Using Patient-Derived Cell Cultures

Glioblastomas (GBM) are the most common, primary brain tumors in adults. Despite advances in neurosurgery and radio- and chemotherapy, the median survival of GBM patients is 15 months. Recent large-scale genomic, transcriptomic and epigenetic analyses have shown the cellular and molecular heterogeneity of GBMs, which hampers the outcomes of standard therapies. We have established 13 GBM-derived cell cultures from fresh tumor specimens and characterized them molecularly using RNA-seq, immunoblotting and immunocytochemistry. Evaluation of proneural (OLIG2, IDH1R132H, TP53 and PDGFRα), classical (EGFR) and mesenchymal markers (CHI3L1/YKL40, CD44 and phospho-STAT3), and the expression of pluripotency (SOX2, OLIG2, NESTIN) and differentiation (GFAP, MAP2, β-Tubulin III) markers revealed the striking intertumor heterogeneity of primary GBM cell cultures. Upregulated expression of VIMENTIN, N-CADHERIN and CD44 at the mRNA/protein levels suggested increased epithelial-to-mesenchymal transition (EMT) in most studied cell cultures. The effects of temozolomide (TMZ) or doxorubicin (DOX) were tested in three GBM-derived cell cultures with different methylation status of the MGMT promoter. Amongst TMZ- or DOX-treated cultures, the strongest accumulation of the apoptotic markers caspase 7 and PARP were found in WG4 cells with methylated MGMT, suggesting that its methylation status predicts vulnerability to both drugs. As many GBM-derived cells showed high EGFR levels, we tested the effects of AG1478, an EGFR inhibitor, on downstream signaling pathways. AG1478 caused decreased levels of phospho-STAT3, and thus inhibition of active STAT3 augmented antitumor effects of DOX and TMZ in cells with methylated and intermediate status of MGMT. Altogether, our findings show that GBM-derived cell cultures mimic the considerable tumor heterogeneity, and that identifying patient-specific signaling vulnerabilities can assist in overcoming therapy resistance, by providing personalized combinatorial treatment recommendations.