bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of underlying cirrhosis etiologies in hepatocellular carcinoma patients of Hispanic versus non-Hispanic ethnicity.
Authors: Chang Jeremy , Ajmera Veeral , Fowler Kathryn J , Ting Stephanie , Tamayo Pablo , Burgoyne Adam
Published: June 2022

e16163

Background: While the incidence and rates of mortality are in decline for the vast majority of cancers, those of hepatocellular carcinoma (HCC) continue to increase. Forecasts from the Surveillance, Epidemiology, and End Results (SEER) database suggest that the Hispanic population will have the highest incidence rate of HCC in the United States by the end of this decade. As a result, further studies are needed to identify specific risk factors for the development of HCC in this ethnic group. Methods: This was a retrospective, single center study conducted in Southern California to identify the prevalence of underlying cirrhosis etiologies in HCC patients of Hispanic versus non-Hispanic ethnicity. Causes of cirrhosis included nonalcoholic fatty liver disease (NAFLD), viral hepatitis, alcohol, and other chronic liver disease. The designation of NAFLD cirrhosis was assigned to patients in whom there was an exclusion of viral hepatitis B, viral hepatitis C, significant alcohol consumption, other etiology of chronic liver disease, and who had the presence of fatty liver on imaging or were diagnosed with cirrhosis with a concomitant metabolic risk factor (diabetes mellitus, hypertension, hyperlipidemia, or obesity). Results: A total of 165 patients were included in this study. There were 57 patients of Hispanic ethnicity and 108 patients of non-Hispanic ethnicity. No significant differences in age or gender were found between the two groups. When analyzing the prevalence of cirrhosis etiologies, 17 patients (29.8%) of Hispanic background were found to have underlying NAFLD cirrhosis compared to 10 patients (9.3%) of non-Hispanic background (p = 0.001). In contrast, 67 patients (62%) in the non-Hispanic group had diagnoses of cirrhosis associated with viral hepatitis B or C compared to 22 patients (38.6%) in the Hispanic group (p = 0.005). There was no significant difference in the prevalence of alcoholic cirrhosis (24.6% vs 13%, p = 0.08), cirrhosis due to other chronic liver disease (1.8% vs 2.8%, p = 1), or HCC without cirrhosis (5.3% vs 13%, p = 0.178) between Hispanic and non-Hispanic patients, respectively (Table). Conclusions: There were significantly higher rates of NAFLD cirrhosis identified in HCC patients of Hispanic ethnicity compared to those of non-Hispanic ethnicity. With the continually rising incidence rate of HCC in this patient group, it is important for providers to be aware of this association so that appropriate surveillance and prevention strategies may be pursued.[Table: see text]
Outcomes of hepatocellular carcinoma in obese patients: Insights from a nationwide database.
Authors: Farooq Umer , Franco Diana , Tarar Zahid , Anwer Faiz
Published: June 2022

e16178

Background: Obesity is associated with hepatocellular carcinoma (HCC), affecting mortality and post-surgical outcomes. Growing epidemiological obesity trends parallel the constant rise of HCC incidence. Therefore, we sought to examine outcomes of HCC in obese patients. Methods: We investigated the National Inpatient Sample and National Readmission Database 2018-2019 using International Classification of Diseases-10 codes for adult patients with HCC. Analyses were performed using STATA (v 14.2), considering 2 sided P< 0.05 as statistically significant. Proportions were compared using Fisher exact test and continuous variables using Student’s t-test. Confounding variables were adjusted using multivariate logistic and linear regression analyses. Results: Obese patients with HCC had lower odds of inpatient mortality and higher odds of hospice discharge ( P< 0.05). Obesity was associated with a higher length of stay (LOS) by 0.90 days and hospital cost by 5,453 USD ( P< 0.01). We found higher odds of acute renal failure (Adjusted odds ratio (aOR) 1.37, P< 0.01) and a higher prevalence of HCV, smoking, and alcohol use in obese patients. There were no differences in lobectomy, partial hepatectomy, or transarterial radioembolization; however, higher odds of liver transplant were observed (aOR 1.82, P< 0.01). A higher proportion of obese HCC patients had lymph nodes metastasis (6.43% vs. 6.08%, P:0.64). Rates of respiratory problems, ICU admission, cardiac arrest, HIV, DVT, myocardial infarction, and stroke were not different between the two groups ( P> 0.05). Conclusions: Obese patients with HCC appear to have an advanced stage at presentation leading to lower rates of lobectomy, partial hepatectomy, and TARE and higher rates of liver transplant and hospice utilization. Future studies need to address the barriers leading to delays in diagnosis.[Table: see text]
Comprehensive genomic analysis of early and late-onset hepatocellular carcinoma.
Authors: Shao Yang , Chen Xin , Pang Jiaohui , Zhang Yaru , Ou Qiuxiang , Yin Jiani , Wu Xue
Published: June 2022

e16186

Background: Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancer and is a leading cause of cancer-related death worldwide. HCC is highly therapy-resistant, and biomarker-driven therapies are emerging as important treatment options. Risk factors have been implied to distinguish early and late-onset patients. A high prevalence of non-cirrhotic HCC attributed to hepatitis B virus infection was found in young Asian patients. In late-onset patients, genetic aberrations accumulated with age in liver cirrhosis and other chronic liver diseases could provide the basis of tumorigenesis. Thus, diverse genomic alteration modes may underlie HCC of different onset ages, but the analysis is lacking. This study aims to explore genomic distinctions underlying early and late-onset HCC, thus facilitating personalized biomarker-driven treatments. Methods: The plasma and tumor samples from 222 Chinese HCCs underwent genomic profiling with hybridization capture-based targeted next-generation sequencing. The patients were categorized into early (male < 40 years or female < 50 years) or late (male ≥ 40 years or female ≥ 50 years) onset in accordance with the American Association for the Study of Liver Diseases guideline. We compared the clinical and molecular characteristics and explored differences between the early and late-onset cohorts. Results: The late-onset cohort accounts for 83.3% (185/222) of all HCC cases, and its male incidence rate is significantly higher than that of early-onset (88.6% vs 56.8%, p< 0.0001). More younger cases have a family history of HCC (21.6% vs 14.6%). The mean somatic alteration numbers per patient are comparable between early and late-onset (8.30 vs 9.92). While TP53, TERT, and MCL1 are the most frequently mutated genes in both cohorts, we identified eight genes with significantly higher mutation frequencies in early-onset. OncoKB Levels 1 to 4 actionable alterations are present in 48.7% and 44.3% of younger and older patients, respectively, whereas the early-onset cohort has a significant enrichment of actionable MDM2 alterations (10.8% vs 1.1%, p= 0.0078). The prevalence of DNA Damage Response and Repair (DDR) gene mutations (35.1% vs 48.6%) and tumor mutation burden (TMB, mean: 4.17 muts/Mb vs 8.11 muts/Mb) are elevated in older patients. Notably, individuals harboring DDR mutations are associated with higher TMB in late-onset (mean TMB in DDR-mutated: 10.44 vs DDR- wildtype: 5.90, p= 0.0016) but not early-onset (mean TMB in DDR-mutated: 3.47 vs DDR- wildtype: 4.54, p= 0.280). Conclusions: Tumors from early and late-onset HCC demonstrated differences in genes and other biomarkers relevant to cancer biology and response to therapy. Specifically, DDR-mutated patients in the late-onset cohort are associated with higher TMB and may benefit from combining targeted and immunotherapy. Future studies are warranted to examine the response to biomarker-driven treatment strategies.
Combination of transarterial chemoembolization (TACE) and tyrosine kinase inhibitors (TKIs) compared to TACE alone as bridging therapy transplant recipients with hepatocellular carcinoma: An update.
Authors: Esmail Abdullah , Victor David , Kodali Sudha , Graviss Edward A. , Nguyen Duc T. , Moore Linda W. , Saharia Ashish , McMillan Robert , Fong Joy N. , Uosef Ahmed , Elshawwaf Mahmoud , Heyne Kirk , Ghobrial Rafik Mark , Abdelrahim Maen
Published: June 2022

e16201

Background: Hepatocellular carcinoma (HCC) is the world's sixth most prevalent cancer and the third leading cause of cancer-related death. For patients with advanced HCC, trials combining TACE with tyrosine kinase inhibitors (TKIs) such as Sorafenib have given mixed outcomes. (TACE) plus lenvatinib led showed significant improvement in OS compared to lenvatinib alone in the first-line setting in patients with advanced HCC according to phase 3 LAUNCH trial which was presented at the 2022 ASCO Gastrointestinal Cancers Symposium. This study was aimed to compare the outcome of HCC patients who received TACE plus TKI agent versus TACE alone. Methods: Retrospectively all subjects with unresectable HCC were included in this study, who underwent liver transplantation (LT) and were treated by either TACE alone (TA) or TACE plus Sorafenib (TandS) between July 2008–December 2021. For categorical factors, HCC recurrence after LT was reported as frequencies and proportions, while for continuous variables, the median and interquartile range (IQR) or mean was used. For categorical variables, Chi-square or Fisher's exact tests were used, while for continuous variables, Kruskal-Wallis test was used. Results: Seven hundred patients were screened; only 128 patients in total underwent LT with most being males (77%); the median age of 61.5 years. The TA group included 79 (77%) subjects who matched Milan Criteria (MC) and 24 (23%) who did not, but the TandS group had a greater number of cases who did not meet MC: 16 (64%) versus 9 (36%); p = 0.01. There was a significant variation in five-year disease-free survival (DFS) across the therapy groups investigated, with 100% DFS in the TandS group vs 67.2 percent in the TAne group (p = 0.07). The TandS group had a five-year patient survival rate of 77.8% compared to 61.5 percent in the TA group (p = 0.51). However, beyond the MC, patients who were treated with TA had the average percentage of necrotic tumor on resected histology of 43.8 %, 32 % compared to 69.6 %, 32.8 % for cases treated with TandS, p = 0.03. Conclusions: We have found that using TandS is generally well tolerated and demonstrated improved OS compared to TA in patients with unresectable HCC. A prospective clinical study (NCT05171335) is ongoing at our institution to further investigate this concept.
Salvage 177Lu-dotatate therapy in patients with progressive metastatic neuroendocrine tumors.
Authors: Hoe Hui Jing , Wyld David
Published: June 2022

e16212

Background: 177Lu-dotatate (LuPRRT) is effective in selected patients with metastatic neuroendocrine tumours (NETs). Most of these patients will subsequently have progressive disease with limited treatment options available. We analyzed the outcomes and toxicities of salvage LuPRRT in this study. Methods: This is a retrospective cohort study. Patients who had salvage LuPRRT at Royal Brisbane and Women’s Hospital (RBWH) from November 2016 to January 2021 were identified and included in this study. We manually reviewed the hospital electronic medical records and radiology databases to review patient characteristics, outcomes, and toxicities from salvage LuPRRT. Results: Of the 37 patients included, 37.8% (14/37) had small bowel primary, 27.0% (10/37) had pancreatic primary and 10.8% (4/37) had pulmonary primary. 83.8% (31/37) received 4 cycles of initial LuPRRT (I-PRRT) with a median dose of 32.0 GBq. The median duration of response to I-PRRT was 31 months. These patients had salvage LuPRRT (R-PRRT) on progression with 83.8% (31/37) received 2 cycles with a median cumulative 177LuTate dose of 48.0 GBq. Partial response, stable disease and progressive disease were observed in 10.8% (4/37), 40.5% (15/37) and 27.0% (10/37) of patients respectively. Median duration of response with R-PRRT was 8 months. 2.7% (1/37) developed Grade 3 anaemia and 2.7% (1/37) developed Grade 3 thrombocytopenia with R-PRRT. 8.1% (3/37) developed nephrotoxicity Grade 1 nephrotoxicity. 21.6% (8/37) of patients had re-retreatment with further LuPRRT (RR-PRRT) on progression. The median retreatment cycles were 2 and the median cumulative 177LuTate dose received was 58.8 GBq. Partial response, stable disease and progressive disease were seen in 25% (2/8), 12.5% (1/8) and 62.5% (5/8) of patients respectively. Median duration of response with RR-PRRT was 4 months. There were no reported Grade 3 haematologic toxicities with RR-PRRT. 1 patient developed Grade 1 nephrotoxicity with RR-PRRT. At time of data analysis in April 2021, 27% (10/37) had ongoing response while 73% (27/37) had progressed. Conclusions: Salvage LuPRRT is an effective and safe treatment option for selected patients with progressive metastatic NETs.
Fecal metagenome analysis in long-term survivors (LTS) of pancreas cancer.
Authors: Kharofa Jordan , Hussein Walaa , Sohal Davendra , Olowokure Olugbenga Olanrele , Ahmad Syed A. , Patel Sameer H. , Wilson Gregory , Weiss Alison , Haslam David , Apewokin Senu
Published: June 2022

e16298

Background: Despite improvements in median survival in pancreas adenocarcinoma (PCa), the 5 year overall survival remains less than 10%. Clinical and tumor genomic characteristics have not differentiated PCa long term survivors (LTS) from unselected patients, however specimens in LTS show enhanced tumor immune response. In preclinical studies, fecal transplant experiments from LTS of PCa reveal delayed tumor growth through unknown mechanisms involving the fecal microbiota (Riquelme Cell 2019). However, features of the fecal microbiome in patients with LTS are unknown. Methods: In this cross-sectional study, comprehensive shotgun metagenomics were performed on stool from PCa patients with LTS (n = 16). LTS was defined as > 4 years from pancreatectomy and all therapy without evidence of recurrence. LTS were compared to control patients with PCa who completed pancreatectomy and chemotherapy (n = 6). Stool was sequenced using an Illumina NextSeq500. Raw reads were processed with Kneaddata for trimming, Kracken2 for taxonomic profiling, Bracken for abundance estimation, and Humann3 for metabolic pathway analyses. Statistical analyses were performed in R with MicrobiomeSeq and Phyloseq for comparison of LTS and controls. Results: At diagnosis, the median age of LTS was 60 with a median time from pancreatectomy of 6 years (4-14 years) at donation. The median age of control patients was 65 with a median disease-free survival of 17 months from pancreatectomy. All patients underwent pancreatectomy and chemotherapy prior to sample donation. No material differences were observed in overall microbial diversity for LTS and controls using Shannon/Simpson indexes. The overall composition of bacteria, eukaryotes, viruses and archaea were similar in LTS relative to controls. Lefse analyses revealed significant enrichment of species relative abundance in LTS for the Ruminococacceae family and the Faecalobacterium genus including the Faecalobacterium prausnitzii species. Enriched species in control patients included Clostridium perfringes. Metabolic pathway analyses of the fecal metagenome of LTS revealed several gene families enriched in Faecalobacterium prausnitzii responsible for starch degradation, ribonucleotide biosynthesis, and thiamin degradation as well gene products from Akermannsia mucinophilia representing unknown pathways. Conclusions: Stool from patients cured from PCa share unique microbial features relative to control populations including enrichment of species in the Faecalobacterium genus and Ruminococacceae family . Interestingly, similar species enrichments are observed in metastatic melanoma patients who respond to PD-1 inhibition (Gopalakrishnan Science 2017). Additional studies are needed to explore underlying immune mediated mechanisms in which the fecal microbiota may influence long term survival in PCa.
Influence of type 2 diabetes mellitus and concomitant anti-diabetic medications in patients with metastatic pancreatic ductal adenocarcinoma.
Authors: Pretta Andrea , Cimbro Erika , Giampieri Riccardo , Spanu Dario , Lai Eleonora , Pecci Federica , Balconi Francesca , Lupi Alessio , Pozzari Marta , Murgia Sara , Bardanzellu Fabio , Maccioni Antonio , Contu Fabiana , Persano Mara , Donisi Clelia , Pusceddu Valeria , Puzzoni Marco , Ziranu Pina , Berardi Rossana , Scartozzi Mario
Published: June 2022

e16301

Background: The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated. Indeed, DM2 can be both an epiphenomenon of PDAC and a risk factor. However, the data on the influence of DM2 and concomitant drug therapy in the progression of pancreatic neoplasms are conflicting. The present study aimed to investigate the correlation between overall survival (OS) and antidiabetic drugs in patients with metastatic pancreatic ductal adenocarcinoma and DM2. Methods: Data from 232 patients were collected retrospectively from 2014 to 2021. 174 from the Department of Medical Oncology of the University Hospital of Cagliari and 58 from the Department of Medical Oncology, AOU Ospedali Riuniti of Ancona. All patients had stage IV disease and received gemcitabine plus nab-paclitaxel first-line chemotherapy. Statistical analysis was performed with the MedCalc package. We aimed to evaluate the correlation between DM2, anti-diabetic medications (ADMs) and median overall survival (mOS). Survival distribution was assessed by Kaplan-Meier curves. Finally, multivariate analysis was performed, taking into consideration the following prognostic factors: sex, ECOG-PS, LDH, Ca19.9, and metastatic sites. Results: The median age was 69 y.o. (range 40-84 y.o.), 127 (54,7%) were male. All patients received first-line treatment with gemcitabine plus nab-paclitaxel. 138 (59,4%) patients were not affected by DM2, 94/232 (40,6%) were affected by DM2. Among DM2 patients, 57 (%) were insulin-treated and 37 (%) were metformin-treated. DM2 patients showed a statistically significant higher median overall survival (26 versus 11 months, 95% CI, p = 0,0002). Furthermore, among DM2 patients insulin-treated and metformin-treated showed a mOS of 21 months and 33 months, respectively (95% CI, p = 0.0002). Finally, multivariate analysis showed that treated-DM2 is an independent prognostic factor ( p = 0.03). Conclusions: The results of our study showed a correlation between DM2 on treatment (with insulin or metformin) and higher mOSin patients with metastatic PDAC. However, the limitations due to retrospective data collection must be considered. The mechanisms underlying these findings could be explained by maintaining optimal insulin concentration and good glycemic control during treatments, or by the activity of anti-diabetic medication in neoplastic tissues. However, further studies in this setting are needed.
Body composition parameter as risk predictor in metastatic renal cell carcinoma (mRCC)?
Authors: Heetfeld Constantin , Hensen Bennet , Eggers Hendik , Peters Inga , Kuczyk Markus A , Grünwald Viktor , Ivanyi Philipp
Published: June 2022

e16506

Background: Imaging-derived data for patient’s (pts) prognostication in advanced/metastatic (m)RCC remains scarce. Recently, imaging body composition parameters such as muscle radiation attenuation (MA) and skeletal muscle index (SMI) as prognostic markers for cancer became a matter of interest. Here, impact of MA and SMI in mRCC pts, treated in our tertiary center, were retrospectively investigated. Methods: During the observation period 01/03 – 05/16, 401 pts mRCC receiving first line medical treatment were identified and analyzed. Pts were included for MA- and SMI-analysis based on Computed tomography (CT) scan data and recorded height and bodyweight, respectively. SMI and MA were assessed by a self-designed software-module using MeVisLab. SMI- and MA-subgroups were established by cutoff points, established using an optimum risk stratification method. Descriptive statistics and overall survival (OS) with Log-rank analysis were administered. Parameters with differences in MA-subgroups (p < 0.2) were analyzed with univariable and multivariable Cox-Regression, once p < 0.2 at each subsequent step. Results: 133 pts were eligible for MA-, 123 pts for SMI-analysis. The median age was 62 (range: 39-84) years, and 65.4% of pts showed an ECOG = 0. 87/133 (65.4%) and 71/123 (57.7%) pts showed low MA and low SMI, respectively. At time of mRCC diagnosis pts with low MA were significantly older (mean: 65 vs. 58 years, p < 0,001), while T-, N-, and M-status, as well as MSKCC did not differ. Low MA was associated with a median OS of 27 (95% CI: 17,1-36.3) mo., compared to 60 (95% CI: 36.7-83.3) mo. for high MA (Log-Rank p = 0.001). Multivariable analysis identified low MA as an independent risk factor for OS (HR 2.07; 95% CI 1.24-3.48; p = 0.006). SMI did not reach significance (p = 0.1) (Tab.1). Conclusions: Here, MA provided a robust prognostic parameter regarding OS in mRCC pts. Interestingly, SMI showed no prognostic impact. CT-derived MA could be a promising addition to existing risk-scores. Further research is needed to validate these finding.[Table: see text]
Urban-rural kidney cancer disparities: The role of health literacy, cancer literacy, smoking status, and urinary bother.
Authors: Su Christina , Linnenbringer Erin , Dynda Danuta , Delfino Kristin , Lyons Sarah , Kim Sharon , Alanee Shaheen , McVary Kevin
Published: June 2022

e16513

Background: Kidney cancer (KCa) does not currently have efficacious screening methods, therefore targeting modifiable risk factors is a strong approach to primary prevention. Prior research from our group identified a significant difference in KCa incidence and mortality between the urban and rural populations in Illinois, but the reason(s) for this geographic variation were unclear. The objective of this pilot study was to investigate KCa-relevant knowledge and health behaviors in order to explain our observed urban-rural differences in KCa incidence and mortality, and to inform approaches to KCa prevention. Methods: A convenience sample was surveyed from five study sites between June 2016 and February 2018. These included 207 urban and 53 rural patients presenting at urology and primary care clinics. Four outcome measures related to KCa were assessed using validated measures: 1) health literacy, 2) cancer health literacy, 3) smoking status and knowledge of its association with KCa, and 4) degree of bother caused by urologic symptoms. Multivariate logistic regression models were used to examine these outcome measures between the two populations. Smoking history, personal and family history of cancer, and socio-demographic characteristics were controlled for in the analysis. Results: The overall model for predicting health literacy was significant (Wald Pvalue = 0.0269). When accounting for all covariates, rural versus urban residence was not a significant predictor of adequate health literacy (p = 0.4871). However, participants with higher levels of education (p = 0.0005), higher household income (p = 0.0395), and participants who were female (p = 0.0104) were all more likely to have adequate vs. low health literacy. We did not identify a statistically significant difference in cancer health literacy, knowledge of smoking as a KCa risk factor, or measurement of urinary bother between urban and rural residents in this population. Conclusions: The analyses revealed significant differences in health literacy by education, income, and gender, but not by geographic location. While there were no statistically significant geographical differences found in three of our four domains, this may have been attributed to the low proportion of rural-residing clinic patients recruited in this study. With potential limitations of using RUCA as a measure of rurality, future work is needed to better reach this population and validate results to understand the disparity of improving KCa outcomes in rural areas.
PBRM1 genomic alterations as a predictive biomarker to immune checkpoint inhibitors (ICI) and/or anti-angiogenic therapies (anti-VEGF) in metastatic renal cell carcinoma (mRCC): A systematic review and meta-analysis.
Authors: Ghiglione Lucio , Fernandez-Mañas Laia , Ferrer-Mileo Laura , Aversa Caterina , Garcia de Herreros Marta , Laguna Juan Carlos , Gorria Teresa , Marin Mercedes , Jiménez Natalia , Prat Aleix , Maurel Joan , Mellado Begona , Reig Oscar
Published: June 2022

e16515

Background: Combination therapy with ICI and anti-VEGF has become the standard first-line (1L) therapy for metastatic clear cell RCC (mccRCC). However, about 25% of patients (pts) are long responders to anti-VEGF monotherapy. PBRM1 genomic alterations (ga) are present in around 40% mccRCC pts and contradictory results have been reported about its role as a predictive biomarker. We performed a systemic review and meta-analysis to assess the role of PBRM1 ga as a predictive biomarker of response to ICI, anti-VEGF, or its combination. Methods: A systematic review of PubMed, EMBASE, Cochrane, and Web of Science databases was performed (February 2022) to identify studies involving mRCC pts who received systemic therapy and had PBRM1 status and clinical outcomes reported. Study design, baseline characteristics, treatment data, and hazard ratios (HRs) with 95% confidence intervals (CI) for each clinical outcome were extracted. HRs were combined across studies using a random effect model. The primary endpoint was to correlate PBRM1 status with progression-free survival (PFS) to anti-VEGF, ICI, or its combination. Results: The systematic review included 12 out of 892 publications (n = 6528 pts), 98% (n = 6372) mccRCC; 3297 pts (51%) treated with anti-VEGF monotherapy, 1574 (24%) ICI (PD-L1 (n = 1019, 65%) or CTLA4 + anti PD-L1 (n = 555, 35%)), 997 pts (15%) anti-VEGF + ICI, and 660 pts (10%) with other therapies (e.g., mTORi or INF). PBRM1 status was assessed by NGS in 3841 pts (59%) and detected in 1595 (41%). Nine out of 12 publications were considered for the meta-analysis; excluding those with duplicated pts or lack of information. Six studies (n = 2593 pts) evaluated PBRM1 status in first-line (1L) therapies, including anti-VEGF in monotherapy (n = 1487, 57%) and ICI (n = 1106, 43%; combined w/anti-VEGF (n = 773), w/CTL4 (n = 262) or in monotherapy (n = 71)). In 1L setting, PBRM1 ga pts had longer PFS under monotherapy with anti-VEGF ( PBRM1 ga 44%; HR = 0.74 (95% CI, 0.62 - 0.88), p < 0.01) but not under ICI ( PBRM1 ga = 42%; HR = 1 (95% CI, 0.85 - 1.17), p = 0.38) nor ICI + anti-VEGF treatment ( PBRM1 ga = 33.5%; HR = 0.93 (95% CI, 0.73 - 1.18), p = 0.56). Two studies evaluated PBRM1 status in second line (2L) ICI-treated mRCC pts (n = 517 pts). PBRM1 ga pts had longer PFS under ICI in 2L ( PBRM1 ga = 36%, HR = 0.64 (95% CI, 0.49 - 0.83), p = 0.0007). Conclusions: mRCC pts with PBRM1 ga showed longer PFS to 1L anti-VEGF and 2L ICI therapy, supporting its role as a predictive biomarker. Anti-VEGF + ICI combination de-escalation strategies merits further investigation in PBRM1 ga mRCC patients.
Efficacy and toxicity of antibody-drug conjugates (ADCs) in the treatment of metastatic urothelial cancer (mUC): A systematic review.
Authors: Padua Tiago Costa de , Malena Greta , Moschini Marco , Martini Alberto , Marandino Laura , Raggi Daniele , Briganti Alberto , Montorsi Francesco , Necchi Andrea
Published: June 2022

e16536

Background: mUC is an aggressive disease with limited overall survival. Recently, immunotherapy with checkpoint inhibitors (ICI) has dramatically improved outcomes but with limited response rates and overall survival. ADC were designed with the intent to deliver potent cytotoxic drugs selectively to antigen-expressing tumor cells by linking cytotoxins to mAbs and have emerged as a new option of treatment with promising results. We aimed to realize a systematic review of efficacy, treatment-related AEs (trAEs) and impact on quality of life of ADC in mUC. Methods: A systematic review of the literature has been performed in January 2022 using Pubmed and Embase database according to the Preferred Reported Items for Systematic Reviews and Meta-analyses (PRISMA) statement. After excluding review, duplicate and non-relevant articles, 10 clinical trials were included in the analysis. The search method involved querying for the terms bladder carcinoma or urothelial carcinoma with any of the following: enfortumab vedotin (EV), sacituzumab govitecan (SG), antibody-drug conjugate. Only prospective clinical trials were included. Results: The systematic review yielded 1103 records using MEDLINE (741 records) and EMBASE (362 records). Ultimately, 9 phase 1, 2 or 3 clinical trials with 1355 patients were selected for inclusion and 4 drugs were identified: Enfortumab vedotin (EV), sacituzumab govitecan (SG), an anti-HER2 compound (RC48-ADC), and an anti- SLITRK6 drug (ASG-15ME). Efficacy outcomes are presented in table 1. Phase 2 trials have reported promising response rates in mUC and one randomized phase 3 trial showed the superiority of EV vedotin over CT after failure to platinum-based CT and ICI with improvement in overall survival. TRAEs of any grade occurred in more than 90% of patients in phase 2 or 3 trials, with high rates of discontinuation (table 2). TRAEs of special interest related to EV were rash, neuropathy, and hyperglycemia. SG is associated with diarrhea and hematologic toxicity. Data from phase 2 and 3 trials of EV suggest no impact on quality of life and an improvement in some parameters. Conclusions: ACDs represent a very promising new option for the treatment of mUC. A phase 3 trial confirmed the superiority of EV over CT after platinum and IO failure. A high incidence of potential adverse events was observed in phase 2 and 3 trials, including rash, neutropenia, hematologic toxicity, and neuropathy. Practitioners’ oncologists should be aware of potential adverse events and optimal management. Quality of life is preserved during the treatment with EV.
Molecular mechanism in urothelial carcinoma with FGFR3 mutation.
Authors: Liu Huanhuan , Zhang Yanrui , Lou Feng , Cao Shanbo , Wang Huina
Published: June 2022

e16548

Background: Specific genomic alterations in the FGFR (fibroblast growth factor receptor) family are well-known to be characteristic driver events of urothelial carcinoma and is a therapeutic target. However, molecular mechanism differences of urothelial carcinoma (UC) stratified by the FGFR mutation status has not yet been described. Methods: Patients diagnosed with UC were enrolled in the study. Tumor tissue and matching blood were sequenced by next-generation sequencing (NGS) techniques with Acornmed panel with 808 cancer-related genes. Results: A total of 368 patients with UC were enrolled including 75 patients with FGFR2/3 mutation and 293 patients with FGFR2/3 wildtype. In FGFR2/3 mutation cohorts, the five most frequently mutated genes were FGFR2/3 (100%), KMT2D (56%), KMT2C (35%), CREBBP (32%) and FAT1 (31%). For FGFR2/3 wildtype cohorts, the five most frequently mutated genes were TP53 (46%), KMT2D (41%), BRD4 (23%), ARID1A (15%), and KMT2C (14%). 87 frequently mutated genes were significant difference between FGFR2/3 mutation and FGFR2/3 wildtype cohorts, such as KMT2D, KMT2C, STAG2, CREBBP and FAT1, excluding the FGFR2/3 gene. Signature 1 for spontaneous deamination of 5−methylcytosine and signature 22 for exposure to aristolochic acid (AA) existed in both cohorts. Although there were APOBEC Cytidine Deaminase signatures in both groups, they were projected to different COSMIC signatures (signature 2 and 13, respectively). Signature 10 for defects in polymerase POLE (4.81%) were only observed in the FGFR2/3 mutation cohorts. In the FGFR2/3 mutation cohorts, mutated genes were mainly enriched in the cancer pathway, PI3K-Akt signaling pathway, and Ras signaling pathway. However, in the FGFR2/3 wildtype cohorts, the primary pathways included the cancer pathway, PI3K-Akt signaling pathway, and Rap1 signaling pathway. Conclusions: There were characterized the genomic differences and similarities, stratified by the TP53 status, which may reflect the UC patients with TP53 mutation harbored specific molecular mechanism.
Clinical utility of urine tumor DNA in bladder cancer patients.
Authors: Hu Hailong , Niu Yuanjie , Wang HaiTao , Guo Zhaoxia , Liu Huanhuan , Shen Chong , Da La , Zhao Gangjian , Wang Lili , Wu Zhouliang , Zhang Zhe , Cao Shanbo , Lou Feng , Wang Huina
Published: June 2022

e16560

Background: Concordance between tumor DNA (tDNA) and urine tumor DNA (utDNA) profiles using paired samples was analyzed. Genomic analysis of utDNA and tDNA showed a high consistency, indicating that urine is an optional sample for noninvasive detection and response evaluation of bladder cancer (BC). Methods: Methods and results data were analyzed from an ongoing study, collecting all cases from Second Hospital Affiliated to Tianjin Medical University. Cases with pathologically confirmed BC and matching tissue/urine/whole blood before treatments were recruited. In 85 patients, 48 with paired samples were enrolled in this analysis after excluding 37 paired samples failed in sample QC or sample collection. WES (Whole Exome Sequence) was applied to tDNA and paired white blood cell (WBC) DNA. An Acornmed 808-Gene panel was applied to utDNA and paired WBC DNA. Somatic events, including SNV (single nucleotide variant), InDel (insertion and deletion) of hot genes were analyzed. Consistency of tDNA and utDNA were identified and analyzed in the intersection set between the two chips, and tDNA profiling was used as the“golden standard”. Results: Among 48 patients, 24(50.0%) were MIBC, 21(43.8%) were NMIBC and 41 (81.5%) were male. With neoadjuvant therapy, 23(47.9%) are identified as responders (CR or PR), 7(14.6%) identified as non-responders (SD or PD), 18(37.5%) are still following up. Overall, 75.4% (214/284) tDNA mutations were found in utDNA, and 75.1% (214/285) utDNA mutations were found in tDNA. The top20 genes’ mutation landscape of utDNA highly resembled that of tDNA. The top20 genes could cover 97.9% (47/48) tissue samples and 89.6% (43/48) urine samples. Also, top20 mutated genes showed a strong correlation between tDNA and utDNA(r = 0.7371, p = 0.0002). TP53, KMT2D, ARIDA1A, CREBBP, ERBB2, ERCC2 and KDM6A are the most frequent abnormalities captured in tDNA and utDNA. Interestingly, we also found that the consistency of top20 genes in responders (n = 23, r = 0.7015, p = 0.0006) are higher than non-responders (n = 7, r = 0.4118, p = 0.1853). As a consequence, 70.1% (157/224), 61.8% (21/34) tDNA mutations were found in utDNA, and 72.0% (157/218), 25.0% (21/84) utDNA mutations were found in tDNA in responders and in non-responders, respectively. Conclusions: In brief, utDNA was robustly consistent and highly associated with tDNA, with 61.8%̃75.4% tDNA variations detected in utDNA target sequecing by acornmed 808 panel. The consistency would be higher if TERT promoter included in WES panel. While in non-responders, only 25.0% utDNA mutations were found in tDNA, indicating a spatial and temporal tumor heterogeneity. Our data provided initial prospective evidence on further developing urine as an optional sample for noninvasive detection and response evaluation of BC. The large prospective cohort study is still ongoing.
A systematic review of racial disparities in enrollment into clinical trials and clinical outcomes in men with metastatic prostate cancer.
Authors: Lawal Oluwadolapo D , Shui Irene M , Ghate Sameer
Published: June 2022

e17028

Background: Men of African ancestry have a disproportionately higher incidence of prostate cancer than Caucasians. Yet, men of African ancestry have historically been underrepresented in clinical trials for metastatic prostate cancer (MPC). Further, differences in the magnitude of clinical benefit from treatment by race have been reported. The objective of this study was to assess the racial disparities in clinical trial enrollment of men with MPC and the magnitude of difference in clinical benefit between men of African ancestry and Caucasians with MPC. Methods: A systematic review of MEDLINE was conducted to identify studies published between January 2001 to May 2021. We included: (a) studies that enrolled adults with metastatic castration-resistant prostate cancer (mCRPC) or metastatic hormone sensitive prostate cancer; (b) clinical trials with complete race-stratified frequencies for enrolled subjects; or (c) clinical trials or observational studies that reported race-stratified subgroup analyses or adjusted effect estimates for efficacy/effectiveness outcomes. Outcome measures included overall survival (OS) and progression-free survival (PFS). Results: Of 2,140 retrieved articles, 39 studies involving 39,181 subjects met eligibility criteria. The majority of the studies (n = 35) enrolled mCRPC subjects. Of the 39 studies, 24 were clinical trials and 15 were observational studies. Twenty-one studies enrolled only patients in the US while 18 were multinational studies. Of the 15,761 subjects enrolled in clinical trials, 1750 (11.1%) were men of African ancestry and 12,321 (78.1%) Caucasian. The median (interquartile range) enrollment rate of men of African ancestry in clinical trials was 5.7% (2.3%, 10.1%). Of the 39 eligible studies, 15 reported race-stratified clinical outcomes. Three studies compared men of African ancestry vs Caucasians, 2 men of African ancestry vs non-African ancestry, 3 Caucasian vs others or vice-versa. The remaining 7 studies reported separate estimates on survival by race. All 5 studies comparing men of African ancestry versus other racial groups were conducted in mCRPC subjects. No difference in survival risks by race was observed in the 3 studies that compared men of African ancestry vs Caucasian (HR: 1.09 [0.77, 1.53], 0.68 [0.36, 1.29] and 1.05 [0.97, 1.14]). HRs of 0.90 [0.52, 1.57] and 0.76 [0.61, 0.95] were reported in the 2 studies comparing OS in men of African ancestry vs non-African ancestry. No studies reported a significant increased risk of death by race. Conclusions: Overall, men of African ancestry were largely underrepresented in MPC clinical trials. Concerted efforts are needed to increase the enrollment of this at-risk population in future clinical trial programs. Additional studies are needed to confirm the absence of differences in survival by race in real-life settings.
Impact of PSMA-targeted PET/CT in the clinical management of men with advanced prostate cancer.
Authors: Tucker Matthew D , Chen Yu-Wei , Yasin Hesham Abdallah , Ancell Kristin Kathleen , Barocas Daniel Ari , Beckermann Katy , Chang Sam S. , Davis Nancy B. , Jessop Aaron , Kaiser Elizabeth , Kirschner Austin Noah , Kluwe Christien Alexandre , Luckenbaugh Amy , Moses Kelvin A. , Penson David F. , Sherer Philip , Smelser Woodson , Wallace Deborah , Schaffer Kerry , Rini Brian I.
Published: June 2022

e17053

Background: 18F-DCFPyL (piflufolastat F 18) is a PSMA-targeted agent FDA-approved for PET imaging in men with prostate cancer. Given the recent availability for clinical use, we sought to evaluate the impact and potential changes in management after the incorporation of 18F-DCFPyL (PyL) PET/CT at an academic medical center. Methods: We reviewed the first 100 PyL PET/CT scans performed at the Vanderbilt-Ingram Cancer Center for men with prostate adenocarcinoma. Patient demographics, treatment history, and prior imaging results were recorded, along with PyL PET results, most recent PSA, and clinical management plans. Management changes were designated as change in systemic therapy, radiation, or surgery and were determined by two independent reviewers with a third reviewer for any discordant cases. Results: There were 100 men included with PyL PET scans dating from 9/1/21 to 12/31/21. The median age was 69 years, 76% of patients were white and 13% were black. The median Gleason sum at diagnosis was 7 (4+3), 55% of men had prior prostatectomy, and 38% had prior radiation to the prostate/pelvis. The median PSA prior to PyL PET scan was 1.86 (IQR 0.53-9.95 ng/mL), 32% of men had previous ADT exposure, and 15% were on ADT at the time of PyL PET scan. The clinical setting prior to PyL PET scan was initial staging 22%, biochemical recurrence 59%, m1HSPC 14%, m0CRPC 2%, and m1CRPC 3%. There were 16 patients who had a prior 18F-fluciclovine within six months of PyL PET; of these 69% (11/16) had additional disease on PyL PET not previously identified. Activity in lymph nodes was observed in 48%, bone 37%, visceral sites 3%, prostate/prostate bed 46%, and 15% had no PSMA-avid disease. Clinical staging was altered after the PyL PET scan in 55% of patients, with the most common change being from BCR to m1HSPC (40/55). Clinical management was altered in 59% of cases: systemic therapy 38%, radiation planning 46%, and surgical planning 6% (Table). Conclusions: Clinical management was affected in 59% of cases after implementation of PyL PET in this retrospective, single center review. Given the rapid adoption of PSMA-targeted PET imaging agents, further studies are needed to evaluate the clinical impact of subsequent changes to management planning, as well as to develop multidisciplinary consensus statements and protocols to guide management.[Table: see text]
Exploring the accuracy of multiparametric MRI in prostate cancer staging: An institutional retrospective study.
Authors: Denisenko Andrew , Mico Vasil , McPartland Connor , Clark Cassra B , Shumaker Andrew , Gomella Patrick H. , Izes Joseph , Mann Mark Jonathan , Trabulsi Edouard John , Mark James Ryan , Lallas Costas D. , Gomella Leonard G. , Chandrasekar Thenappan
Published: June 2022

e17056

Background: Multiparametric Magnetic Resonance Imaging (mpMRI) has been increasingly utilized in prostate cancer (PCa) diagnosis and staging. While there is Level 1 data supporting MRI utility in identifying clinically significant PCa and guiding PCa diagnosis, there is little data on its ability to predict surgical outcomes and its utility as a staging study. We aimed to evaluate the accuracy of mpMRI in predicting common surgical pathology outcomes in patients who underwent radical prostatectomy (RP). Methods: Men who underwent either open radical prostatectomy (ORP) or robotic assisted laparoscopic prostatectomy (RALP) for prostate adenocarcinoma from January-December 2021 at a single tertiary level care academic medical center were identified. Chart review for relevant patient demographics, mpMRI related variables and final surgical pathology was completed. In patients who had pre-operative mpMRI, we evaluated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of mpMRI in predicting relevant surgical outcomes, including presence of pT2N0 organ confined disease (OCD), extracapsular extension (ECE), seminal vesicle invasion (SVI), lymph node involvement (LNI), and bladder neck invasion (BNI). Results: 168 eligible patients were identified in a 12-month period. The mean age was 63.5±6.24 years and mean Prostate Specific Antigen (PSA) was 11.4±23.7, with 166 (98.8%) patients undergoing RALP and 115 (68.5%) having pre-operative mpMRI. Median GGG was 2 in both MRI and CT subsets (p = 0.580), and patients who had pre-op MRI were more likely to have higher PSA (12.7 ±28.1 vs 8.38± 6.32, p = 0.073) and clinically node positive disease (p < 0.001) than those with CT. However, there was no significant difference in final surgical pathology or positive surgical margin rates between these two groups. On subset analysis of the MRI subset, Table summarizes the sensitivity, specificity, PPV, and NPV of pre-op MRI to predict OCD, ECE, SVI, LNI, and BNI. While specificity of pre-op MRI was adequate for all outcomes (89.1-100%), sensitivity (2.9-49.2%), PPV (40-100%), and NPV (56.3-94.3%) were poor. Conclusions: At present, pre-op MRI of the prostate does not appear to be accurate in its ability to predict important pathologic outcomes at the time of radical prostatectomy and should be used cautiously as a local staging tool. More work is needed before MRI can be used as a reliable staging tool for PCa.[Table: see text]
Ex ante budget impact analysis (BIA) of PD-1 inhibitor toripalimab plus gemcitabine-cisplatin (T+GC) versus a simulated pembrolizumab regimen in first line (1L) treatment of recurrent or metastatic nasopharyngeal cancer (rmNPC).
Authors: Abraham Ivo , Geller Robert B. , Walden Paul D. , MacDonald Karen
Published: June 2022

e18024

Background: Interim results of the JUPITER-02 randomized double-blind phase 3 trial demonstrated a PFS benefit for T+GC (11.7 m) vs placebo+GC (8m) in 1L treatment of rmNPC. The KEYNOTE-028 nonrandomized (single group assignment) phase 1b trial showed the potential benefit of pembrolizumab in previously treated NPC. The trials were not comparable in population and design, precluding a direct comparison. We performed an ex ante BIA comparing T+GC to a simulated pembrolizumab+GC (sP+GC) regimen under an assumed equivalence in efficacy and safety. Methods: An ex ante budget impact model (budget holder perspective; accrual approach) compared a treatment mix “without” T+GC (only sP+GC) to one “with” T+GC in an annual incident US population of 1200 patients (year 1), a 5y time horizon, and a fixed 50/50 market share split. Population adjustments were for discontinuation, death, and progression with corresponding medication adjustments to estimate fully treated patient equivalents. Cost inputs included: drugs (average sales price), drug administration, and grade 3/4 adverse event (AE) management. Three scenarios were modeled: toripalimab priced at 70%, 80% and 90% of pembrolizumab. Results: In the “without” scenario, the 5y costs of sP+GC treatment totaled $2,062,509,042 and the 5y cost of managing AEs $210,382,926, for a total of $2,272,891,967. In the “with” scenario at 50% market share, the corresponding 5y costs for sP+GC declined to $1,031,254,521 for treatment and $105,191,463 in AE costs, for a total of $1,136,445,984. The corresponding costs for T+GC priced at 70%, 80%, 90% of pembrolizumab were $746,834,887, $841,641,432 and $936,447,976 (treatment) and $105,191,463 (AE management), for 5y gross budget impacts of $852,026,350, $946,832,895 and $1,041,639,439. Net savings “with” T+GC were $49,331,430, $32,887,620 and $16,443,810 in 2022 rising to $64,974,264, $43,316,176 and $21,658,088 by 2026. The total 5y net budget impact of adding T+GC to the treatment mix totaled $284,419,634, $189,613,089 and $94,806,545 in savings. Conclusions: Citing the findings from the JUPITER-02 trial of T+GC, regimens including a PD-1 inhibitor, gemcitabine and cisplatin are now a NCCN category 2A recommendation for 1L treatment of rmNPC. This ex ante BIA demonstrates the substantial savings potential of toripalimab (at a discounted cost compared to pembrolizumab) in rmNPC. With forthcoming final JUPITER-02 data showing a PFS benefit of 21.4m, the value of an available, lower-priced and efficacious anti-PD1 agent is highly significant to patients, providers and payers in terms of both clinical efficacy and cost efficiency. Emerging data suggest that toripalimab may be effective in more frequently occurring tumor types and the savings from such expanded access are likely to be multifold.