Median Survival Of Patients Research Articles

DDDR-33. TNG908, A BRAIN-PENETRANT MTA-COOPERATIVE PRMT5 INHIBITOR, IS EFFICACIOUS IN PRECLINICAL MTAP-DELETED MODELS INCLUDING GLIOBLASTOMA

Abstract Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. The median overall survival (OS) of GBM patients is poor (1-2 years) with standard of care therapies, demonstrating the significant need for the development of novel therapeutics. TNG908 is a clinical stage MTA-cooperative PRMT5 inhibitor that is selectively active in MTAP-deleted cells by leveraging a synthetic lethal interaction. Approximately 40% of GBM tumors have MTAP loss due to a co-deletion event with the proximal tumor suppressor gene, CDKN2A. In preclinical in vitro studies, TNG908 was 15-fold more potent in MTAP-deleted cancer cell lines than in MTAP WT cells. TNG908 has high passive permeability and is neither a substrate for P-glycoprotein nor Breast Cancer Resistant Protein (BCRP) efflux transporters. Consistent with these favorable attributes, TNG908 demonstrated in vivo brain penetration in multiple preclinical models, including non-human primates and mice. TNG908 on-target pharmacodynamic activity was determined by dose-dependent decreases in SDMA-modified protein levels in a GBM subcutaneous 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 6-fold reduced Kpuu in rodents (Kpuu ~0.15) relative to non-human primates (Kpuu 0.9), 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, MTA-cooperative PRMT5 inhibitor that drives strong antitumor activity in preclinical models of MTAP-deleted GBM. TNG908 is currently enrolling patients with MTAP-deleted tumors including glioblastoma in a Phase I/II clinical trial (NCT05275478).

Sex differences in long-term outcomes among hospitalized heart failure patients across the spectrum of ejection fraction: findings from the Get with the guidelines - heart failure registry

Abstract Background Sex differences in 5-year outcomes across heart failure (HF) ejection fraction (EF) subtypes are not well known. Purpose To assess the interaction between sex and EF for risk of long-term adverse outcomes after hospitalization with HF. Methods Patients from American Heart Association’s Get With The Guidelines – Heart Failure registry enrolled between 1/1/2006 – 12/31/2014 with age ≥ 65 years with available 5-year follow-up data, ascertained through linkage with Medicare fee-for-service Part A administrative claims, were included. HF subtypes included HF with reduced EF (HFrEF) with EF ≤ 40%, HF with mildly reduced EF (HFmrEF) with EF 41-49%, and HF with preserved EF (HFpEF) with EF ≥ 50%. Sex differences in 5-year all-cause mortality and readmission for each HF subtype were assessed using unadjusted cumulative incidence methods and adjusted Cox models. Median survival across HF subtypes was compared to median survival of U.S. adults. Results 155,670 patients (mean age 81 years, 53.4% females) were included. Male patients were younger and had a higher prevalence of prior myocardial infarction or coronary artery bypass graft surgery and were more likely to have HFrEF, while women were more likely to have history of hypertension and HFpEF. The median post-hospitalization survival of patients with HF was substantially lower than the age- and sex-specific U.S. life expectancy across each HF subtype (Figure 1).Patients with HF had high 5-year mortality rates (HFrEF male: 81.3%, female: 78.4%; HFpEF male: 80.5% vs female 79.5%). In adjusted analysis, female (vs. male) patients had a significantly lower 5-year mortality risk (HR [95%CI]: 0.89 [0.87 – 0.90], p<0.01) and a higher 5-year readmission risk (all-cause: 1.03 [1.02 – 1.04]), CV: 1.05 [1.04 – 1.07]), HF: 1.06 [1.04 – 1.08], p<0.01 for each). HF subtype modified the association between sex and 5-year outcomes (pinteraction <0.05 for mortality and CV and HF readmission), with the greatest risk reduction of mortality for female vs. male patients with HFrEF and the greatest risk increase of readmission (CV and HF) among female vs. male patients with HFmrEF and HFpEF (Figure 2). Conclusion Among patients with HF, the overall survival post-HF hospitalization is very low for each HF subtype. Female patients have a lower 5-year mortality risk but a higher risk of HF or CV readmission regardless of EF.Figure 1Figure 2

Correlation of the Geriatric Assessment with Overall Survival in Older Patients with Cancer

AimsGlobal guidelines recommend that all older patients with cancer receiving chemotherapy should undergo a geriatric assessment. However, utilisation of the geriatric assessment is often constrained by its time-intensive nature, which limits its adoption in settings with limited resources and high demand. There is a lack of evidence correlating the results of the geriatric assessment with survival from the Indian subcontinent. Therefore, the aims of the present study were to assess the impact of the geriatric assessment on survival in older Indian patients with cancer and to identify the factors associated with survival in these older patients. Materials and methodsThis was an observational study, conducted in the geriatric oncology clinic of the Tata Memorial Hospital (Mumbai, India). Patients aged 60 years and older with cancer who underwent a geriatric assessment were enrolled. We assessed the non-oncological geriatric domains of function and falls, nutrition, comorbidities, cognition, psychology, social support and medications. Patients exhibiting impairment in two or more domains were classified as frail. ResultsBetween June 2018 and January 2022, we enrolled 897 patients. The median age was 69 (interquartile range 65–73) years. The common malignancies were lung (40.5%), oesophagus (31.9%) and genitourinary (12.1%); 54.6% had metastatic disease. Based on the results of the geriatric assessment, 767 (85.4%) patients were frail. The estimated median overall survival in fit patients was 24.3 (95% confidence interval 18.2–not reached) months, compared with 11.2 (10.1–12.8) months in frail patients (hazard ratio 0.54; 95% confidence interval 0.41–0.72, P < 0.001). This difference in overall survival remained significant after adjusting for age, sex, primary tumour and metastatic status (hazard ratio 0.56; 95% confidence interval 0.41–0.74, P < 0.001). In the patients with a performance status of 0 or 1 (n = 454), 365 (80.4%) were frail; the median overall survival in the performance status 0–1 group was 33.0 months (95% confidence interval 24.31–not reached) in the fit group versus 14.4 months (95% confidence interval 12.25–18.73) in the frail patients (hazard ratio 0.50; 95% confidence interval 0.34–0.74, P = 0.001). In the multivariate analysis, the geriatric assessment domains that were predictive of survival were function (hazard ratio 0.68; 95% confidence interval 0.52–0.88; P = 0.003), nutrition (hazard ratio 0.64; 95% confidence interval 0.48–0.85, P = 0.002) and cognition (hazard ratio 0.67; 95% confidence interval 0.49–0.91, P = 0.011). DiscussionThe geriatric assessment is a powerful prognostic tool for survival among older Indian patients with cancer. The geriatric assessment is prognostic even in the cohort of patients thought to be the fittest, i.e. performance status 0 and 1. Our study re-emphasises the critical importance of the geriatric assessment in all older patients planned for cancer-directed therapy.

Combination of Circulating Plasma Cells Enhances the Efficacy of R2-ISS Stage System for Risk Stratification of Newly Diagnosed Multiple Myeloma: A Single-Center Real-World Study

Previous studies identified the prognostic significance of quantifying circulating plasma cells (CPCs) by multiparametric flow cytometry (MFC) in newly diagnosed multiple myeloma (NDMM) patients. Recently it was reported that the R2-ISS stage is a simple prognostic staging system allowing a better stratification of patients with intermediate-risk NDMM. We evaluated if a similar quantification of CPCs could add prognostic value to the R2-ISS classification of 279 consecutive NDMM patients treated in our center from 2017 to 2022. Those patients with R2-ISS stage II and stage III disease were re-classified according to the CPCs numbers ≥0.05% (CPC high) or＜0.05% (CPC low) for the purposes of this study. The median progression free survival (PFS) for patients were as follows: not reached (R2-ISS I), 43 months (R2-ISS II with CPC low),24 months(R2-ISS II with CPC high), 23 months (R2-ISS III with CPC low),12 months (R2-ISS III with CPC high) and 14 months (R2-ISS IV). The median overall survival (OS) for patients were as follows: not reached (R2-ISS I, R2-ISS II with CPC low, R2-ISS II with CPC high and R2-ISS III with CPC low) , 46 months (R2-ISS III with CPC high) and 32 months (R2-ISS IV). Finally, ≥ 0.05% CPCs retained its adverse prognostic significance in a multivariable model for PFS and OS. Hence, quantifying CPCs by MFC can potentially enhance the R2-ISS classification of a subset of NDMM patients with stage II and III disease by identifying those patients with a worse than expected survival outcome.

CPX-351 Versus FLAG-IDA with or without Venetoclax in Previously Untreated and Relapsed or Refractory Acute Myeloid Leukemia

1. Introduction A recent randomized comparison of liposomal daunorubicin and cytarabine (CPX-351) did not improve response rates or overall survival compared with FLAG-IDA in newly diagnosed acute myeloid leukemia (AML) - although subgroup analyses appeared to show some benefit with CPX-351. The real-world outcomes of these cohorts are unknown. Additionally, there is little data on the relative outcomes of these cohorts in the relapsed or refractory (RR) setting. We aimed to explore the efficacy of CPX-351 and FLAG-IDA with or without venetoclax in newly diagnosed and RR AML outside of clinical trials. 2. Methods We analyzed 142 patients from the Project ERIS database with newly diagnosed or relapsed or refractory (RR) AML treated with CPX-351 or FLAG-IDA from January 1, 2013 to April 18, 2023 at VCU Massey Comprehensive Cancer Center. We recorded baseline patient-related and disease characteristics, including age, ECOG, Charlson comorbidity index (CCI) scores, molecular profiling and ELN 2022 cytogenetic risk, dates of regimen initiation, and survival. We used the D'Agostino &amp; Pearson method for normality testing and the t-test or Mann-Whitney (as applicable) tests for between-group comparisons. Categorical comparisons used Fischer's exact test. We applied the Bonferroni correction if multiple comparisons were made. The Wilson-Brown method was used for 95% confidence intervals. We analyzed survival by the Kaplan-Meier method with significance determined by the log-rank test. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. 3. Results First, we analyzed 43 (30.3%) patients with newly diagnosed AML fit for intensive chemotherapy: 33 (76.7%) received CPX-351 and 10 (23.3%) received FLAG-IDA. In the FLAG-IDA cohort, three (30.0%) patients received concurrent venetoclax. There were no significant differences in baseline characteristics, including age, sex, race, or CCI scores, shown in Table A. However, patients in the CPX-351 cohort had significantly worse ECOG performance status compared with the FLAG-IDA cohort (median, 1 vs 0, p = 0.007). There were no significant differences in the proportion of patients that had ELN 2022 adverse risk cytogenetics between the CPX-351 and FLAG-IDA cohorts (65.6% vs 55.6%, p = 0.701). The composite complete response rate (CRc; CR + CRi + CRh) was 53.6% (95% CI: 35.8-70.5) in the CPX-351 cohort and 62.5% (95% CI: 30.6-86.3) for FLAG-IDA (p = 0.709). The rate of MRD negativity was 33.3% for CPX-351 (95% CI: 5.9-70.0) and 50.0% (95% CI: 2.6-97.4) for FLAG-IDA. A similar proportion of patients proceeded to allogeneic stem cell transplant (alloSCT; 39.4% vs 40.0%, p &amp;gt; 0.999). There was no significant difference in the median overall survival in patients treated with CPX-351 or FLAG-IDA (16.1 m. vs 11.4 m., p = 0.129, Figure B). Next, we analyzed 96 (90.7%) patients that received FLAG-IDA and ten (9.3%) that received CPX-351 for RR AML in any subsequent line; three (2.1%) patients in the overall cohort received either CPX-351 or FLAG-IDA in the first-line setting, then crossed over to the other arm at disease progression. Sixteen (16.7%) patients received venetoclax with FLAG-IDA. There were no significant baseline differences between cohorts, as shown in Table A. The CRc for CPX-351 was 33.3% (95% CI, 5.9-70.0) compared with 47.7% (95% CI, 37.6-58.0, p = 0.681) for FLAG-IDA. The rate of MRD negativity was 50.0% (95% CI, 2.6-97.4) for CPX-351 and 66.7% for FLAG-IDA (95% CI, 39.1-86.2, p &amp;gt; 0.999). There was no significant difference in the median overall survival in patients treated with CPX-351 or FLAG-IDA (12.7 m. vs 14.5 m., p = 0.561). 4. Discussion There was no significant difference in the rates of CRc, MRD negativity, or overall survival in patients that received CPX-351 or FLAG-IDA with or without venetoclax in the first-line setting or at the time of disease progression. Both approaches appear to be viable in carefully selected cohorts of patients. A comprehensive toxicity analysis and exploratory molecular subgroup analysis are ongoing.

Long-Term Follow-up of Humanized and Murine CD19 CAR-T Cell Therapy for B-Cell Malignancies

Aim: CD19 chimeric antigen receptor T cell (CAR-T) therapy is a revolutionary treatment for relapsed/refractory (R/R) B-cell hematologic malignancies. However, the safety and efficacy of murine CAR-T cells which have been widely used as commercialized products still need to be improved. Similarly, murine CAR-T encountered the problem that CAR-related immunogenicity existed after the infusion, which led to the failure of the re-infusion of CAR-T cells. As an improved generation of murine CAR-T cells, whether humanized CAR-T therapy can overcome the above shortcomings remains to be explored. Methods: In this study, the differences in safety, efficacy, and long-term follow-up results of murine and humanized CD19 CAR-T cells in patients with B-cell malignancies were collected and analyzed. A total of 130 patients were enrolled, including 35 patients with murine CAR-T and 95 with humanized CAR-T cells (NCT 02965092, NCT 04008251). Results： The proportion of patients with cytokine release syndrome (CRS) in the murine and humanized groups was 54.3%（19/35） and 61.1%（58/95）, respectively. A significantly higher proportion of patients suffered from severe CRS in the murine group than that in the humanized CAR-T group (17.14% vs. 7.4%, P=0.0233), and one patient in each group died of Grade 5 CRS. The incidence of grade 1-2 Immune effector cell-associated neurotoxicity syndrome (ICANS) was 11.4% (murine: 4/35) and 5.3% (humanized: 5/95), but high-grade ICANS was not observed. Among patients receiving murine CAR-T cells, 80% achieved objective response (OR), 71.43% achieved complete response (CR) and the CR rate of patients with leukemia was 74.19%. The OR rate and CR rate of patients in the humanized group were 75.79% and 63.16%, respectively, while the CR rate of patients with leukemia receiving humanized CAR-T cells was 89.58%. The median follow-up time of patients in the murine and humanized groups was 7 months (0.6-75 months) and 5.5 months (0.5-34 months), respectively. The median progression-free survival (PFS) of patients with murine CAR-T cells was 11 months and that of patients with humanized CAR-T products was 12 months. Both of the median overall survival (OS) were not reached. Among the 48 patients with a bone marrow burden over 20% at baseline, humanized CAR-T therapy was associated with a higher OS rate (84.64% vs. 59.26%, P=0.1479) and a significantly improved PFS (43.94% vs. 33.33%, P=0.0217, Figure 1). Bridging transplantation was an independent factor in prolonging OS (x 2=8.017, p=0.0046) and PFS (x 2=6.584, p=0.0103) of patients with leukemia. Neither species of chimeric antigen receptor nor common risk factors such as age, recurrence, bone marrow burden, BCR-ABL fusion gene had significant effect on patients' long-term follow-up outcomes (Table 1). Four patients received CAR-T therapies more than once. Three of them still achieved varying degrees of long-term remission after multiple humanized CAR-T infusions. However, one patient relapsed as soon as one month after his second infusion of murine CAR-T cells. Conclusion: Results indicate that humanized CAR-T therapy showed better safety and durable efficacy, especially in patients with higher tumor burden in bone marrow. Moreover, it could overcome immunogenicity-induced CAR-T resistance, providing treatment options for patients' failures of CAR-T therapies.

The Presence of Ring Chromosomes in Patients with Myeloid Neoplasms Is Predictive of a Poor Outcome

Cytogenomic analysis is an important tool in the risk stratification of patients with hematologic malignancies. Complex chromosomal alterations are associated with a poor prognosis (Döhner et al., Blood 2022). Ring chromosomes (RC) are circular chromosomal structures associated with loss or gain/amplification of genetic material and are associated with poor prognosis in acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS) (Rosenbaum et al., Human Path 2017). Due to their rarity, the impact of RC on response to therapy has not yet been well characterized. We further examined the significance of RC in AML, MDS and myeloproliferative neoplasms (MPN) by retrospectively analyzing records of patients identified to have RC and myeloid neoplasms at our institution between 2017 and 2023 and collected demographic, diagnostic, treatment, molecular, cytogenomic, and outcomes data. We identified 27 cases with RC with clinical data available for 25. Demographic and treatment details are described in Table 1. The most common chromosomes involved were r(11) and r(7), 6 and 4 cases respectively, followed by r(6) and r(19) with 2 cases each. The most frequently observed diagnosis was AML in 12 patients (48%) followed by MDS with 9 cases (36%) and MPN in 4 cases (16%). In 17 cases (68%) the RC was cytogenetically detected at diagnosis and was not observed in the context of prior therapy. Remarkably, mutations in TP53 were present in 14 cases (56%) and accompanied by loss of 17p (bi-allelic) in 7 cases (28%). The next most commonly observed gene mutations were in DNMT3A (7 cases), TET2 (4 cases) and ASXL1 (3 cases). In 11 cases (44%) the alterations in TP53 were not associated with prior therapy for other malignancies. The median time from prior chemotherapy to detection of the RC was 5.1 years (range 0.6 to 13.5 years). Chromothripsis (a single DNA catastrophic event resulting in extensive genomic rearrangements of one or a few chromosomes) as detected by CGH+SNP array and homogenous staining regions (autonomously replicating extra-chromosomal elements that are frequently associated with gene amplification) were observed in 3 patients each. RC were the sole genetic abnormality in 5 patients. A Kaplan-Meier analysis of median overall survival (mOS) in patients with AML and MDS with RC at diagnosis revealed that patients who received supportive care had significantly shorter mOS than patients who received hypomethylating agents (HMA), HMA/Venetoclax(VEN), or anthracycline-based chemotherapy (log rank test, p = 0.001). A significant difference in mOS between patients who received HMA alone versus HMA/VEN versus chemotherapy was not observed (11.4 vs 3.1 vs 7.3 months, p = 0.8) (Figure 1). Patients who received any of the therapies outlined above likewise demonstrated a significantly longer progression free survival (log rank test, p = 0.001). There was no effect on mOS for any of the other tested prognostic parameters, including the presence of a complex karyotype, TP53 allele status, or therapy-related neoplasm, nor for pair-wise interactions between those categories and first-line therapies (p &amp;gt; 0.05 for all tested associations). These data represent a large single-institution cohort of patients with RC and is the first to investigate the impact of therapy and molecular profiles in this population. We observed a high prevalence of TP53 mutations and loss of 17p, however we lacked longitudinal data to make causal inferences regarding the relationship between these abnormalities and ring formation. Of note, 68% of patients did not have prior exposure to therapy, and 36% of all patients lacked TP53 mutations or chromosomal p53 loss, indicating a high rate of de novo ring formation. This is a novel finding perhaps suggesting that inherent chromosomal instability characterizes these patients. Comparing response to type of therapy and outcomes of patients, we conclude that the mOS in patients with RC without therapy is significantly shortened compared with any of the therapeutic options described above, and that the addition of VEN to HMA did not positively influence mOS or PFS compared to HMA alone or chemotherapy in our cohort. Furthermore, the presence of a complex karyotype or a mutation and/or deletion of TP53 with a RC was not independently associated with inferior mOS, suggesting that the presence of a ring chromosome alone may be an important adverse risk factor in myeloid malignancies.

Mean Platelet Volume to Lymphocyte Ratio: A New Biomarker Predicting Response in Patients with Solid Tumors Treated with Nivolumab.

Although immune checkpoint inhibitors (ICIs) are widely used in cancer treatment, identifying factors that predict treatment response remains a challenge in clinical practice. There is a need for biomarkers to identify patients who may not benefit from these treatments. It is crucial to identify a simple and cost-effective biomarker that can be easily incorporated into clinical practice. This study aims to investigate the mean platelet volume to lymphocyte ratio (MPVLR), as measured by a hemogram test, and median overall survival (mOS) in patients with cancer treated with nivolumab. A total of 131 adult patients with metastatic cancer, including malignant melanoma (MM), renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and head and neck cancer (HNC), were included in this study. Baseline demographics, ECOG (Eastern Cooperative Oncology Group) performance status, tumor type, and blood count parameters were recorded. Univariate and multivariate analyses were conducted to evaluate potential risk factors. The median age of the patients was 59.87 ± 11.97 years, and the median follow-up period was 20.20 months (IQR, 12.80-27.60). RCC (43.5%) and MM (25.9%) were the most common diagnoses. Patients with ECOG scores of 0-1 had a longer mOS than those with scores of 2-3 (mOS: 20.60 months [95% CI, 14.94-25.29] vs. 5.24 months [95% CI, 0-16.42], p < 0.001). Additionally, patients with lactate dehydrogenase (LDH) levels within the normal range had a longer mOS than those with high LDH levels (mOS: 24.54 months [95% CI, 14.13-34.96] vs. 13.10 months [95% CI, 4.49-21.72], p = 0.038). Patients with low MPVLR also had a longer mOS than those with high MPVLR (mOS: 33.70 months [95% CI, 25.99-41.42] vs. 11.07 months [95% CI, 6.89-15.24], p < 0.001). In the multivariate Cox regression analysis, high MPVLR, ECOG score of 2-3, and high LDH level were associated with shorter mOS (p < 0.001, p = 0.001, and p = 0.046, respectively). This study demonstrates that MPVLR could serve as a novel biomarker for predicting response to nivolumab treatment. Incorporating MPVLR into clinical practice may aid in identifying patients who are less likely to benefit from the treatment.

Prognosis Prediction of CRAFITY Score in HCC Undergoing TACE Combined with PD-(L)1 Inhibitors and Molecular Targeted Therapy.

The CRAFITY (C-reactive protein and alpha-fetoprotein in immunotherapy) score has demonstrated prognostic significance in hepatocellular carcinoma (HCC) patients undergoing immunotherapy. The study aimed to validate accuracy of CRAFITY score on predicting prognosis for patients with HCC treated with transarterial chemoembolization (TACE) combined with PD-(L)1 inhibitors and molecular targeted therapy. Eighty-five HCC patients who underwent TACE in combination with molecular targeted therapy (MTT) and PD-(L)1 Inhibitors were consecutively enrolled from November 2019 to November 2022. Patients were divided into CRAFITY 0 score (n=32), CRAFITY 1 score (n=31), and CRAFITY 2 score (n=22), respectively. The primary outcomes were overall survival (OS) and progression-free survival (PFS), and the secondary outcomes included tumor response rate and treatment-related adverse events (TRAEs). Factors affecting survival were identified via Cox regression analysis. The median overall survival (OS) for HCC patients with CRAFITY scores of 0, 1, and 2 was 33.4 months (95% confidence interval [CI]: 27.1-39.7), 34.5 months (95% CI: 23.1-45.9), and 24.2 months (95% CI: 13.9-39.3), respectively, there were statistical differences among the three groups (p<0.05). The progression-free survival (PFS) was 14.1 months (95% CI: 10.0-18.2), 14.1 months (95% CI: 9.0-19.2), and 9.3 months (95% CI: 7.2-11.4) for patients with CRAFITY scores of 1, 2, and 3, respectively, with a significant difference between the three groups (p<0.05). In patients with CRAFITY scores of 1, 2, and 3, the disease control rates (DCR) were 94%, 84%, and 73%, respectively (p < 0.05), while the overall response rates (ORR) were 78.1%, 67.7%, and 59.1%, respectively (p = 0.318). A higher CRAFITY score showed a correlation with an increased frequency of fatigue and grade 3 fever (p<0.05). Moreover, CRAFITY 2 score was an independent risk factor for both OS (HR = 2.610(1.281-4.564), p = 0.014) and PFS (HR = 2.419(1.281-4.564), p = 0.006). The CRAFITY score may provide an efficient predictive capacity for prognosis in HCC patients undergoing TACE combined with PD-(L)1 inhibitors and molecular targeted therapy.

Resection rates and intention-to-treat outcomes in borderline and locally advanced pancreatic cancer: real-world data from a population-based, prospective cohort study (NORPACT-2).

Systemic chemotherapy is the initial treatment strategy for borderline resectable and locally advanced pancreatic cancer to facilitate curative resection. The aim of this study was to investigate the resection rates and overall survival in patients with borderline resectable pancreatic cancer and locally advanced pancreatic cancer. Consecutive patients with borderline resectable pancreatic cancer/locally advanced pancreatic cancer discussed by Oslo University Hospital multidisciplinary team between 2018 and 2020, serving a population of 3.1 million within a geographically defined area in south-eastern Norway, were included in this prospective Norwegian Pancreatic Cancer Trial-2 study, according to intention-to-treat principles. The total number of patients with pancreatic cancer was sought from the Cancer Registry of Norway. A total of 1178 patients were diagnosed with pancreatic cancer, of whom 618 were referred to Oslo University Hospital. After multidisciplinary team evaluation, 230 patients were considered to have borderline resectable pancreatic cancer/locally advanced pancreatic cancer. The final study group consisted of 188 patients (borderline resectable pancreatic cancer n = 96, locally advanced pancreatic cancer n = 92) who were fit to receive primary chemotherapy. Resection rates were 46.9% (45 of 96) for borderline resectable pancreatic cancer and 13% (12 of 92) for locally advanced pancreatic cancer (P <0.001). Median overall survival was 14.6 months (borderline resectable pancreatic cancer 16.4 months; locally advanced pancreatic cancer 13.7 months, (P = 0.2)). Adjusted for immortal time bias, median overall survival for patients undergoing resection versus only chemotherapy was 24.4 months versus 10.1 months (P <0.001) for borderline resectable pancreatic cancer and 28.4 months versus 12.6 months for locally advanced pancreatic cancer (P = 0.001). Resection rates and survival in patients with borderline resectable pancreatic cancer and locally advanced pancreatic cancer treated at a high-volume centre in a universal healthcare system compare well with those treated at international expert centres.Registration number: NCT04423731 (http://www.clinicaltrials.gov).

Impact of Ferroptosis Inducers on Chronic Radiation-exposed Survivor Glioblastoma Cells.

The median survival of patients diagnosed with glioblastoma is very poor, despite efforts to improve the therapeutic effects of surgery, followed by treatment with temozolomide (TMZ) and ionizing radiation (IR). The utilization of TMZ or IR survivor cell models has enhanced the understanding of glioblastoma biology and the development of novel therapeutic strategies. In this present study, naïve U373 and clinically relevant U373 IRsurvivor (Surv) cells were used, as the IR-Surv cell model mimics the chronic long-term exposure to standardized radiotherapy for patients with glioblastoma in the clinic. As the role of ferroptosis in the IR survivor cell model has not previously been reported, we aimed to clarify its involvement in the clinically relevant IR-Surv glioblastoma model. Transcriptomic alterations of ferroptosis-related genes were studied on naïve U373 and IR-Surv cell populations. To determine the effects of glutathione peroxidase inhibitors, ferroptosis-inducing agent 56 (FIN56) and Ras synthetic lethal 3 (RSL3), on the cells, several properties were assessed, including colony formation, cell viability and lipid peroxidation. Results from the transcriptomic analysis identified ferroptosis as a critical mechanism after radiation exposure in glioblastoma. Our findings also identified the role of ferroptosis inducers (FINs) in IR-survivor cells and suggested using FINs to treat glioblastoma. FINs serve an important role in radioresistant cells; thus, the results of the present study may contribute to improving survival in patients with glioblastoma.

Clinical Profile and Treatment Outcomes of Malignant Mixed Mullerian Tumors of the Uterus: A Single-Center Experience.

Background A malignant mixed Mullerian tumor (MMMT), otherwise known as carcinosarcoma, is a rare and aggressive malignancy involving the uterus. Despite aggressive treatment, they have poor outcomes. We performed this study to analyze the clinical profile, prognostic features, and treatment outcomes of patients treated for MMMT of the uterine corpus in our center. Methodology A study sample from a database of patients treated at a tertiary care center in South India between January 2015 and December 2019 was analyzed retrospectively. A total of 29 non-metastatic patients were included in the study. The diagnosis of MMMT was confirmed by a pre-operative biopsy specimen or endometrial curettage. Information regarding the patient, tumor characteristics, details of the surgery, adjuvant therapy, and follow-up details were collected retrospectively. Disease-free survival (DFS) and overall survival (OS) were plotted using the Kaplan-Meier method, and the log-rank test was used to identify any significant prognostic factor. Statistical analyses were performed using IBM SPSS software, version 21 (IBM Corp., Armonk, NY). Results The population's median age was 60 years (interquartile range (IQR): 52-65). The homologous type was the most common pathology seen in 21 patients. The median size of the tumor was 7 centimeters (cm) (IQR: 6-10). Around two-thirds of the patients received adjuvant radiation therapy. Paclitaxel and carboplatin-based adjuvant chemotherapy were used in 60% of the patients. Nearly 90% of the recurrences were distant recurrences. During the follow-up, 17 patients developed a recurrence. The median DFS was 12 months (95% CI: 7.7-16.2). The median OS was 26 months (95% CI: 10.6-41.3). The three-year OS rate was 42%. Patients with an age >60 years had a median overall survival of 11 months, compared to 37 months for patients <60 years (p = 0.026). The median overall survival of patients with tumor sizes >10 cm was 12.5 months, and it was 35 months when the tumor size was less than 10 cm (p = 0.03). Patients receiving radiotherapy (RT) had an improved survival (39 months) compared to those who did not receive RT (12.5 months) (p = 0.046). The median overall survival for patients after the recurrence was 12 months. As most patients were elderly with an Eastern Cooperative Oncology Group (ECOG) performance status of two at baseline, only a few patients were fit for second-line chemotherapy. Conclusion A malignant mixed Mullerian tumor is an aggressive tumor of the uterine corpus with poor survival rates. Surgical resection remains the mainstay of treatment. Adjuvant radiation therapy improves survival. The age of the patient, myometrium invasion, tumor size, and positive peritoneal cytology were found to be prognostic factors.

Association between hospital volume and outcomes in invasive ovarian cancer in Belgium: A population-based study

ObjectivesTo study the association between hospital volume and outcomes in patients with invasive epithelial ovarian cancer (EOC). MethodsThis study included 3988 patients diagnosed with invasive EOC between 2014 and 2018, selected from the population-based database of the Belgian Cancer Registry (BCR), and coupled with health insurance and vital status data. The associations between hospital volume and observed survival since diagnosis were assessed with Cox proportional hazard models, while volume associations with 30-day post-operative mortality and complicated recovery were evaluated using logistic regression models. ResultsTreatment for EOC was very dispersed with half of the 100 centres treating fewer than six patients per year. The median survival of patients treated in centres with the highest-volume quartile was 2.5 years longer than in those with the lowest-volume quartile (4.2 years versus 1.7 years). When taking the case-mix of hospitals into account, patients treated in the lowest volume centres had a 47% higher hazard to die than patients treated in the highest volume centres (HR: 1.47, 95% CI: 1.11–1.93, p = 0.006) over the first five years after incidence. A similar association was found when focussing on the surgical volume of the hospitals and considering only operated patients with invasive EOC. Lastly, the 30-day post-operative mortality decreased significantly with increasing surgical volume. ConclusionsThe large dispersion of care and expertise within Belgium and the volume-outcome associations observed in this study support the implementation of the concentration of care for patients with invasive EOC in reference centres.

Switch to generic formulation of temozolomide results in statistically significant increase in grade 3 and 4 bone marrow toxicity in glioma patients in the province of Alberta.

Temozolomide (TMZ) is an oral, systemic chemotherapy used chiefly for treating high-grade glioma. Due to the rising costs of systemic chemotherapy, many jurisdictions have replaced brand name with generic formulations. The aim of this study was to determine whether or not there was difference in the incidence of grade 3 or 4 bone marrow toxicity and median overall survival in patients treated with brand name versus generic TMZ in the province of Alberta, Canada. The province suspended the use of generic TMZ based on preliminary data pointing to excess toxicity. This multicenter, retrospective study included data from patients with newly diagnosed high-grade glioma that received treatment with TMZ in Alberta. Multivariate logistic regression analysis was performed to determine the association between grade 3 or 4 toxicity to generic versus brand name TMZ exposure, ECOG score, and age. Kaplan-Meier survival estimates and log-rank testing were used to determine differences in overall survival between the brand name and generic TMZ cohorts, as well as the cytopenic versus non-cytopenic patients. Furthermore, a screening analysis for grade 3 or 4 bone marrow toxicity was conducted on all de novo glioma patients treated with brand name TMZ after Alberta preemptively stopped generic TMZ. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 15% and 19% of patients treated with generic TMZ (n = 156) as compared to 3% and 5% of patients (n = 100) treated with brand name TMZ-treated patients; P= .003 and .001. A trend toward increased median overall survival in glioblastoma patients treated with generic TMZ (13.7 months) versus brand name (15.8 months, P = .178.) was also observed through meeting statistical significance. Based on these results, the province stopped the use of generic TMZ and reverted to the Merck TMZ. An initial review of all new glioma patients (n = 89) treated with Merck TMZ since the province stopped the generic drug demonstrated 3.4% and 10.1% grade 3 or 4 neutropenia, respectively. The statistically significant difference in toxicity profile has prompted the province of Alberta to replace generic TMZ with brand name TMZ in high-grade glioma patients pending more detailed analysis. Our study provides evidence supporting the importance of conducting prospective studies on long-term safety for generic chemotherapies.

Radiogenomics Provides Insights into Gliomas Demonstrating Single-Arm 1p or 19q Deletion.

IDH-mutant gliomas are further divided on the basis of 1p/19q status: oligodendroglioma, IDH-mutant and 1p/19q-codeleted, and astrocytoma, IDH-mutant (without codeletion). Occasionally, testing may reveal single-arm 1p or 19q deletion (unideletion), which remains within the diagnosis of astrocytoma. Molecular assessment has some limitations, however, raising the possibility that some unideleted tumors could actually be codeleted. This study assessed whether unideleted tumors had MR imaging features and survival more consistent with astrocytomas or oligodendrogliomas. One hundred twenty-one IDH-mutant grade 2-3 gliomas with 1p/19q results were identified. Two neuroradiologists assessed the T2-FLAIR mismatch sign and calcifications, as differentiators of astrocytomas and oligodendrogliomas. MR imaging features and survival were compared among the unideleted tumors, codeleted tumors, and those without 1p or 19q deletion. The cohort comprised 65 tumors without 1p or 19q deletion, 12 unideleted tumors, and 44 codeleted. The proportion of unideleted tumors demonstrating the T2-FLAIR mismatch sign (33%) was similar to that in tumors without deletion (49%; P = .39), but significantly higher than codeleted tumors (0%; P = .001). Calcifications were less frequent in unideleted tumors (0%) than in codeleted tumors (25%), but this difference did not reach statistical significance (P = .097). The median survival of patients with unideleted tumors was 7.8 years, which was similar to that in tumors without deletion (8.5 years; P = .72) but significantly shorter than that in codeleted tumors (not reaching median survival after 12 years; P = .013). IDH-mutant gliomas with single-arm 1p or 19q deletion have MR imaging appearance and survival that are similar to those of astrocytomas without 1p or 19q deletion and significantly different from those of 1p/19q-codeleted oligodendrogliomas.

Disparities in Pancreatic Cancer Outcomes in the Disaggregated Asian American Population.

The Asian American, Native Hawaiian, and Pacific Islander (AANHPI) population is among the fastest-growing population in the USA. However, this is not reflected in scientific research, in which ethnic groups are often combined. We identified trends in treatment and outcomes for pancreatic cancer in a disaggregated AANHPI population. We hypothesize that patients from different AANHPI groups have differences in survival. A retrospective analysis of the National Cancer Database between 2010 and 2019 identified patients treated for pancreatic cancer. We identified demographic factors for patients of Caucasian, African American, and disaggregated Asian subpopulations. Survival curves were generated and multivariate analysis was performed to help determine which factors impacted overall survival. A total of 296,448 patients met the inclusion criteria. Of those, 8568 (3%) patients were Asian. Median survival of AANHPI patients was 11.3 months, as compared with Caucasians (8.9 months) and African Americans (8.1 months) (p<0.0001). Asian Indians had the highest median survival (14.3 months), whereas the Japanese subpopulation had the lowest (7.6 months) (p<0.0001). There were significant differences in median survival between the different AANHPI subpopulations irrespective of stage. Multivariate analysis demonstrated that belonging to an AANHPI racial/ethnic group, excluding Japanese and Filipino, was associated with decreased risk of overall mortality. Significant differences were identified in the overall median survival for patients with pancreatic cancer between AANHPI subpopulations. Disparities in socioeconomic factors may have played a role in overall survival. This study highlights the need to include disaggregated data in future studies to subdue disparities in cancer care for patients.

Establishment and validation of a nomogram to select patients with metastatic sarcomatoid renal cell carcinoma suitable for cytoreductive radical nephrectomy

IntroductionMetastatic renal cell carcinoma (mRCC) with sarcomatoid features has a poor prognosis. Cytoreductive radical nephrectomy (CRN) can improve prognosis, but patient selection is unclear. This study aimed to develop a prediction model for selecting patients suitable for CRN.Materials and methodsPatients with a diagnosis of mRCC with sarcomatoid features in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015 were retrospectively reviewed. CRN benefit was defined as a survival time longer than the median overall survival (OS) in patients who did not receive CRN. A prediction nomogram was established and validated using the SEER cohort (training and internal validation) and an external validation cohort.ResultsOf 900 patients with sarcomatoid mRCC, 608 (67.6%) underwent CRN. OS was longer in the CRN group than in the non-CRN group (8 vs. 6 months, hazard ratio (HR) = 0.767, p = 0.0085). In the matched CRN group, 124 (57.7%) patients survived &amp;gt;6 months after the surgery and were considered to benefit from CRN. Age, T-stage, systematic therapy, metastatic site, and lymph nodes were identified as independent factors influencing OS after CRN, which were included in the prediction nomogram. The monogram performed well on the training set (area under the receiver operating characteristic (AUC) curve = 0.766, 95% confidence interval (CI): 0.687–0.845), internal validation set (AUC = 0.796, 95% CI: 0.684–0.908), and external validation set (AUC = 0.911, 95% CI: 0.831–0.991).ConclusionsA nomogram was constructed and validated with good accuracy for selecting patients with sarcomatoid mRCC suitable for CRN.

Epidemiology and survival outcomes of colorectal mixed neuroendocrine–non-neuroendocrine neoplasms and neuroendocrine carcinoma

BackgroundMixed neuroendocrine–non-neuroendocrine neoplasms are a rare subtype of neuroendocrine neoplasm consisting of ≥30% each of neuroendocrine and non-neuroendocrine differentiation. Neuroendocrine carcinomas are poorly differentiated neuroendocrine tumors. The epidemiology and prognosis of colorectal mixed neuroendocrine–non-neuroendocrine neoplasms and neuroendocrine carcinomas are not clearly defined in the literature. We sought to examine the presentation, patterns of care, and outcomes of patients with mixed neuroendocrine–non-neuroendocrine neoplasms and neuroendocrine carcinomas. MethodsWe identified patients diagnosed with stage I–III colorectal (excluding appendix) mixed neuroendocrine–non-neuroendocrine neoplasms or neuroendocrine carcinomas with only one-lifetime cancer diagnosis who underwent surgical resection between 2010 and 2018 from the National Cancer Database. We performed bidirectional selection to identify variables to include in a multivariable Cox proportional hazards model. ResultsWe identified 189 patients with a diagnosis of stage I to III colorectal mixed neuroendocrine–non-neuroendocrine neoplasms, 66% of whom had poorly differentiated tumors and 482 with neuroendocrine carcinomas. Among patients with stage III disease, 68% of patients with mixed neuroendocrine–non-neuroendocrine neoplasms and 54% of patients with neuroendocrine carcinomas received adjuvant chemotherapy. The median survival for the overall patients with mixed neuroendocrine–non-neuroendocrine neoplasms and neuroendocrine carcinomas cohorts were 38 and 42 months, respectively (P = .22), and the median survival for patients with mixed neuroendocrine–non-neuroendocrine neoplasms and neuroendocrine carcinomas with stage III disease were 30 and 25 months, respectively (P = .27). In multivariable analysis, fewer number of positive nodes and receipt of adjuvant chemotherapy were independently associated with decreased risk of mortality for patients with mixed neuroendocrine–non-neuroendocrine neoplasms and neuroendocrine carcinomas. ConclusionAdjuvant chemotherapy is associated with improved survival in stage III mixed neuroendocrine–non-neuroendocrine neoplasms and neuroendocrine carcinomas. Future studies are warranted to identify subsets of patients benefiting most from adjuvant therapy.

Sustained improved survival of patients with metastatic melanoma after the introduction of anti-PD-1-based therapies

BackgroundThe introduction of modern therapies improved the median survival of patients with metastatic melanoma (MM). Here, we determined the real-world impact of modern treatments on the long-term survival of MM. MethodsIn a population-based study, we extracted all cases of MM diagnosed in four non-consecutive years marked by major changes in available 1st line treatments (2012, 2014, 2016, and 2018) from the Danish MM Database. Patients were grouped into “trial-like” and “trial-excluded” based on common trial eligibility criteria. ResultsWe observed a sustained improved survival of “trial-like” patients diagnosed in 2016 or in 2018, compared to 2012 or 2014, but no major differences in 2018 versus 2016. In contrast, while survival of “trial-excluded” patients in 2016 was better compared to 2014 and 2012, survival in 2018 was improved over all previous years. We then developed a prognostic model based on multivariable stratified Cox regression, to predict the survival of newly diagnosed MM patients. Internal validation showed excellent discrimination and calibration, with a time-area-under-the-curve above 0.79 at multiple time horizons, for up to four years after diagnosis. ConclusionsThe introduction of modern treatments such as anti-PD-1 has led to a sustained, improved survival of real-world patients with MM, regardless of their eligibility for clinical trials. We provide an updateable prognostic model that can be used to improve patient information. Overall, these data highlight a positive population-based impact of modern treatments and can help health technology assessment agencies worldwide to evaluate the appropriateness of drug pricing based on known cost-benefit data.

Gastric remnant cancer and long-term survival in Central Norway 2001 to 2016 – A population-based study

IntroductionGastric remnant cancer (GRC) has been defined as a distinct clinical entity and is reported to account for 1–8% of all gastric cancers. We aimed to characterize GRC patients and assess survival in a Western population. MethodsRetrospective population-based cohort study including 1217 patients diagnosed with gastric adenocarcinoma in Central Norway 2001–2016. GRCs (n = 78) defined as adenocarcinomas arising in the residual stomach after distal gastrectomy were compared to non-GRC (n = 1139) and to proximal non-GRC (n = 595). Results78 (6.4 %) gastric cancers were GRC. The annual number and proportion of GRC declined during the study period (p = 0.003). Median latency from distal gastrectomy to GRC diagnosis was 37.6 years (15.7–68.0) and previous Billroth II reconstruction was most common (87.7%). Compared to controls, GRC patients were more frequently males (83.3%), diagnosed in earlier TNM stages and were older at diagnosis. A smaller proportion of GRC patients received perioperative or palliative chemotherapy, but the R0/R1resection rate of 41.0% was no different from non-GRC patients. Overall median survival for GRC patients irrespective of treatment was 7.0 months, which did not differ from non-GRCs or proximal non-GRC. In multivariate analyses TNM stage and age were independently associated with mortality, whereas GRC per se was not. ConclusionsNumbers of GRCs declined during the study period, but the latency between distal gastrectomy and GRC diagnosis was long. GRC patients were more frequently male and older than other gastric cancer patients. GRC was not independently associated with survival after adjusting for TNM stage and tumor location.