bluuebunny/crossref_metadata_2025 huggingface dataset:
Soluble urokinase-type plasminogen activator receptor, suPAR, as a prognostic biomarker in advanced pancreatic cancer.
Authors: Eefsen Rikke Løvendahl , Christensen Ib Jarle , Calatyud Dan , Johansen Astrid Zedlitz , Chen Inna Markovna , Rasmussen Louise Skau , Pfeiffer Per , Hollander Niels Henrik , Andersen Fahimeh , Johansen Julia S. , Hoyer-Hansen Gunilla
Published: June 2023

e16277

Background: High levels of intact and cleaved forms of the urokinase-type Plasminogen Activator Receptor (uPAR) in tissue and blood are associated with a poor prognosis in several types of cancer, including lung, colon, bladder, and cholangiocarcinoma. The soluble forms of uPAR (suPAR) have not been investigated in patients with pancreatic ductal adenocarcinoma (PDAC). The aim was to determine if circulating levels of intact and cleaved suPAR were associated with overall survival (OS) in patients with advanced PDAC. Methods: Patients with PDAC stage 3 or 4 were consecutively included in the BIOPAC study (ClinicalTrials.gov ID: NCT03311776) in a training cohort (n = 230, age 45-89 years, 56% females) from Herlev Hospital and a validation cohort (n = 115, age 40-82 years, 59% females) from four other Danish hospitals between 2008 to 2014. A total of 95% of the patients in the training cohort and 93% in the validation cohort received first-line palliative chemotherapy. One patient was alive at the time of analysis at 8 years follow-up. Serum samples were collected prior to palliative chemotherapy. Different suPAR forms were determined using time-resolved fluorescence immunoassays (TR-FIA). The Cox proportional hazards model was used for uni- and multivariate analyses. Age, performance status, stage (4 vs 3), gender, Charlson age-adjusted comorbidity index, and CA19-9 were included in the multivariate analysis for OS. Results: In the training cohort, high level of suPAR domain I was an independent biomarker of short OS (HR, 1.37, 95% CI 1.15-1.63, p = 0.0004). High CA19-9 (HR, 1.08, 95% CI 1.04-1.12, p < 0.0001), PS, and stage were also independent prognostic parameters in the training cohort. In the validation cohort, high level of suPAR domain I (HR, 1.91, 95% CI 1.36-2.69, p = 0.0002) and CA 19-9 (HR, 1.09, 95% CI 1.01-1.17, p = 0.02) were confirmed as independent prognostic biomarkers for short OS. No correlation was observed between suPAR domain 1 and CA19-9 (r = 0.059, p = 0.21). Conclusions: A high pretreatment circulating level of suPAR domain I is associated with a short OS in patients with advanced PDAC, and the biomarker is independent of CA19-9. The results warrant further investigation of suPAR domain 1 as a biomarker in patients with PDAC.
Utilization of germline testing in patients with early-onset pancreatic cancer (EOPC).
Authors: Ehsan Hamid , Symanowski James Thomas , Athens Aly , Wilson Katherine , Tobik Katie , Elrefai Sara , Salem Mohamed E. , Hwang Jimmy J. , Kadakia Kunal C.
Published: June 2023

e16300

Background: EOPC is associated with significant life years lost. Approximately 5%-10% of pancreatic adenocarcinoma (PAC) have an underlying genetic predisposition and national guidelines recommend testing in all patients with PAC. Certain germline mutations such as BRCA2 and PALB2 predict response to specific treatments including platinum and targeted therapies. It is currently unknown to what extent patients with EOPC pursue recommended germline testing. We examined the utilization of germline testing in patients with EOPC who were referred to genetics. Methods: A retrospective review of patients with EOPC at the Levine Cancer Institute (LCI), defined as ≤60 years of age at time of diagnosis, who were referred and seen by genetics between January 2019 and December 2021 was performed. Germline testing was performed using multi-gene cancer panels. Positive germline testing was considered as any known pathogenic or likely pathogenic variant not including variants of unknown significance (VUS). Results: We identified 69 patients with EOPC who were evaluated by genetics. The median age was 55 years (range 25-60) with 36 (52%) male, 33 (48%) female, 48 (70%) white, 16 (23%) Black, 61 (89%) with ECOG 0-1, 36 (52%) current or prior smoking history, and 28 (42%) presenting with metastatic disease. As shown, out of 69 patients, 10 (14%) declined testing or had unknown results, 30 (43%) had negative germline testing, 29 (42%) had genetic testing that revealed 19 (65%) had VUS, and 10 (34%) had pathogenic variants. The most frequently seen pathogenic variants were ATM (30%), BRCA1 (30%), BRCA2 (10%), MLH1 (10%), RAD51C+ (10%) and CFTR (10%). Conclusions: Our data suggest that most patients with EOPC who are evaluated undertake germline testing. Given the predictive nature of certain pathogenic mutations on PAC treatment options, characteristics of patients with EOPC who decline testing should be further explored. There is need for larger studies to confirm the high incidence of pathogenic variants observed in our cohort of EOPC patients. [Table: see text][Table: see text]
Prognostic impact of hyponatremia in patients with pancreatic cancer: A nationwide analysis.
Authors: Kumar Vikash , Kumar Naresh , Vachhani Bhavyakumar , Singh Surbhi , Naz Sidra , Shulimovich Max
Published: June 2023

e16304

Background: Hyponatremia has historically been reported to increase mortality and length of stay in hospitalized patients with solid tumors. There are sparse reports of hyponatremia linked to Pancreatic cancer in the published literature. Therefore, we evaluated mortality, morbidity, and resource utilization in Pancreatic cancer patients secondary to hyponatremia. Methods: A retrospective analysis was performed by utilizing the National Inpatient Sample database 2019 and the ICD- 10 codes to identify the patients > 18 years old with the principal diagnosis of Pancreatic cancer. Effect of hyponatremia was studied on mortality, morbidity, and resource utilization. Categorical variables were compared using the chi-square test, and continuous variables were compared using the t- test. Multivariable regression analyses were performed adjusting for demographics, hospital-level characteristics, and relevant comorbidities. Confounding variables were adjusted using multivariate logistic and linear regression analyses. These included: gender, race, Charlson Comorbidity Index, chronic kidney disease, congestive heart failure, cirrhosis, nephrotic syndrome, hypothyroidism, alcohol use disorder, and various patient and hospital characteristics. Results: We identified a total of 110,980 patients with primary diagnosis of pancreatic cancer in 2019, Of whom 18.1% (5,845) had hyponatremia on presentation. Patients with hyponatremia had 9.48 % in-hospital mortality, while 6.68% for patients without hyponatremia. After adjusting for confounders, hyponatremia imparted higher odds of mortality (Adjusted odds ratio (aOR) for mortality 1.46, 95% confidence interval (CI): 1.28–1.67, P< 0.01). Pancreatic cancer patients with hyponatremia have higher odds of Sepsis (Odd ratio = 1.64), Acute kidney injury (Odd ratio = 2.03), Peritonitis (Odd ratio = 2.40), and ICU admission (Odd ratio = 3.82). Hyponatremia also resulted in higher resource utilization marked by the length of stay, and hospital charges, (higher mean LOS by 1.16 days, and higher mean total hospital charges by $ 12,320). Conclusions: Hyponatremia in Pancreatic cancer patients had a prevalence of 18.1% and resulted in increased in-hospital mortality. Whether time-efficient treatment of hyponatremia would help reduce mortality and improve outcomes remains to be determined in future studies. [Table: see text]
Pancreatic cancer associated ascites: Risk factors, outcomes, and management.
Authors: Wang Justin Dejia , Hendifar Andrew Eugene
Published: June 2023

e16305

Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with significant morbidity and mortality as most patients present with advanced disease. The development of ascites has been associated with poor outcomes and further characterization and contemporary management strategies are needed. Therefore, we performed a comprehensive analysis of PDAC patients with ascites, including clinical and biological data, to describe its incidence, associated clinical factors, and outcomes. Methods: Patients were prospectively consented and enrolled the Gastrointestinal Biobank (“GI-Bank”) at Cedars-Sinai Medical Center, which collected patient specimens, associated clinical data, and self-reported questionnaires. Data was consolidated using a standard software tool (Redcap). Statistical analysis was conducted using Excel and using Datatab.net software tools. Results: Of the 437 patients with PDAC, 182 (41.6%) developed ascites. Overall survival (OS) between ascites and non-ascites groups were significantly different by log-rank test (p = 0.001), and estimated median OS was 473 days (95% CI [407, 537]) in ascites patients versus 554 days [467, 678] in non-ascites patients. In Cox proportional hazards model analysis, ascites status, but not sex or race, was associated with decreased survival (HR 1.49, [1.18, 1.87]). Ascitic fluid data was obtained in 77 patients; 62 (80.5%) had SAAG > 1.1; 14(22.6%) of SAAG > 1.1 patients also had positive cytology. The estimated median OS from the diagnosis of ascites was 100 days [76, 128] and median time to puncture was 4 days. Estimated median time from first tap to death was 56 days [42, 95]. 90 (49.5%) were treated with diuretics and 41 (22.5%) were treated with PleurX catheter. Patients with ascites had a worse survival and were more likely to receive greater than one chemotherapy regimen. There was no relationship between ascites and receipt of surgery or radiation. Conclusions: The development of ascites in patients with pancreatic cancer is common and contributes to significant morbidity and mortality. The use of diuretics is lower than would be expected for patients with elevated SAAG. Prospective evaluation of management strategies is needed to improve this important clinical conundrum.
Characteristics of survivors with peritoneal mesothelioma.
Authors: Muminovic Meri , Samuels Shenae , Erskine Aja , Ferraro Pablo H. , Gannon Christopher J. , Llaguna Omar H.
Published: June 2023

e16325

Background: Peritoneal mesothelioma (PM) is a rare, fatal malignancy. The aim of the study is to determine the clinical and sociodemographic characteristics associated with long-term survival (LTS). Methods: The 2004 - 2019 National Cancer Database was queried for patients with PM. LTS was defined as having survived at least 5 years following diagnosis. Univariate and multivariate logistic analyses were performed to identify characteristics associated with LTS. A nomogram predicting the likelihood of LTS was developed. Results: 3,636 patients were identified, of which, 18% experienced LTS. The median overall survival (OS) for the entire study population was 17.7 months. The median OS for the LTS cohort was 92 months and 11.7 months for non-long-term survivors (NLTS). In univariate analysis, LTS was more likely to occur in younger (< 50 years), healthy (Charlson-Deyo = 0), female and privately insured patients that traveled farther for care, were treated at an academic or very high-volume center, had epithelial histology, underwent radical surgery and received chemotherapy (p < 0.001). Interestingly, among those who were treated non-operatively, LTS was associated with a longer time-to-chemotherapy (LTS = 50 days, NLTS = 32 days, p < 0.001). Although not statistically significant, among those who received surgery, results suggest that LTS was more likely achieved in those who received hyperthermic intraperitoneal chemotherapy (HIPEC) (p = 0.086). Patients who underwent surgery plus HIPEC experienced the longest median OS (65.9 months) when compared those who underwent surgery plus systemic therapy (38 months) or surgery alone (9.6 months) (p < 0.001). Multivariate logistic regression analysis suggests that age, female gender, and surgical margins are independent predictors of LTS. Based on our nomogram, patients with favorable characteristics resulted in a total score of at least 19 and had an approximate 50% chance of LTS. Conclusions: Age, gender and surgical margins were found to be independent predictors of LTS. Additionally, our nomogram may help predict LTS among patients with PM.
Technical performance of cancer detection and TOO identification of PanSeer7, a targeted bisulfite sequencing assay for non-invasive multi-cancer detection.
Authors: Sun Jin , Su Ming-Yang , Xu Min-Jie , He Qi-Ye , Ma Jian-Hua , Su Zhi-Xi , Yang Xin-Rong , Liu Rui
Published: June 2023

e16338

Background: Many cancers are symptoms free in early clinical stages, resulting in nearly half of cancer patients diagnosed in advanced-stages when therapeutic options are limited. Early cancer detection is key to improve clinical outcomes. We developed PanSeer7, a multi-cancer detection assay based on targeted bisulfite sequencing of circulating cell-free DNA (cfDNA) and evaluated its technical performances of reproducibility and sensitivity. Methods: The panel of PanSeer7 consists of 2447 markers which were either differentially methylated between healthy and cancer samples, or distinctively methylated in a specific cancer. We assessed PanSeer7’s reproducibility by using it to sequence technical replicates of cfDNA samples. For its limit of detection (LOD), we prepared samples mimicking cancer plasma DNA by diluting fragmented cancer cell line DNA, which represent 7 common cancer types, into GM12878 control at ratios of 1/10,000 to 1/100. We further tested PanSeer7’s ability to identify tissue of origin (TOO) by analyzing DNA samples from formalin-fixed paraffin-embedded (FFPE) tissues and healthy plasma. Results: We analyzed PanSeer7’s reproducibility by sequencing 40 replicates of synthetic healthy cfDNA samples on four independent batches and with different inputs (from 2ng to 20ng). Results show that at a minimum of 10ng input, PanSeer7 produced highly consistent methylation levels among replicates. As to cancer signal detection, we found that PanSeer7’s technical LOD was 1/10,000 for lung cancer cell line H1650, liver cancer line HepG2, gastric cancer line HGC27, esophageal cancer line KYSE150 and colorectal cancer line SW480; it was slightly lower as 5/10,000 for pancreatic cancer line PANC1 and breast cancer line MDA-MB-231. To evaluate PanSeer7’s accuracy of TOO identification, we sequenced 38 healthy plasma and 121 FFPE tissues (17 of liver cancer, 13 of pancreatic cancer, 21 of gastric cancer, 18 of esophageal cancer, 16 of colorectal cancer, 14 of lung cancer, and 22 of breast cancer). Clustering analysis showed that they were segregated according to their TOO based on methylation levels. We also generated 3500 sets of simulated data by mixing the reads of cancer tissue into those of healthy plasma at ratios of 1/10,000 to 1/100, and trained TOO-predicting models with train data sets. At a ratio of 5/10,000, the model predicted TOO of test data sets with an accuracy of over 95%. Conclusions: PanSeer7 required as low as 10ng input DNA for high reproducibility. Its technical LOD in detecting cancer signal was no lower than 5/10,000 for all 7 cancer cell lines tested, and has an in silico TOO detection LOD of 5/10,000. Thus, PanSeer7 had excellent performances in both cancer signal detection and TOO identification, showing promise to be clinically applied for non-invasive multi-cancer detection after future optimization and validation.
Risk factors, clinical characteristics, and treatment outcomes for hepatocellular carcinoma in Rwanda.
Authors: Uwimana Ange , Kubwayo Prince Alain , Dukundane Damas , Nkeshimana Menelas , Naveed Ammara , Gupta Neil , Seruyange Eric , Bosland Maarten C , Rubagumya Fidel
Published: June 2023

e16339

Background: Hepatocellular carcinoma (HCC) is increasing worldwide with limited treatment options, a poor prognosis, and survival rates of less than 5 years. In Sub-Saharan Africa, over 46,000 new cases are reported every year, and HCC is commonly associated with alcohol consumption, viral hepatitis, especially Hepatitis B (HBV) and C (HCV), aflatoxin exposure, obesity, type II diabetes, and HIV infection. In Rwanda, often young people are diagnosed with HCC in the late stages of the disease, and treatment options are limited. Rwanda has made great achievements in the prevention and treatment of HBV and HCV. However, there is a lack of data on HCC in Rwanda and its associated risk factors. In this study, we report the prevalence of common risk factors, available treatment options, and treatment outcomes among patients with HCC in Rwanda. Methods: This was a retrospective study of patients aged 18 years of age and above diagnosed with HCC from 2016 to 2021 in three tertiary hospitals: University Teaching Hospital of Kigali, King Faisal Hospital, and Rwanda Military Hospitals. Data were abstracted from patients’ paper charts and electronic medical records and recorded in REDCap and analyzed in STATA. Results: Overall, 219 individuals were included in the study. 32.9% were female, the median age was 32 (26–54) years, and 48.4% came from the capital city of Kigali. Only 13.3% of patients had histo-pathological confirmation of HCC, while 86.7 % were diagnosed clinically with radiological images, alpha-fetoprotein, and other clinical findings. The most common risk factors were HCV and HBV infection with a prevalence of 27.4% and 20.1%, respectively. HIV infection and diabetes mellitus were present in 6.9% and 6.2% of patients, respectively. More than 80% of patients had had clinical or ultrasound evidence of cirrhosis, including ascites or hepatic encephalopathy and only 8.9% of patients received Sorafenib, and no patient had surgical resection, ablation, or liver transplant. Only 15.1% of patients received palliative care with opiate therapy. Among all patient diagnosed with HCC, 36% died within 3 months of diagnosis. Conclusions: In this retrospective study of the three largest treatment centers in Rwanda, the majority of HCC cases occurred at a young age with a high rate of mortality. HBV and HCV were the most frequent risk factors, and the majority of patients had clinical characteristics of decompensated liver failure. There is a clear lack of diagnostic tools, most glaringly pathologic diagnosis, and an extreme lack of treatment options. Increased awareness for HBV and HCV prevention and screening as well as further studies on etiology of HCC cases and management are needed.
The emerging use of immunotherapy as a treatment option in metastatic renal cell carcinoma: Real-world evidence from a single UK tertiary cancer centre.
Authors: Liu Justin KH , Irvine Andrew F. , Altarqane Mustafa , Arif Mariyam , Bansal Vikram , Boyle Anne , Campbell Fiona C , Elsayed Noha , Hafiz Mdehteshamul E. , Huda Ashraful , Soe Aye , Maraveyas Anthony , McGrane John , Muazzam Iqtedar A
Published: June 2023

e16509

Background: The landscape of systemic anticancer therapy (SACT) options for the treatment of metastatic renal cell carcinoma (mRCC) has recently evolved following results from the CheckMate 214 trial in 2018 which demonstrated improved overall survival in patients with International mRCC Database Consortium (IMDC) intermediate- and poor-risk mRCC clear cell histological subtype receiving combination immunotherapy (Ipilimumab/Nivolumab) in the first-line setting compared to Sunitinib. This is in addition to other treatment options including: vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) (e.g. Sunitinib, Pazopanib, Tivozanib, Cabozantinib, etc.), combination immunotherapy/TKI (e.g. Avelumab/Axitinib), VEGF/mammalian target of Rapamycin (mTOR) inhibitors (e.g. Lenvatinib/Everolimus) and single-agent immunotherapy (e.g. Nivolumab) in both first- and second-line settings. Methods: An audit of SACT prescribing practices in mRCC between 2019-2022 in a single UK tertiary cancer centre (Castle Hill Hospital, Hull, UK) was conducted as part of a national collaboration multi-centre UK audit looking into the real-world landscape and treatment choices in mRCC. Information was derived from the Somerset Cancer Registry and a dataset containing 87 patients with a coded diagnosis of ‘malignant neoplasm of kidney, except renal pelvis (CX64X)’ and ‘secondary malignant neoplasm of kidney & renal pelvis (C790)’ was generated. Results: Of the 81 patients included in the final analysis, 65% (n = 53) were male and 81% (n = 66) had a clear cell histological subtype. The main sites of metastases were lung (n = 58) and lymph nodes (n = 45). Most of the patients (n = 72) received either one or two lines of SACT. Of those with clear cell mRCC, 74% (n = 51/69) were classed as having IMDC intermediate- or poor-risk features with almost half (n = 34/69) receiving combination Ipilimumab/Nivolumab. Comparing overall survival (OS) and progression-free survival (PFS) to the published Kaplan-Meier curves in the CheckMate 214 trial, no significant differences in OS (p = 0.6) and PFS (p = 0.13) were observed, although there was an overall trend towards improved PFS in the first 6 months (82.4% vs 63.3%) in our local dataset. Conclusions: The results of our real-world evaluation of prescribing practices in mRCC favoured the use of combination immunotherapy in the first-line setting for the treatment of IMDC intermediate- and poor-risk clear cell mRCC with similar outcomes to the published data in the CheckMate 214 trial. The overall trend towards improved PFS in the first 6 months in our local dataset highlights the importance of patient selection when using immunotherapy.
Salvage lenvatinib/everolimus (LE) combination therapy after immune checkpoint inhibitor (ICI) and VEGFR tyrosine kinase inhibitor (TKI) for metastatic renal cell carcinoma (mRCC).
Authors: Khorasanchi Adam , Kwok Christopher , Psutka Sarah P. , Hinkley Megan , Dason Shawn , Yang Yuanquan (Aaron) , Verschraegen Claire F. , Gross Evan , Orcutt Delaney , Yin Ming
Published: June 2023

e16520

Background: The optimal treatment for mRCC patients (pts) who have progressed after both ICI and TKI remains uncertain. LE is frequently used as a salvage treatment due to different antitumor mechanisms, but efficacy and toxicity data in this setting are limited. Methods: We retrospectively reviewed charts from two academic centers for 71 adult mRCC pts who received LE after prior ICI and TKI exposure. Collected data included patient demographics, histology, International mRCC Database Consortium (IMDC) risk group, treatment history, and toxicity details using CTCAEv5. Outcomes were objective response rate (ORR) per RECIST 1.1, median time to treatment failure (mTTF), and toxicity. Descriptive statistics, Cox proportional hazards model and Kaplan-Meier method were utilized. Results: The median age was 64 (range: 31–84). Most pts had clear cell histology (84.5%) and had undergone nephrectomy (75%). IMDC risks were favorable (19.7%), intermediate (int) (66.2%), poor (11.3%), and unknown (2.8%). Pts received a median of 3 (range 1-10) prior therapy lines (L) and 42 pts had sequential ICI and TKI, while 29 received ICI/TKI combination therapy. Average ORR was 26.8%, but numerically better when given earlier (2L/3L vs. ≥4L: 28.6% vs. 22%). The mTTF was 5.5 months (m) (95% confidence interval [CI], 3.5–7.6 m), which was not significantly changed by sequential or combinational ICI/TKI treatment exposure. In multivariable Cox analyses, int/poor IMDC risk was associated with a significantly worse TTF compared to favorable risk (HR, 2.2, 95% CI, 1.1-4.1; mTTF: 4.5 vs 12.9 m), and so was ≥4L treatment compared to 2L/3L treatment (HR, 3.2, 95% CI, 1.3-7.6; mTTF: 4.5 vs. 6.6 m). In 57 pts with int/poor IMDC risk, ≥4L treatment was associated with a significantly worse TTF (HR, 2.3, 95% CI, 1.2-4.5; mTTF: 3.6 vs. 6.6 m), while prior nephrectomy was associated with a significantly better TTF (HR, 0.46, 95% CI, 0.22-0.97; mTTF: 5.4 vs. 3.1 m) compared to those without nephrectomy. Of the 71 pts, 64% had ≥ grade 3 adverse events, 60% had treatment interruption, 44.3% had dose reduction, and 21% stopped treatment due to intolerance. Conclusions: LE therapy is feasible but has modest efficacy following ICI/TKI treatment. Pts with favorable risk, prior nephrectomy or early salvage may have a better treatment response. These observations need to be confirmed in prospective studies.
Association between time to treatment initiation and survival in metastatic renal cell cancer: A population-based study of 5,193 cases from the California Cancer Registry (2010-2019).
Authors: Benjamin David Joseph , Shrestha Anshu , Fellman Dimitra , Rezazadeh Arash
Published: June 2023

e16530

Background: The treatment of metastatic renal cell cancer (RCC) has changed since the approval of the first tyrosine kinase inhibitor (TKI) in 2005. Since then, combination therapy with immunotherapy and TKI is considered standard-of-care. Despite multiple drug approvals, it remains unclear whether patients should be initiated on treatment immediately (within 30 days) as opposed to delay treatment (after 30 days), and if time to initiating treatment correlates with survival. Methods: Adults aged 20 years and older with newly diagnosed metastatic RCC between 2010 and 2019 were identified through the California Cancer Registry (n = 5,193). Time to treatment was calculated as duration between date of diagnosis and date of treatment initiation, then categorized into: No treatment, treatment within 30 days, between 31-60 days, and > 60 days. Association between treatment timing and overall and cancer-specific survival were assessed using Cox proportional hazard model and Fine and Gray sub-distribution hazard model accounting for competing risk. Both models included patient and baseline clinical characteristics. Results: 47.6% (n = 2,470) of patients received treatment with 30 days of diagnosis, while 24.3% received treatment between days 31-60 from diagnosis and 14.1% started treatment at 61 days or after from the time of diagnosis. After adjusting for all covariates, patients who received treatment at 61 days or later were less likely to experience mortality from cancer (HR 0.76, 95% 0.69-0.84, p < 0.0001) compared to those who started treatment within 30 days. Patients who started treatment between days 31-60 from diagnosis were also less likely to experience mortality from cancer (HR 0.82, 95% CI 0.76-0.89, p < 0.001). There were no statistically significant associations between cancer-specific survival and variables such as sex, race/ethnicity, or neighborhood SES. Conclusions: Patients who started treatment within 30 days of diagnosis of metastatic kidney cancer experienced worse cancer-specific survival compared to those who started treatment between days 30-60 or after day 61 from time of diagnosis. The differences in survival may be a reflection of tumor biology and high- versus low-risk disease groups. Further research is warranted to identify which patients benefit from early versus delayed treatment initiation. [Table: see text]
A randomized, open-label, phase II study of high-dose interleukin 2 vs high-dose interleukin 2 plus entinostat in renal cell carcinoma.
Authors: Pili Roberto , Quinn David I. , Hauke Ralph J. , Kuzel Timothy , Han Yan , Adra Nabil , Logan Theodore F.
Published: June 2023

e16540

Background: Immunosuppressive factors such as regulatory T cells (Tregs) limit the efficacy of immunotherapies such as high dose interleukin 2 (HD-IL2). We previously reported that the histone deacetylase (HDAC) inhibitor entinostat has antitumor effects in combination with HD-IL2 by decreasing Tregs function in a preclinical model of kidney cancer. Based on these preliminary data, we hypothesized that HDAC inhibition may enhance or resensitize patients (pts) with clear cell renal cell carcinoma (ccRCC) to HD-IL2. Our group has previously conducted a Phase II, single arm, clinical trial of entinostat in combination with HD-IL2 in ccRCC, which showed an objective response rate (ORR) of 37% and a median progression-free survival (mPFS) of 13.6 months as compared to historical data with single agent HD-IL2 of 20-25% and 4.2 months, respectively. Thus, we designed a multi-center, randomized, open label Phase II study with entinostat in combination with HD-IL2 in ccRCC patients. Methods: The primary objective was to estimate and compare PFS in pts randomized to receive either HD-IL2 plus entinostat (Arm 1) or HD-IL2 (Arm 2) and stratified by no prior therapies vs prior therapies. Due to unforeseen circumstances, enrollment halted after the first 10 patients. The treatment schedule was HD-IL2 600,000 units/kg administered IV every 8 hrs on Days 1-5 and Days 15-19 (maximum 28 doses) +/- entinostat 5 mg orally given every 2 weeks starting on Day-14, continuously. The study was originally designed to detect a 100% improvement of median PFS to 8.4 months in ARM 1. A one-sided stratified log-rank test with an overall sample size of 46 subjects (23 per group) achieves 80% power at a 0.10 significance level to detect a hazard ratio of 0.5 (median PFS of 4.2 months vs 8.4 months). Results: 10 pts (6 pts in Arm 1 and 4 pts in Arm 2) were enrolled. Among the 10 pts, only one had prior therapy (Arm 1). The most common treatment-related toxicities ( > 50%, any grade) were diarrhea, hypotension, nausea, hypomagnesemia, hypophosphatemia, pruritus, hypocalcemia and thrombocytopenia, hypophosphatemia, proteinuria, diarrhea, fatigue, and neutropenia. The most common ≥ grade 3 toxicities were hypotension (80%), hypophosphatemia (70%), and thrombocytopenia (60%). Two pts (33%: CI 4.3%-77.7%) achieved a partial response in Arm 1 and no pts in Arm 2. The median PFS was 12.4 months (CI 2.3-NE) in Arm 1 (13.3 months in pts with no prior therapies) and 2.8 months (CI 1.2-3.3) in Arm 2 (Logrank p-value 0.0167). We have collected blood samples to conduct several correlative studies including flow cytometry and gene expression analysis on peripheral blood mononuclear cells. Conclusions: The preliminary results from this study confirm that the combination of entinostat and HD-IL2 may be more active than HD-IL2 alone in pts with ccRCC. Clinical trial information: NCT03501381 .
Blood-based molecular profiling of Chinese patients with advanced renal cell carcinoma.
Authors: Fan Xiaodong , Li Mingwei , Ma Xiaoxue , Qin Jiayue , Cao Shanbo
Published: June 2023

e16550

Background: The therapeutic landscape of renal cell carcinoma (RCC) has rapidly expanded, and there is an urgent need to develop noninvasive biomarkers that can select an optimal therapy in real time. Next-generation sequencing (NGS)-based profiling of circulating tumor DNA (ctDNA) shows promise for noninvasive detection. To evaluate the clinical utility of ctDNA analysis in RCC, we aimed to analyze the molecular characteristics of RCC using ctDNA by NGS. Methods: A total of 189 plasma samples and 26 matched tumor tissues from Chinese patients with advanced renal cell carcinoma (n = 189) were analyzed by Acornmed panel with 808 cancer-related genes, and matched white blood cell as germline comparators. Results: Overall, 29 germline mutations were detected in 14.3% (27/189) patients, such as TSC2 (5/189, 2.65%), FH (3/189, 1.6%) and VHL (2/189, 1.1%), of which 10 germline aberrations in DNA damage repair (DDR) genes were detected in 5.3% patients (10/18). In addition, a total of 1590 somatic variations were identified in 96.8% (183/189) ctDNA, including 1278 nonsynonymous single nucleotide variants, 126 small insertions or deletions, 75 copy number variations. And the median blood tumor mutation burden (bTMB) was 4.36 mut/Mb. Mutations in VHL (36/189, 19.4%) were the most prominent variation, followed by those in TP53 (19/189, 10.0%), BAP1 (12/189, 6.3%), PBRM1 (10/189, 5.3%) and SETD2 (7/189, 3.7%). Moreover, totals of 154 clinically actionable mutations from 92 patients (48.7%) were identified. In 26 patients with both tumor tissues and plasma samples, sequencing detected alterations in 100% (26/26) tumor tissue DNA (tDNA) and 96.2% (25/26) ctDNA, respectively. Furthermore, 29.6% of mutations of tissues were founded in ctDNA, and 21.6% of mutations of ctDNA were detected in tissues. Among them, 73.1% (19/26) patients had at least one overlapping variant called by tDNA and ctDNA. The most common shared mutation was VHL (5/26, 19.2%). Meanwhile, four shared copy number variants were detected in two patients (15.4%). Conclusions: Our study contributes to understand the molecular characteristics of RCC using ctDNA, which is a viable option for tissue when tissue is difficult to obtain. Furthermore, ctDNA testing by NGS is helpful for drug selection and provides more effective treatment options for RCC, particularly for hereditary RCC.
The evolution of treatment patterns in patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC) and clinical outcomes: Results of a longitudinal observational cohort study in England.
Authors: Mahmoudpour Seyed Hamidreza , Knott Craig , Kearney Mairead , Boutmy Emmanuelle , Verpillat Patrice
Published: June 2023

e16559

Background: Treatment (tx) guidelines for pts with la/mUC in England have evolved over the last decade following the approval of successive immune checkpoint inhibitors (ICIs). However, the impact of this evolution on routine clinical practice (RCP) remains unclear. We aimed to describe shifts in tx patterns and associated clinical outcomes in RCP in England. Methods: This retrospective cohort study included pts aged ≥18 years, with primary stage III/IV UC diagnosis (dx) between Jan 1, 2013 and Dec 31, 2020, in the National Cancer Registration Dataset with follow-up to May 31, 2022. Pts’ dx were stratified at Dec 31, 2017, to split the cohort into pre- and post-ICI eras. Lines of systemic therapy were derived via an algorithm using data from the Systemic Anti-Cancer Therapy dataset. Summary statistics and overall survival (OS) were calculated and compared using χ2 and log-rank tests, respectively. The Kaplan-Meier method was used to estimate median OS from dx and from systemic tx initiation. Results: In the pre- and post-ICI groups, the majority of pts were male (65.7% and 65.5%) and mean modified Charlson-Deyo Comorbidity Index was 3.4 and 3.5, respectively. Mean age was 73.2 years in both groups, while a higher percentage of pts in pre-ICI era had stage IV disease at dx (68.3% and 50.0%; p<0.001). The rate of first line (1L) tx increased from 30.4% to 35.3% (p<0.001) and second line (2L) from 31.2% to 37.3% (p<0.001). The proportion of pts who received ICI in any line increased from 13.7% to 31.6% (p<0.001). Median OS from 1L tx improved from 13.8 to 15.5 mo. Conclusions: While pt demographics did not change considerably between the two groups, 1L and 2L tx rates moderately increased over time, although remained below 40%. In both groups, >85% of treated pts received 1L platinum chemotherapy, consistent with guidelines. In the post-ICI era, approximately one-third of treated pts received ICI therapy in any line. Improved OS from 1L tx could be partially attributable to the increased availability and uptake of ICIs. [Table: see text]
Homologous recombination-related (HRR) gene mutation profiling and the association with TMB in Chinese patients with urological cancer.
Authors: Yu Bin , Yi Huan , Yu Yangyang , Xiao Mingzhe , Qi Chuang
Published: June 2023

e16561

Background: Homologous recombination deficiency (HRD) is associated with tumorigenesis and could predict the response of PARP inhibitor (PARPi) therapy and immunotherapy. Loss of function or deleterious mutations in homologous recombination-related (HRR) genes contribute to HRD phenotype. Methods: Tumor tissue samples from 484 Chinese patients with urological cancer were sequenced with 551 cancer-related genes. 957 patients with WES data from the TCGA datasets were included for analysis. Results: In the Chinese cohort, 35.88% (47/131) bladder cancer (BCa) patients, 15.47% (28/181) renal cell carcinoma (RCC) and 37.21% (64/172) prostate cancer (PCa) patients exhibited somatic HRR (sHRR) gene mutations. The most frequently mutated genes were BRCA2 (12% in BCa, 5% in RCC) and CDK12 (17% in PCa), respectively. The germline HRR (gHRR) gene mutations were identified in 62.6% (82/131) BCa, 55.33% (96/180) RCC and 60.62% (97/160) PCa patients. The most frequently mutated gene was BRCA2 (24% in BC, 18% in RCC, 26% in PCa). 7.6% (10/131) BCa patients, 1.7% (3/181) RCC patients and 2.9% (5/173) Pca patients carried both germline and somatic HRR gene mutations. In the TCGA cohort, 38.69% (159/411) BCa patients, 11.62% (43/370) RCC and 6.25% (11/176) PCa patients exhibited somatic HRR (sHRR) gene mutations. The most frequently mutated gene was ATM (14% in BCa, 4% in RCC, 5% in PCa). Interestingly, for the patients with PCa, the somatic mutant frequency of HRR genes in Chinese cohort was higher than that in TCGA cohort (37.21% vs 6.25%, p < 0.001). The sHRR-Mut patients had a higher median TMB compared to the sHRR-WT patients (Chinese cohort: BCa 13.97 vs 4.96, p < 0.001; RCC, 4.96 vs 2.84, p < 0.001; PCa, 5.64 vs 2.84, p < 0.001, TCGA cohort: BCa, 7.21 vs 3.63, p < 0.001; RCC, 1.68 vs 1.42, p = 0.003; PCa, 1.03 vs 0.71, p < 0.001). However, the median TMB was similar between the gHRR-Mut and the gHRR-WT patients (Chinese cohort, BCa 6.38 vs 7.09 p = 0.646; RCC, 3.55 vs 2.84, p = 0.229; PCa, 3.55 vs 2.84, p = 0.111). Conclusions: Our data reported the genetic landscape of HRR gene in Chinese urological cancer patients and suggested that patients with altered HRR genes may be rational candidates for precision oncology treatment and provide new opportunities to predict the tumor response to multiple treatments.
Comparison of the genomic profiles of primary and recurrent lesions in patients with advanced bladder carcinomas.
Authors: Chen Lijuan , Lin Guomin , Pang Fei
Published: June 2023

e16575

Background: Bladder carcinomas (BCs) is featured by high incidence of recurrence which remains to be a big clinical challenge. This study aimed to compare the genomic profiles of primary and recurrent BCs in advanced stage. Methods: Primary and recurrent tissues (and control blood) were collected and somatic variants including short variants, copy number variations, gene rearrangements and TMB (Tumor Mutation Burden) were analyzed following the CAP/CLIA-certificated workflows. Chi-Square Test/Fisher Test was applied to compare the difference between two variables. Results: To eliminate the impact of stage, only patients in advanced stages were included (stage III-IV) in this study. 53 patients were investigated, including 43 primary and 10 recurrent (evidence of tumor observed after radical treatment). It should be noted that matched primary and recurrent samples were not obtained from the same patient. Median age of the patients was 64 years old. The proportion of male patients was 86% (n = 37) in the primary cohort and 60% (n = 6) in the recurrent cohort. Among the primary cases, the most frequent alterations were detected in TP53 (58.1%), TERT (51.2%), KMT2D (27.9%), KDM6A (23.3%) and RB1 (23.3%). Among the recurrent cases, the most frequent alternations were showed in TERT (70%), KMT2D (50%), PIK3CA (50%), TP53 (50%) and KDM6A (40%). PIK3CA substitution and KRAS substitution showed significant difference when comparing between the two cohorts. PIK3CA substitution preferentially occurred in recurrent samples (50% recurrent vs 14% primary, p-value = 0.01), mostly occurred in E545K; while KRAS substitution showed 4.7% in primary and 30% in recurrent with p-value = 0.04, all presented as G12V. TMB showed no significant difference between the two cohorts (6.2 vs 6.3 muts/Mb, p-value = 0.72). Conclusions: By NGS, we observed that substitutions in PIK3CA and KRAS showed significant difference between primary and recurrent samples from advanced BCs patients. PIK3CA and KRAS mutations were reported to be associated with local recurrence in CRC, but no association was observed in early stage non-muscle-invasive BCs. Our findings may provide a different insight into the treatment selections for advanced BCs, although the sample size is small.
Monoamine oxidase as a potential target for the development of new therapeutic strategies for bladder cancer.
Authors: Camargo Gabriela Cardoso de Arruda , Oliveira Gabriela , Alonso João Carlos Cardoso , Ribeiro de Souza Bianca , Silva Santos Bruna Nayara Nayara Silva , Ávila Monaliza , Roberto Isadora Manzato , Duran Nelson , Fávaro Wagner José
Published: June 2023

e16611

Background: Bladder cancer (BC) is the most common malignancy of the urinary tract and one of the most prevalent cancers worldwide. As the overall prognosis of BC has not changed over the past 30 years, there is a pressing medical need to develop new diagnostic and therapeutic approaches. At present, efforts to deeply understand the pathogenic mechanisms that support urothelial carcinogenesis could help in identifying new therapeutic targets. Monoamine oxidases (MAOs) A and B are oxidative isoenzymes that catalyze the conversion of biogenic amines into their corresponding aldehydes and ketones through oxidative deamination. Recently, MAOs expression have been associated with metastasis and decreased overall survival in various types of cancer. However, the role of MAOs in BC is still poorly explored. This study characterized and compared the molecular profiles of MAO-A and MAO-B isoenzymes in the different histological stages of non-muscle (NMIBC) and muscle (MIBC) invasive bladder cancer, aiming the adaptation of these biomarkers as a criterion of clinical response, risk stratification and outcome prognosis. Methods: Sixty formalin-fixed paraffin-embedded samples of bladder were obtained from 34 to 96-year-old patients (mean 65 years) with BC diagnosis in University of Campinas and Paulinia Municipal Hospital/ Brazil. Subsequently, the samples were divided into 6 groups: pTis group, low-grade pTa group, high-grade pTa group, pT1 group and pT2 group; and submitted to immunohistochemistry analysis for MAO-A and MAO-B. The retrospective anonymous study was approved by the local ethics committee (Clinical Trial: RBR-6swqd2). Results: All stages and grades of NMIBC and pT2 (MIBC) showed positive immunoreactivity for both MAO-A and MAO-B. MAO-A immunoreactivities were significantly higher (p < 0.01) in the high-grade pTa, pTis and pT2 groups in relation to low-grade pTa and pT1. Likewise, MAO-B immunoreactivities were remarkably higher (p < 0.01) in the high-grade pTa and pT2 groups. No statistical differences were found between pTis and low-grade pTa for MAO-B. Interestingly, pT1 group showed the lowest (p < 0.01) MAO-A and MAO-B immunoreactivities in relation to other stages and grades of BC, probably due to disruption of the extracellular matrix, with consequent reduction in O2 delivery (hypoxia). Conclusions: These findings collectively characterize the contribution of MAOs in BC pathogenesis and suggest that MAOs have potential as a therapeutic target in BC.
Circulating chromatin conformation signatures to enhance PSA positive predictive value and overall accuracy for prostate cancer detection.
Authors: Akoulitchev Alexandre , Hunter Ewan , Salter Matthew , Powell Ryan , Naithani Tarun , Green Jayne , Fiorentino Francesca , Ahmed Hashim Uddin , Pchejetski Dmitri , Winkler Mathias
Published: June 2023

e17016

Background: Prostate cancer (PCa) has a high lifetime prevalence (one out of six men), but currently there is no widely accepted screening programme. Widely used prostate specific antigen (PSA) test at cut-off of 3.0 ng/mL does not have sufficient accuracy for detection of any prostate cancer, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance in some men with PCa. We have recently identified circulating chromosome conformation signatures (CCSs, Episwitch PCa test) allowing PCa detection and risk stratification in line with standards of clinical PCa staging. The purpose of this study was to determine whether combining the Episwitch PCa test with the PSA test will increase its diagnostic accuracy. Methods: n = 109 whole blood samples of men enrolled in the PROSTAGRAM screening pilot study and n = 38 samples of patients with established PCa diagnosis and cancer-negative controls from Imperial College NHS Trust were used. Samples were tested for PSA, and the presence of CCSs in the loci encoding for of DAPK1, HSD3B2, SRD5A3, MMP1, and miRNA98 associated with high-risk PCa identified in our previous work. Results: PSA > 3 ng/mL alone showed a low positive predicted value (PPV) of 0.14 and a high negative predicted value (NPV) of 0.93. EpiSwitch alone showed a PPV of 0.91 and a NPV of 0.32. Combining PSA and Episwitch tests has significantly increased the PPV to 0.81 although reducing the NPV to 0.78. Furthermore, integrating PSA, as a continuous variable (rather than a dichotomised 3 ng/mL cut-off), with EpiSwitch in a new multivariant stratification model, Prostate Screening EpiSwitch (PSE) test, has yielded a remarkable combined PPV of 0.93 and NPV of 0.95 when tested on the independent prospective cohort. Conclusions: Our results demonstrate that combining the standard PSA readout with circulating chromosome conformations (PSE test) allows for significantly enhanced PSA PPV and overall accuracy for PCa detection. The PSE test is accurate, rapid, minimally invasive, and inexpensive, suggesting significant screening diagnostic potential to minimise unnecessary referrals for expensive and invasive MRI and/or biopsy testing, with further extended prospective blinded validation of the new combined signature in a screening cohort with low cancer prevalence as the next step for PSE adoption in PCa screening.
Do we need to redefine the phoenix criteria after the arrival of the new generation imaging techniques?
Authors: Muelas Rodrigo , Puerto Francés Clara , Morillo Virginia , Sanchez Angel L. , Piquer Teresa , Fernández Camacho Encarnación , Aznar-Tortonda Vanessa , Plaza Patricia , Mingarro de leon Maria , Ferrer-Albiach Carlos
Published: June 2023

e17018

Background: The biochemical recurrence (BCR) criteria are different depending on the primary tumour treatment: PSA ≥0.2 ng/mL after radical prostatectomy (RP) and PSA ≥ 2 ng/mL above the nadir after radiotherapy (RT)[Phoenix criteria]. The latter was established based on the detection of metastasis by conventional imaging tests (CT and bone scanning). Next generation imaging (NGI) techniques (18F-choline PET/CT and specially 18F-PSMA PET/CT), allow detection of metastasis with PSA values much lower than the Phoenix criteria. The purpose of this study is to compare the profile of patients diagnosed with metastatic hormone sensitive prostate cancer (mHSPC) by NGI techniques after BCR according to the primary tumour treatment performed. Methods: Patients diagnosed with mHSPC in our Radiation Oncology Department after BCR between February 2021 and December 2022 were reviewed. All of them underwent NGI: 18F-choline PET/CT if there was BCR following RT or a PSA level > 2 ng/ml after PTR; 18F-PSMA PET/CT if there was BCR after PTR or if 18F-choline PET/CT offered diagnostic uncertainties. Then, were stratified according to primary treatment: PTR (+/- salvage RT to the prostatic bed) vs RT (external or brachytherapy). PSA levels prior to NGI, number of metastases (≤5: oligometastatic vs > 5: polymetastatic) and their location (M1a: exclusive lymph node metastasis, M1b: presence of bone metastasis and M1c: presence of visceral metastasis) were compared. Results: A total of 38 patients were idiagnosed with mHSPC: 42.1% after PTR and 57.9% after RT. PTR group had PSA levels prior to NGI of 1.08 ng/ml, of which 75% were 18F-PSMA PET/CT. Twenty-five per cent of patients in this group were classified as polymetastatic. In RT group the median PSA levels prior to NGI was 3.5 ng/ml, of which 68.2% were 18F-choline PET/CT. The proportion of polymetastatic patients was 50%. The location of metastases in PTR and RT group was: M1a (68.8% vs 59.1%), M1b (31.3% vs 36.4%) and M1c (0% vs 4.5%). Conclusions: The percentage of polymetastatic patients in RT group is double that of PTR group, which is a worse prognostic factor. (4). This difference in the number of metastases is due to the higher PSA levels prior to NGI in RT group, which is directly related to the definition established by the Phoenix criteria(3). Given that NGI techniques can detect metastases with PSA values below the Phoenix criteria, it would be reasonable to redefine it in order to reduce the percentage of polymetastatic patients through earlier detection and thus improve their prognosis.