tbuckley/cabot-search huggingface dataset:
Unraveling the web of frailty: A novel approach to frailty using a CGA-derived spider plot.
Authors: Dana Cavanaugh, Sarah K Holt, Erin Petersen, Samia Jannat, Jonathan L. Wright, John L. Gore, George Schade, Sarah P. Psutka
Journal: Journal of Clinical Oncology (2024)

579 Background: Frailty in bladder cancer predicts increased complications and mortality. Measuring frailty is challenging because relying on one frailty instrument risks oversimplifying patients’ multidimensional vulnerability profiles. Current guidelines recommend using a comprehensive geriatric assessment (CGA) to quantify frailty across domains of physical function, mental health/cognition, nutrition, and multimorbidity in older adults. However, the CGA’s extensive data can be hard to synthesize and integrate into busy clinical practice. We propose a novel CGA-derived Frailty Spider Plot, synthesizing CGA-identified vulnerabilities into a clinically useful frailty profile. Methods: Urothelial cancer patients, prospectively enrolled between 9/2020 and 7/2021 in a multidisciplinary bladder cancer clinic, completed a CGA incorporating validated assessments of functional status, multimorbidity, nutrition, cognition, and mental health, augmented with CT-derived assessments of muscle mass and adiposity. Spearman Correlation Coefficients were used to quantify relationships between frailty tools and domains. Novel Frailty Spider plots were then created to visualize individuals’ distinct frailty phenotypes. The CGA instruments, grouped by domain, were the spokes of the plot, with each node determined by validated thresholds. Outer ring values indicated greater frailty. Results: The cohort included 67 patients (median age 71, 16.4% female), most with muscle-invasive bladder cancer (77.6%; cN+: 20.9%, M1: 7.6%). The CGA identified 31.4% vulnerable-to-moderately frail, 23.9% at risk for falls, 13.4% with mild depression, 7.5% with moderate-severe depression, 3% with mild/moderate dementia, 34% at risk for malnutrition, and 6% malnourished. Frailty measures were generally weakly correlated (rho &lt;|0.5|). Individuals’ specific risk profiles were plotted on the novel Frailty spider plot which visually distinguished patients according to their frailty phenotypes. For instance, a patient with a high risk Mini-nutritional Assessment score, hypoalbuminema, and sarcopenic skeletal muscle mass, is distinguished with a Spider plot dominated by nutritional frailty spokes. Conclusions: In this prospective observational cohort, a CGA identified key vulnerabilities beyond a standard risk assessment. Frailty domains provide unique risk insights beyond relying on simple frail/not frail nomenclature. Notably, even within a domain, instruments had low correlations, contributing distinct insights into a patient’s vulnerability profile. Our novel Spider plot approach visually synthesizes this data in a single depiction of the predominant components of frailty that can be targeted by personalized prehabilitation interventions. Future work will refine risk assessment instruments to best predict clinical outcomes, creating parsimonious Frailty spider plots for clinical use.
Safety and clinical validity of tumor genomic testing for guiding active surveillance selection in men with NCCN intermediate-risk prostate cancer.
Authors: Lauren Lenz, Wyatt Clegg, Diana Iliev, Howard Korman, Todd Matthew Morgan, Jason Hafron, Alexander DeHaan, Ronald F. Tutrone, Timothy Richardson, Kevin Cline, Paul M. Yonover, Jeff Jasper, Alexander Gutin, Robert Finch, Thomas Paul Slavin, Todd Cohen
Journal: Journal of Clinical Oncology (2024)

336 Background: Clinicopathologic features are considered the gold standard for predicting prostate cancer (PCa) disease severity and guiding decisions on the use of active surveillance (AS) or definitive treatment (DT). However, tumor genomic testing has been shown to provide valuable information as an addition to clinical risk stratification measures, allowing for more accurate identification of AS candidates. This study evaluated the safety of genomic testing for guiding AS selection in patients with National Comprehensive Cancer Network (NCCN) intermediate-risk PCa. Methods: In this retrospective observational cohort study, patients with NCCN intermediate-risk PCa underwent Prolaris testing at diagnosis from 9/2015–12/2018. The Prolaris test combines a molecular cell cycle progression score with clinicopathologic features (USCF Cancer of the Prostate Risk Assessment [CAPRA] score, inclusive of Gleason score), generating a Combined Clinical Risk (CCR) score to identify patients as candidates for AS or DT. Patients with a CCR-based 10-year disease-specific mortality (DSM) risk ≤3.2% were recommended to AS. Clinical follow up data, including initial treatment selection and time to metastasis, were retrospectively collected from the treating clinics. Kaplan-Meier estimates were used to evaluate the safety of AS in patients who initially selected AS. Cox proportional hazards models were used to evaluate CCR as a predictor of metastasis in all patients. Results: In total, 3204 patients were included in this analysis, with 1468 (46%) recommended to AS and 1736 (54%) recommended to DT. Among the 973 (30%) patients who initially selected AS, 613 (63%) were recommended to AS and 360 (37%) were recommended to DT. In patients who were recommended to AS and initially selected AS, the observed risk of metastasis within 5 years of diagnosis was 0.37% (95% confidence interval [CI], 0.09%–1.47%). Patients who were recommended to AS had a significantly lower rate of metastasis than patients who were recommended to DT after accounting for initial treatment decision (AS vs DT) and CAPRA score (hazard ratio 4.20 [95% CI, 1.41–18.04], P-value = 0.03). Conclusions: For patients with NCCN intermediate-risk PCa who were identified by genomic testing as candidates for AS, AS is safe based on the very low observed metastasis risk. The CCR score is a strong predictor of metastasis beyond clinicopathologic factors.
PD-L1 expression and its prognostic value in metastatic papillary renal cell carcinoma: Results from a GETUG multicenter retrospective cohort.
Authors: Mathilde Cancel, Jérémie Naffrichoux, Pierre Poupin, William Pouillot, Claude Linassier, Nathalie Rioux-Leclercq, Manon De Vries-Brilland, Loic Mourey, Brigitte Laguerre, Stephane Oudard, Marine Gross-Goupil, Gwenaelle Gravis, Frederic Rolland, Laura Moise, Sheik Muhummud Fardeen Emambux, Cecile Vassal, Sylvie Zanetta, Nicolas Penel, Laurence Albiges, Gaelle Fromont
Journal: Journal of Clinical Oncology (2024)

463 Background: Papillary renal cell carcinoma (pRCC) is a rare and aggressive cancer with no specifically established therapeutic strategy in the metastatic setting. Combinations of tyrosine kinase and immune checkpoint inhibitors are a promising option. We aimed to study the immune landscape of metastatic pRCC, and its associations with angiogenesis pathways expressions, to search for potential therapeutic targets. Methods: The expression of immune markers (PD-L1, PD-1, PD-L2, LAG-3) and angiogenic pathways (CAIX, c-MET), was analyzed by immunohistochemistry on 75 metastatic pRCC retrieved from a retrospective multicenter GETUG cohort. Our primary endpoint was to evaluate the prognostic impact on overall survival (OS) of PD-L1 expression in metastatic pRCC. Secondary endpoints were to describe the expression of the other immune markers and of angiogenic pathways and to estimate the associations between the expression of PD-L1 and the expressions of the other markers or angiogenic pathways. Results: In median, patients were 61 years old at metastatic diagnosis. Concerning their first-line metastatic treatment, 67 (89%) had received Sunitinib, and 8 (11%) had received Everolimus. The Karnofsky Performance Score at treatment initiation was ≥ 80 for 62 (83%) patients. Overall, 25.3% of tumors were PD-L1 positive. PD-L2 was more frequently expressed (45.3%), PD-1 and LAG-3 were positive in 17.3% both. Concerning the angiogenic markers, CAIX was expressed in 46.7% of tumors, c-MET in 41.3%. None of these markers were significantly associated with PD-L1 expression. 64% (48/75) expressed at least one immune marker, and 40% (30/75) were “double-positive”, as they expressed both immune and angiogenic markers. In univariate analysis, OS was significantly shorter for patients with PD-L1 positive pRCC (HR=3.3; 95%CI=1.3-8.6; p=0.01). A multivariate analysis confirmed a significant association between PD-L1 expression and shorter survival (HR=5.4; 95%CI=1.4-20.9; p=0.01). Conclusions: These results reinforce clinical data on the expected benefit of immunotherapy in metastatic pRCC treatment, as PD-L1 expression is a factor of poor prognosis in our multicenter cohort.
Glutamine metabolism and VEGF analysis to elucidate and overcome the mechanism of tyrosine kinase inhibitor resistance in renal cell carcinoma.
Authors: Kento Morozumi, Yoshihide Kawasaki, Tomonori Sato, Masamitsu Maekawa, Shinnya Takasaki, Shuichi Shimada, Takanari Sakai, Shinichi Yamashita, Nariyasu Mano, Akihiro Ito
Journal: Journal of Clinical Oncology (2024)

464 Background: Clinical practices have demonstrated improvements in prognosis of patients with advanced renal cell carcinoma (RCC) by combination therapies with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors. However, TKI-resistance is inevitable which hinders further improvement in prognosis. In our previous study, we reported regulating glutamine metabolism could bring about re-sensitivity to Sunitinib (Su) in Su-resistant Renal cell Carcinoma (RCC) cells. However, the mechanism of re-sensitivity and whether it applies to other tyrosine kinase inhibitors (TKIs) has been still unknown. Methods: We established Su and Cabozantinib (Cabo) -resistant cells in 3 RCC cell lines (786-O, Caki-1 and ACHN). We analyzed the activity of glutamine metabolism and VEGF pathway, before and after TKI-resistant、furthermore, conducted antitumor effect in vitro and vivo studies to evaluate re-sensitivity to TKI and relationship between VEGF signaling and regulating glutamine metabolism. Results: In all TKI-resistant cells, the overexpression of glutamine metabolism and VEGF signaling were observed. In vitro and vivo study using Su, the regulating glutaminolysis resulted in 40-74% cell-killing effect in 3 Su-resistant cell lines. Whereas the regulating glutaminolysis also resulted in 35-55% cell-killing effect in 3 Cabo-resistant cell lines. Although the antitumor effect was observed in only 786-O among Su-sensitive cells, it was not observed among Cabo-sensitive cells. Moreover, antitumor effect of regulating glutamine metabolism is more remarkable in vivo. When conducting immunostaining of CD31 to evaluate vascular endothelium, angiogenesis was significantly inhibited by regulating glutamine metabolism.Evaluating VEGF signaling in RT-PCR, VEGFR2 expression and VEGF signaling were downregulated, and PTEN upregulated by suppressing glutamine metabolism. Conclusions: By evaluating glutamate metabolism with VEGF analysis in TKI-resistant RCC cells, we have come to understand a part of the phenomenon of re-sensitivity to TKIs. The inhibition of VEGF signaling and its consequent impact on the tumor microenvironment by regulating glutamine metabolism, are considered to be the mechanisms causing re-sensitivity to TKIs in TKI-resistant cells.We could use TKIs more effectively by regulating glutaminolysis to improve prognosis in advanced RCC patients.
Preclinical testing of a novel PD-L1 inhibitor for the treatment of renal cell carcinoma.
Authors: Michelle Hsu, Zesheng An, Joanina Gicobi, Tianxiao Xu, Susan Harrington, Henan Zhang, Kevin Pavelko, Jacob Hirdler, Christine M. Lohse, Reza Nabavizadeh, Rodrigo Pessoa, Vidit Sharma, Houston R. Thompson, Bradley C. Leibovich, Haidong Dong, Fabrice Lucien
Journal: Journal of Clinical Oncology (2024)

458 Background: Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 axis has revolutionized the therapeutic landscape of patients with advanced and locally advanced renal cell carcinoma (RCC). However, complete response rates remain low and there is a need for novel therapeutic options for ICI-resistant and refractory RCC. Our group has generated a novel humanized anti-PD-L1 antibody, called H1A, that induces PD-L1 degradation preventing not only its interaction with PD-1 but also inhibiting pro-tumorigenic intracellular signaling. In this study, we compared the antitumor activity of H1A with FDA-approved ICI using patient-derived immune cells and humanized mouse tumor models. Methods: In vivo antitumor activity of H1A and atezolizumab (ATZ) was compared in three humanized PD-1/PD-L1 mouse tumor models with different immunogenicity (E0771:high, MC38:moderate, B16-F10:poor). Peripheral blood mononuclear cells (PBMC) were isolated from 14 RCC patients undergoing with nephrectomy. PBMC were treated with H1A, nivolumab (NIV), atezolizumab (ATZ) and pembrolizumab (PEM) to evaluate their efficacy in inducing tumor cell death in an ex-vivo cytotoxicity assay. Mass cytometry was employed to determine the impact of H1A and atezolizumab on the PBMC profile. Results: MC38 tumors showed moderate response to both H1A and ATZ which was abrogated by CD8 T cell depletion. In E0771 tumors, higher percentage of complete responders was observed with H1A compared to ATZ and E0771 rechallenge revealed memory antitumor immunity with complete rejection of tumors. Patient-derived PBMC treated with H1A showed superior tumor cell killing compared to NIV, PEM and ATZ (p&lt;0.01). While H1A treatment of PBMC induced expansion of effector NK and CD8 T cells (GZMB + T-bet + ), ATZ treatment led to enrichment of Tregs (CD25 + ,Foxp3 + ) expressing inhibitory markers PD-1 and LAG-3. Conclusions: H1A demonstrated superior antitumor activity compared to FDA-approved ICI which lays the ground for clinical testing of H1A as a next-generation immune checkpoint inhibitor for the treatment of renal cell carcinoma.
PSMA-based PET as an imaging biomarker of androgen receptor signaling in high-risk localized and locally advanced prostate cancer (PCa).
Authors: Keara English, Curtiland Deville, Nancy Anabaraonye
Journal: Journal of Clinical Oncology (2024)

341 Background: The purpose of this prospective, nonrandomized, pilot imaging study (NCT02420977) is to evaluate prostate-specific membrane antigen (PSMA), [18F]DCFPyL (DCFPyL), as a PET/CT imaging biomarker of androgen receptor (AR) signaling in newly diagnosed PCa. Methods: 23 men with treatment-naïve, newly diagnosed high-risk prostate cancer were enrolled. Patients underwent DCFPyL PET/CT imaging and MRI/ultrasound fusion-guided prostate biopsy before and after 2-3 months of nADT (LHRH agonist and anti-androgen), followed by definitive IMRT. We measured the total number of lesions, lesion location, maximum standardized tumor uptake value (SUVmax), PSA, and changes in those variables between baseline and follow-up scans. Concordance between biopsy pathology results and PSMA imaging parameters before and after ADT was evaluated. Results: 3 patients were excluded after baseline PET/CT due to high-burden metastases, small cell histology, and declining to proceed further. 20 patients remained for evaluation. At baseline, 19/20 and 8/20 had at least 1 avid intraprostatic and extraprostatic lesion, respectively, with a 50 total lesions (28 prostate, 19 nodal, 3 bone); median intraprostatic and extraprostatic SUVmax were respectively 9.6 (range: 3.3-56.8) and 7.0 (range: 2.3-61.9). Post-nADT scans revealed 32 lesions (19 prostate, 11 nodes, 2 bone); median intraprostatic and extraprostatic SUVmax decreased respectively to 4.1 (range 1.9-27.8) and 3.2 (range: 1.7-8.9). 3/19 (15.8%) of the patients demonstrated complete uptake resolution of the avid intraprostatic foci, 15/19 (78.9%) showed decreased uptake (58.3% median decrease in SUVmax), and 1/19 (5.26%) showed increased SUVmax. Of the 8 patients with extraprostatic lesions, 2/8 (25%) demonstrated complete uptake resolution, 5/8 (62.5%) showed partially decreased uptake (66.67% median decrease in SUVmax), and 1/8 (12.5%) showed increased SUVmax. One of the same patients still had 2 lesions, for a total of 13 intraprostatic target lesions. Regarding concordance between pathologic results and PSMA imaging response pre- and post-nADT, 14/19 (73%) had biopsies fully concordant with PSMA scan (i.e. residual tumor and residual PET avidity), 4/19 (21%) had biopsies mostly concordant with the scan (i.e. complete pathologic response with partial PET response or vice versa), and 1/19 (5%) had a biopsy discordant with the PSMA scan (i.e. no pathology response, but complete response on PSMA). Conclusions: Post-nADT PET detected fewer PSMA-positive lesions with overall decreased or resolved tumor uptake, except for 2 separate patients with increased intra- and extraprostatic uptake. 95% of post-nADT PSMA scans were fully or mostly concordant with post-nADT biopsies, suggesting that PSMA scans may be a clinically useful, prognostic imaging biomarker for disease status evaluation post-nADT. Clinical trial information: NCT02420977 .
Tumor characteristics associated with detectable circulating tumor DNA preoperatively in patients with renal masses suspicious for RCC.
Authors: Reuben Ben-David, Parissa Alerasool, Hitasha Kalola, Neeraja Tillu, Kai Tsao, Matt D. Galsky, Kyrollis Attalla, John P. Sfakianos, Peter Wiklund, Nikhil Waingankar, Reza Mehrazin
Journal: Journal of Clinical Oncology (2024)

461 Background: Understanding the specific tumor characteristics associated with detectable ctDNA in the blood of patients with renal cell carcinoma (RCC) is critical to informing future studies seeking to establish the clinical utility of such testing. We characterized pathological and clinical characteristics associated with ctDNA detected preoperatively in patients with renal masses suspicious of RCC. Methods: Using our single institution prospectively maintained database, we identified consecutive patients who underwent partial or radical nephrectomy for non-metastatic suspected RCC (stages cT1b-cT3) during 2022-2023. Included were patients who had undergone tumor-informed ctDNA testing using the commercial Signatera assay (Natera). Baseline characteristics, pathology results, imaging study results, and oncological treatment and follow-up data were collected from the electronic medical records. ctDNA results were collected through the Natera portal. Study findings were reported using descriptive statistics. A p-value of &lt;0.05 was considered statistically significant. R programming language version 4.3 was used for all statistical analyses. Results: A total of 54 patients with a median age of 63 years (IQR 51-71) were included in the study. Twenty-one (39%) were women. The median follow-up time was 4 months (range: 1-21 months). Among the 54 patients, 27 (50%) had detectable ctDNA pre-operatively Post-operative results were available for 33 patients, and 3 (9%) had detectable tDNA (of those 2 had Inferior vena cava involvement). The first patient developed metastatic disease. The two other patients are receiving adjuvant immunotherapy. Analysis of 50 patients with solely malignant RCC revealed that patients with detectable versus undetectable ctDNA were older 67 vs. 54 years (p=0.03), had a higher pathological stage (p= 0.002), larger tumors (7.2 vs. 4.7 cm, p = 0.004), and higher pathological grade (grade 3-4 vs. grade 1-2; p=0.035) (Table 1). All the patients with renal vein or inferior vena cava involvement had detectable ctDNA (n=8). Conclusions: In our cohort, preoperative ctDNA was detectable in 50% of patients with suspected clinically localized RCC. Detectable ctDNA preoperatively correlated with clinically relevant features. The ability of preoperative ctDNA to predict recurrence and survival in patients with clinically localized RCC warrants further evaluation. [Table: see text]
Bladder-sparing treatment for muscle-invasive bladder carcinoma: A single-center, single-arm clinical study of sequential neoadjuvant chemotherapy followed by tislelizumab neoadjuvant immunotherapy.
Authors: Yu Zeng, Changqi Li, Chengcheng Lv, Cheng Fu, Ang Chen, Shui Fu, Huan Bi, Guangyi Shan, Yiding Wang, Zhe Wang, Qiang Liu, Bo Shao
Journal: Journal of Clinical Oncology (2024)

596 Background: Althoughradical cystectomy (RC) in combination with cisplatin-based neoadjuvant chemotherapy is the gold-standard for muscle-invasive bladder carcinoma (MIBC), bladder-sparing treatment have emerged to be an alternative choice for patients who are concerning about the life quality after surgery. The optimal strategy for bladder-sparing treatment such as trimodal therapy (TMT) showed similar effect with RC. Since the TRUCE-01 has illuminated considerable response of neoadjuvant immunotherapy in MIBC, we aim to study whether neoadjuvant chemotherapy plus immunotherapy can improve the bladder-sparing rate in MIBC patients. Methods: 30 planned patients with MIBC (T2-4a N0-1 M0) received cisplatin 70 mg/m 2 or carboplatin AUC 4.5 on days 1 every 3 weeks (Q3W) plus gemcitabine 1000 mg/m 2 on the 1st and 8th day of each 21-day cycle x 4 cycles. Tislelizumab 200 mg was administered on the 14th day of each 21-day cycle at the 3rd and 4th cycles. CT and cystoscopy imaging were carried out to evaluate disease progression. After the 4th treatment, radical cystectomy, partial cystectomy or TURBT were perform in accordance with the disease status. For continuous bladder-spare treatment, 2 additional cycles of tislelizumab were performed. Bladder-sparing rate was settled as exploratory endpoints based on 2-years follow-up and predictive biomarker will be analyzed. Results: To date, 21 of 30 pts have been enrolled and 17 pts have completed the regimen. 2 pts were excluded because of complicating with other disease (suffering cerebral infraction or rectal cancer during the trail), and 2 pts voluntarily quitted due to intolerance of chemotherapeutic adverse effect (fatigue and gastrointestinal symptoms). 2 pts partially response to the therapy and received RC after disease progression. 1 pt have no response to the therapy and received palliative care as unsuitable for surgery. The resting 10 of 17 pts successfully preserved their bladder by achieving pT0 (58.8%) after treatment. Among them 3 pts have been followed up over 1 year and no relapse was observed. Conclusions: These data support neoadjuvant chemotherapy plus immunotherapy a feasible bladder-sparing choice for patients with MIBC. Further completed follow-up data and biomarker analysis will accurately identify patients who are suitable for this therapy. Clinical trial information: ChiCTR2100050763 .