Outcomes in patients treated with frontline immune checkpoint inhibition (ICI) for advanced NSCLC with KRAS mutations and STK11/KEAP1 comutations across PD-L1 levels.

INTRODUCTION: In patients with advanced NSCLC (aNSCLC), the impact of KRAS mutations (m) and comutations with STK11 and KEAP1 on outcomes across different PD-L1 levels remains incompletely understood. We aimed to investigate the frequency of KRAS mutations and comutations across PD-L1 levels, and the association between these mutations and survival, stratified by PD-L1 expression. METHODS: We conducted a nationwide cohort study of patients diagnosed with aNSCLC between 2016 and 2021 treated with frontline (chemo)immunotherapy, who underwent molecular genotyping including KRAS, STK11, and KEAP1. Real-world overall survival (OS) and progression-free survival (rwPFS) were estimated using Kaplan-Meier methodology. Cox multivariable regressions were used to evaluate the association between KRASm and survival across different PD-L1 strata, and to assess whether the association between KRASm and survival differed by PD-L1 level. Finally, within subgroups defined by PD-L1 expression, we used interaction terms to assess whether co-mutations with STK11 and KEAP1 moderated the association between KRAS mutation and survival. RESULTS: Of our 2593-patient cohort, 982 (37.9 %) were KRASm and 1611 (62.1 %) KRASwt. KRASm were enriched in the PD-L1 ≥50 % cohort (334/743, 45 %), but within patients with KRASm, co-mutations with STK11 and KEAP1 were enriched in the PD-L1 0 % cohort. KRASm was associated with significantly worse OS in the PD-L1 0 % cohort compared to the PD-L1 ≥50 % cohort (P for interaction = 0.008). On adjusted analyses stratified by PD-L1, KRASm was associated with worse survival only in the PD-L1 0 % group (OS HR 1.46, p = 0.001). KEAP1 and STK11 comutations were most strongly associated with worse OS in the PD-L1 0 % subgroup; patients with triple KRASm/KEAPm/STK11m PD-L1 0 % NSCLC experienced the worst outcomes. CONCLUSIONS: KRASm are associated with worse overall survival in PD-L1 negative NSCLC; however, this association is largely driven by comutations with STK11 and KEAP1, which are enriched in PD-L1 negative tumors.

Symptomatic and functional recovery after transurethral resection of bladder tumor: Data from ecological momentary symptom assessment.

OBJECTIVES: To quantitatively describe the nature, severity, and duration of symptoms and functional impairment during recovery from transurethral resection of bladder tumors. MATERIALS AND METHODS: All patients scheduled for transurethral resection were approached for enrollment in a text-message based ecological momentary symptom assessment platform. Nine patients reported outcomes were measured 7 days before surgery and on postoperative days 1, 2, 3, 5, 7, 10, and 14 using a 5-point Likert scale. Self-reported degree of hematuria was collected using a visual scale. Clinical data was collected via retrospective chart review. RESULTS: A total of 159 patients were analyzed. Postoperative symptoms were overall mild, with the largest differences from baseline to postoperative day 1 seen in dysuria (median 0/5 vs. 3/5) and ability to work (median 5/5 vs. 4/5). Recovery was generally rapid, with 76% of patients reporting ≥4/5 agreement with the statement "I feel recovered from surgery" by postoperative day 2, although 15% of patients reported persistently lower levels of agreement on postoperative day 10 or 14. Patients undergoing larger resections (≥2cm) did take longer to return to baseline in multiple symptom domains, but the difference of medians vs. those undergoing smaller resections was less than 1 day across all domains. Multivariable analysis suggested that receiving perioperative intravesical chemotherapy was associated with longer time to recovery. 84% of patients reported clear yellow urine by postoperative day 3. CONCLUSION: In this population, hematuria and negative effects on quality of life resulting from transurethral resection of bladder tumors were generally mild and short-lived, although a small number of patients experienced longer recoveries.

Factors Associated With Racial and Ethnic Disparities in Locally Advanced Rectal Cancer Outcomes.

Importance: Hispanic and non-Hispanic Black patients receiving neoadjuvant therapy and surgery for locally advanced rectal cancer (LARC) achieve less favorable clinical outcomes than non-Hispanic White patients, but the source of this disparity is incompletely understood. Objective: To assess whether racial and ethnic disparities in treatment outcomes among patients with LARC could be accounted for by social determinants of health and demographic, clinical, and pathologic factors known to be associated with treatment response. Design, Setting, and Participants: The National Cancer Database was interrogated to identify patients with T3 to T4 or N1 to N2 LARC treated with neoadjuvant therapy and surgery. Patients were diagnosed between January 1, 2004, and December 31, 2017. Data were culled from the National Cancer Database from July 1, 2022, through December 31, 2023. Exposure: Neoadjuvant therapy for rectal cancer followed by surgical resection. Main Outcomes and Measures: The primary outcome was the rate of pathologic complete response (pCR) following neoadjuvant therapy. Secondary outcomes were rate of tumor downstaging and achievement of pN0 status. Results: A total of 34 500 patient records were reviewed; 21 679 of the patients (62.8%) were men and 12 821 (37.2%) were women. The mean (SD) age at diagnosis was 59.7 (12.0) years. In terms of race and ethnicity, 2217 patients (6.4%) were Hispanic, 2843 (8.2%) were non-Hispanic Black, and 29 440 (85.3%) were non-Hispanic White. Hispanic patients achieved tumor downstaging (48.9% vs 51.8%; P = .01) and pN0 status (66.8% vs 68.8%; P = .02) less often than non-Hispanic White patients. Non-Hispanic Black race, but not Hispanic ethnicity, was associated with less tumor downstaging (odds ratio [OR], 0.86 [95% CI, 0.78-0.94]), less frequent pN0 status (OR, 0.91 [95% CI, 0.83-0.99]), and less frequent pCR (OR, 0.81 [95% CI, 0.72-0.92]). Other factors associated with reduced rate of pCR included rural location (OR, 0.80 [95% CI, 0.69-0.93]), lack of or inadequate insurance (OR for Medicaid, 0.86 [95% CI, 0.76-0.98]; OR for no insurance, 0.65 [95% CI, 0.54-0.78]), and treatment in a low-volume center (OR for first quartile, 0.73 [95% CI, 0.62-0.87]; OR for second quartile, 0.79 [95% CI, 0.70-0.90]; OR for third quartile, 0.86 [95% CI, 0.78-0.94]). Clinical and pathologic variables associated with a decreased pCR included higher tumor grade (OR, 0.58 [95% CI, 0.49-0.70]), advanced tumor stage (OR for T3, 0.56 [95% CI, 0.42-0.76]; OR for T4, 0.30 [95% CI, 0.22-0.42]), and lymph node-positive disease (OR for N1, 0.83 [95% CI, 0.77-0.89]; OR for N2, 0.73 [95% CI, 0.65-0.82]). Conclusions and Relevance: The findings of this cohort study suggest that disparate treatment outcomes for Hispanic and non-Hispanic Black patients are likely multifactorial in origin. Future investigation into additional social determinants of health and biological variables is warranted.

Pulsed low-dose-rate radiation (PLDR) reduces the tumor-promoting responses induced by conventional chemoradiation in pancreatic cancer-associated fibroblasts.

Pancreatic cancer is becoming increasingly deadly, with treatment options limited due to, among others, the complex tumor microenvironment (TME). This short communications study investigates pulsed low-dose-rate radiation (PLDR) as a potential alternative to conventional radiotherapy for pancreatic cancer neoadjuvant treatment. Our ex vivo research demonstrates that PLDR, in combination with chemotherapy, promotes a shift from tumor-promoting to tumor-suppressing properties in a key component of the pancreatic cancer microenvironment we called CAFu (cancer-associated fibroblasts and selfgenerated extracellular matrix functional units). This beneficial effect translates to reduced desmoplasia (fibrous tumor expansion) and suggests PLDR's potential to improve total neoadjuvant therapy effectiveness. To comprehensively assess this functional shift, we developed the HOST-Factor, a single score integrating multiple biomarkers. This tool provides a more accurate picture of CAFu function compared to individual biomarkers and could be valuable for guiding and monitoring future therapeutic strategies. Our findings support the ongoing NCT04452357 clinical trial testing PLDR safety and TME normalization potential in pancreatic cancer patients. The HOST-Factor will be used in samples collected from this trial to validate its potential as a key tool for personalized medicine in this aggressive disease.

Effect of neighborhood and individual-level socioeconomic factors on breast cancer screening adherence in a multi-ethnic study.

BACKGROUND: Although mammography can significantly reduce breast cancer mortality, many women do not receive their annual breast cancer screening. Differences in screening adherence exist by race/ethnicity, socioeconomic status (SES), and insurance status. However, more detailed investigations into the impact of neighborhood disadvantage and access to resources on screening adherence are lacking. METHODS: We comprehensively examined the effect of individual social, economic, and demographic factors (n = 34 variables), as well as neighborhood level SES (nSES) indicators (n = 10 variables) on breast cancer screening adherence across a multi-ethnic population (n = 472). In this cross-sectional study, participants were surveyed from 2017 to 2018. The data was analyzed using univariate regression and LASSO for variable reduction. Significant predictors were carried forward into final multivariable mixed-effect logistic regression models where odds ratios (OR), 95% confidence intervals and p-values were reported. RESULTS: Nineteen percent of participants were non-adherent to breast screening guidelines. Race/ethnicity was not associated with adherence; however, increasing age (OR = 0.97, 95%CI = 0.95-0.99, p = 0.01), renting a home (OR = 0.53, 95%CI = 0.30-0.94, p = 0.04), food insecurity (OR 0.46, 95%CI = 0.22-0.94, p = 0.01), and overcrowding (OR = 0.58, 95% CI = 0.32-0.94, p = 0.01) were significantly associated with lower breast cancer screening adherence. CONCLUSION: Socioeconomic indicators at the individual and neighborhood levels impact low breast cancer screening adherence and may help to inform future screening interventions.

Transition to Value-based Healthcare: Development, Implementation, and Results of an Optimal Surgical Care Framework at a National Cancer Institute-designated Comprehensive Cancer Center.

BACKGROUND: The continued rise in healthcare expenditures has not produced commensurate improvements in patient outcomes, leading US healthcare stakeholders to emphasize value-based care. Transition to such a model requires all team members to adopt a new strategic and organizational framework. OBJECTIVE: To describe and report a strategy for the implementation of a novel patient-centered value-based "optimal surgical care" (OSC) framework, with validation and cost analysis in kidney surgery. DESIGN, SETTING, AND PARTICIPANTS: An observational study of care episodes at a single institution from 2014 to 2019 was conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multidisciplinary teams defined OSC by core and procedure-specific metrics using a combination of provider-based ("bottom-up") and "clinical leadership"-based ("top-down") strategies. Baseline OSC rates across were established, while identifying proportions of OSC achieved by coefficient of variation (CV) in total direct costs. Multivariable linear regression comparing cost between OSC and non-OSC encounters was performed, adjusting for patient characteristics. RESULTS AND LIMITATIONS: An analysis of 30 261 perioperative care episodes was performed. Following the implementation of an OSC framework, there was an increase in OSC rates across all procedure buckets using core (25%) and procedure-specific (26%) metrics. Among the tumors tested, kidney cancer surgical episodes held the highest OSC rate improvement (67%) with lowest variability in cost (CV 0.5). OSC was associated with significant total cost savings across all tumor types after adjusting for inflation (p < 0.05). Compared with non-OSC episodes, a significant reduction in the cost ratio of OSC was noted for renal surgery (p < 0.01), with estimated costs savings of $2445.87 per OSC encounter. CONCLUSIONS: Institutional change directing efforts toward optimizing surgical care and emphasizing value rather than focusing solely on expense reduction is associated with improved outcomes, while potentially reducing costs. The strategy for implementation requires serial performance analyses, engaging and educating providers, and continuous ongoing adjustments to achieve durable results. PATIENT SUMMARY: In this study, we report our strategy and outcomes for transitioning to a value-based healthcare model using a novel "optimal surgical care" framework at a National Cancer Institute-designated comprehensive cancer center. We observed an increase in optimal surgical care episodes across all specialties after 5 yr, with a potential associated reduction in cost expenditure. We conclude that the key to a successful and sustained transition is the implementation strategy, focusing on continual review and provider engagement.

Real-time estimation of nephron activity with a linear measurement system (RENAL-MS) predicts postoperative estimated glomerular filtration rate.

OBJECTIVE: To determine whether a simple point-of-care measurement system estimating renal parenchymal volume using tools ubiquitously available could be used to replace nuclear medicine renal scintigraphy (NMRS) in current clinical practice to predict estimated glomerular filtration rate (eGFR) after nephrectomy by estimating preoperative split renal function. PATIENTS AND METHODS: We performed a retrospective review of patients who underwent abdominal cross-sectional imaging (computed tomography/magnetic resonance imaging) and mercaptoacetyltriglycine (MAG3) NMRS prior to total nephrectomy at a single institution. We developed the real-time estimation of nephron activity with a linear measurement system (RENAL-MS) method of estimating postoperative renal function via the following technique: renal parenchymal volume of the removed kidney relative to the remaining kidney was estimated as the product of renal length and the average of six renal parenchymal thickness measurements. The utility of this value was compared to the utility of the split renal function measured by MAG3 for prediction of eGFR and new onset Stage 3 chronic kidney disease (CKD) at ≥90 days after nephrectomy using uni- and multivariate linear and logistic regression. RESULTS: A total of 57 patients met the study criteria. The median (interquartile range [IQR]) age was 69 (61-80) years. The median (IQR) pre- and postoperative eGFR was 74 (IQR 58-90) and 46 (35-62) mL/min/1.73 m2 , respectively. [Correction added on 29 December 2023, after first online publication: The data numbers in the preceding sentence have been corrected.] Correlations between actual and predicted postoperative eGFR were similar whether the RENAL-MS or NMRS methods were used, with correlation using RENAL-MS being slightly numerically but not statistically superior (R = 0.82 and 0.76; P = 0.138). Receiver operating characteristic curve analysis using logistic regression estimates incorporating age, sex, and preoperative creatinine to predict postoperative Stage 3 CKD were similar between RENAL-MS and NMRS (area under the curve 0.93 vs. 0.97). [Correction added on 29 December 2023, after first online publication: The data numbers in the preceding sentence have been corrected.] CONCLUSION: A point-of-care tool to estimate renal parenchymal volume (RENAL-MS) performed equally as well as NMRS to predict postoperative eGFR and de novo Stage 3 CKD after nephrectomy in our population, suggesting NMRS may not be necessary in this setting.

SAR-096: Phase II Clinical Trial of Ribociclib in Combination with Everolimus in Advanced Dedifferentiated Liposarcoma (DDL) and Leiomyosarcoma (LMS).

PURPOSE: Dedifferentiated liposarcoma (DDL) and leiomyosarcoma (LMS) are two common subtypes of soft-tissue sarcoma, a rare group of diseases for which new treatments are needed. Chemotherapy remains the standard option for advanced disease. Targeting cyclin-dependent kinase 4 and 6 (CDK4/6) in DDL and mTOR in LMS is of biologic interest. When combined, the CDK4 inhibitor ribociclib and the mTOR inhibitor everolimus have shown synergistic growth inhibition in multiple tumor models, suggesting that this combination could be beneficial in patients. PATIENTS AND METHODS: This was a single arm, open label, multicenter phase II study of the combination of ribociclib and everolimus. Patients were enrolled into one of two cohorts: DDL or LMS with intact Rb. The primary endpoint was progression-free rate (PFR) at 16 weeks. Secondary endpoints included progression-free survival (PFS) and overall survival, safety and biomarker analyses. RESULTS: In the DDL cohort, 33.3% [95% confidence interval (CI), 15.6%-55.3%] of patients were progression-free at 16 weeks. Median PFS in this cohort was 15.4 weeks (95% CI, 8-36 weeks) with 2 partial responses. In the LMS cohort the PFR at 16 weeks was 29.2% (95% CI, 12.6%-51.1%). Median PFS in this cohort was 15.7 weeks (95% CI, 7.7-NA). Most common toxicities included fatigue (66.7%), anorexia (43.8%), and hyperglycemia (43.8%). Concordance between Rb testing methodologies was poor. CONCLUSIONS: The combination of ribociclib and everolimus demonstrates activity in DDL with prolonged stable disease (≥16 weeks) meeting the primary endpoint. Notably partial responses were observed. The primary endpoint was not reached in the LMS cohort. The combination was well tolerated with expected side effects.

A pooled patient-reported outcomes analysis of moderately hypofractionated proton beam therapy and photon-based intensity modulated radiation therapy for low- or intermediate-risk prostate cancer.

BACKGROUND: We sought to characterize and compare late patient-reported outcomes (PROs) after moderately hypofractionated intensity modulated radiation therapy (IMRT) and proton beam therapy (PBT) for localized prostate cancer (PC). METHODS: This multi-institutional analysis included low- or intermediate-risk group PC patients treated with moderately hypofractionated radiation to an intact prostate stratified by treatment modality: IMRT or PBT. The primary outcomes were prospectively collected patient-reported late gastrointestinal (GI) and genitourinary (GU) toxicity assessed by International Prostate Symptom Score (IPSS) and Expanded PC Index Composite (EPIC). Multivariable regression analysis (MVA) controlling for age, race, and risk group tested the effect of time, treatment, and their interaction. RESULTS: 287 IMRT and 485 PBT patients were included. Intermediate risk group (81.2 vs. 68.2%; p < 0.001) and median age at diagnosis (70 vs. 67 years; p < 0.001) were higher in the IMRT group. On MVA, there was no significant difference between modalities. PBT IPSS did not differ from IMRT IPSS at 12 months (odds ratio [OR], 1.19; p = 0.08) or 24 months (OR, 0.99; p = 0.94). PBT EPIC overall GI function at 12 months (OR, 3.68; p = 0.085) and 24 months (OR 2.78; p = 0.26) did not differ from IMRT EPIC overall GI function. At 24 months, urinary frequency was no different between PBT and IMRT groups (OR 0.35; p = 0.096). CONCLUSIONS: This multi-institutional analysis of low- or intermediate-risk PC treated with moderately hypofractionated PBT and IMRT demonstrated low rates of late patient-reported GI and GU toxicities. After covariate adjustment, late GI and GU PROs were not significantly different between PBT or IMRT cohorts.

Outcomes of patients with blastoid and pleomorphic variant mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival.

Cost-Effectiveness Analysis for Therapy Sequence in Advanced Cancer: A Microsimulation Approach with Application to Metastatic Prostate Cancer.

PURPOSE: Patients with advanced cancer may undergo multiple lines of treatment, switching therapies as their disease progresses. We developed a general microsimulation framework to study therapy sequence and applied it to metastatic prostate cancer. METHODS: We constructed a discrete-time state transition model to study 2 lines of therapy. Using digitized published survival curves (progression-free survival, time to progression, and overall survival [OS]), we inferred event types (progression or death) and estimated transition probabilities using cumulative incidence functions with competing risks. We incorporated within-patient dependence over time; first-line therapy response informed subsequent event probabilities. Parameters governing within-patient dependence calibrated the model-based results to a target clinical trial. We applied these methods to 2 therapy sequences for metastatic prostate cancer, wherein both docetaxel (DCT) and abiraterone acetate (AA) are appropriate for either first- or second-line treatment. We assessed costs and quality-adjusted life-years (5-y QALYs) for 2 treatment strategies: DCT → AA versus AA → DCT. RESULTS: Models assuming within-patient independence overestimated OS time, which corrected with the calibration approach. With generic pricing, AA → DCT dominated DCT → AA, (higher 5-y QALYs and lower costs), consistent for all values of calibration parameters (including no correction). Model calibration increased the difference in 5-y QALYs between treatment strategies (0.07 uncorrected v. 0.15 with base-case correction). Applying the correction decreased the estimated difference in cost (-$5,360 uncorrected v. -$3,066 corrected). Results were strongly affected by the cost of AA. Under a lifetime horizon, AA → DCT was no longer dominant but still cost-effective (incremental cost-effectiveness ratio: $19,463). CONCLUSIONS: We demonstrate a microsimulation approach to study the cost-effectiveness of therapy sequences for advanced prostate cancer, taking care to account for within-patient dependence. HIGHLIGHTS: We developed a discrete-time state transition model for studying therapy sequence in advanced cancers.Results are sensitive to dependence within patients.A calibration approach can introduce dependence across lines of therapy and closely match simulation outcomes to target trial outcomes.

Development of a Multilevel Model to Identify Patients at Risk for Delay in Starting Cancer Treatment.

Importance: Delays in starting cancer treatment disproportionately affect vulnerable populations and can influence patients' experience and outcomes. Machine learning algorithms incorporating electronic health record (EHR) data and neighborhood-level social determinants of health (SDOH) measures may identify at-risk patients. Objective: To develop and validate a machine learning model for estimating the probability of a treatment delay using multilevel data sources. Design, Setting, and Participants: This cohort study evaluated 4 different machine learning approaches for estimating the likelihood of a treatment delay greater than 60 days (group least absolute shrinkage and selection operator [LASSO], bayesian additive regression tree, gradient boosting, and random forest). Criteria for selecting between approaches were discrimination, calibration, and interpretability/simplicity. The multilevel data set included clinical, demographic, and neighborhood-level census data derived from the EHR, cancer registry, and American Community Survey. Patients with invasive breast, lung, colorectal, bladder, or kidney cancer diagnosed from 2013 to 2019 and treated at a comprehensive cancer center were included. Data analysis was performed from January 2022 to June 2023. Exposures: Variables included demographics, cancer characteristics, comorbidities, laboratory values, imaging orders, and neighborhood variables. Main Outcomes and Measures: The outcome estimated by machine learning models was likelihood of a delay greater than 60 days between cancer diagnosis and treatment initiation. The primary metric used to evaluate model performance was area under the receiver operating characteristic curve (AUC-ROC). Results: A total of 6409 patients were included (mean [SD] age, 62.8 [12.5] years; 4321 [67.4%] female; 2576 [40.2%] with breast cancer, 1738 [27.1%] with lung cancer, and 1059 [16.5%] with kidney cancer). A total of 1621 (25.3%) experienced a delay greater than 60 days. The selected group LASSO model had an AUC-ROC of 0.713 (95% CI, 0.679-0.745). Lower likelihood of delay was seen with diagnosis at the treating institution; first malignant neoplasm; Asian or Pacific Islander or White race; private insurance; and lacking comorbidities. Greater likelihood of delay was seen at the extremes of neighborhood deprivation. Model performance (AUC-ROC) was lower in Black patients, patients with race and ethnicity other than non-Hispanic White, and those living in the most disadvantaged neighborhoods. Though the model selected neighborhood SDOH variables as contributing variables, performance was similar when fit with and without these variables. Conclusions and Relevance: In this cohort study, a machine learning model incorporating EHR and SDOH data was able to estimate the likelihood of delays in starting cancer therapy. Future work should focus on additional ways to incorporate SDOH data to improve model performance, particularly in vulnerable populations.

Conditional Dependency of LP-184 on Prostaglandin Reductase 1 is Synthetic Lethal in Pancreatic Cancers with DNA Damage Repair Deficiencies.

The greater efficacy of DNA-damaging drugs for pancreatic adenocarcinoma (PDAC) relies on targeting cancer-specific vulnerabilities while sparing normal organs and tissues due to their inherent toxicities. We tested LP-184, a novel acylfulvene analog, for its activity in preclinical models of PDAC carrying mutations in the DNA damage repair (DDR) pathways. Cytotoxicity of LP-184 is solely dependent on prostaglandin reductase 1 (PTGR1), so that PTGR1 expression robustly correlates with LP-184 cytotoxicity in vitro and in vivo. Low-passage patient-derived PDAC xenografts with DDR deficiencies treated ex vivo are more sensitive to LP-184 compared with DDR-proficient tumors. Additional in vivo testing of PDAC xenografts for their sensitivity to LP-184 demonstrates marked tumor growth inhibition in models harboring pathogenic mutations in ATR, BRCA1, and BRCA2. Depletion of PTGR1, however, completely abrogates the antitumor effect of LP-184. Testing combinatorial strategies for LP-184 aimed at deregulation of nucleotide excision repair proteins ERCC3 and ERCC4 established synergy. Our results provide valuable biomarkers for clinical testing of LP-184 in a large subset of genetically defined characterized refractory carcinomas. High PTGR1 expression and deleterious DDR mutations are present in approximately one third of PDAC making these patients ideal candidates for clinical trials of LP-184.

Clinical Performance of Technetium-99m-Sestamibi SPECT/CT Imaging in Differentiating Oncocytic Tumors From Renal Cell Carcinoma in Routine Clinical Practice.

PURPOSE: Technetium-99m-sestamibi single-photon emission CT/x-ray CT is an emerging clinical tool to differentiate oncocytic tumors from renal cell carcinomas. We report data from a large institutional cohort of patients who underwent technetium-99m-sestamibi scans during evaluation of renal masses. MATERIALS AND METHODS: Patients who underwent technetium-99m-sestamibi single-photon emission CT/x-ray CT between February 2020 and December 2021 were included in the analysis. Scans were defined as "hot" for oncocytic tumor when technetium-99m-sestamibi uptake was qualitatively equivalent or higher between the mass of interest and normal renal parenchyma, suggesting oncocytoma, hybrid oncocytic/chromophobe tumor, or chromophobe renal cell carcinoma. Demographic, pathological, and management strategy data were compared between "hot" and "cold" scans. For individuals who underwent diagnostic biopsy or extirpative procedures, the concordance between radiological findings and pathology was indexed. RESULTS: A total of 71 patients (with 88 masses) underwent technetium-99m-sestamibi imaging with 60 (84.5%) patients having at least 1 "cold" mass on imaging and 11 (15.5%) patients exhibiting only "hot" masses. Pathology was available for 7 "hot" masses, with 1 biopsy specimen (14.3%) being discordant (clear cell renal cell carcinoma). Five patients with "cold" masses underwent biopsy. Out of 5 biopsied masses, 4 (80%) were discordant oncocytomas. Of the extirpated specimens, 35/40 (87.5%) harbored renal cell carcinoma and 5/40 (12.5%) yielded discordant oncocytomas. In sum, 20% of pathologically sampled masses that were "cold" on technetium-99m-sestamibi imaging still harbored oncocytoma/hybrid oncocytic/chromophobe tumor/chromophobe renal cell carcinoma. CONCLUSIONS: Further work is needed to define utility of technetium-99m-sestamibi in real-world clinical practice. Our data suggest this imaging strategy is not yet ready to replace biopsy.

Venous thromboembolism in metastatic pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) carries a high risk of venous thromboembolism (VTE). Several risk assessment models (RAMs) predict benefit of thromboprophylaxis in solid tumors; however, none are verified in metastatic pancreatic cancer (mPC). METHODS: A retrospective mPC cohort treated at an academic cancer center from 2010 to 2016 was investigated for VTE incidence (VTEmets). Multivariable regression analysis was used to assess multiple VTE risk factors. Overall survival (OS) was compared between mPC groups with and without VTE. Survival was analyzed using Kaplan-Meier survival plots and Cox proportional hazards regressions. RESULTS: 400 mPC patients (median age 66; 52% males) were included. 87% had performance status of ECOG 0-1; 70% had advanced stage at PC diagnosis. Incidence of VTEmets was 17.5%; median time of occurrence 3.48 months after mPC diagnosis. Survival analysis started at median VTE occurrence. Median OS was 10.5 months in VTEmets vs. 13.4 in non-VTE group. Only advanced stage (OR 3.7, p = .001) correlated with increased VTE risk. CONCLUSIONS: The results suggest mPC carries a significant VTE burden. VTE predicts poor outcomes from the point of median VTE occurrence. Advanced stage disease is the strongest risk factor. Future studies are needed to define risk stratification, survival benefit, and choice of thromboprophylaxis.

Psychosocial needs of older patients with metastatic breast cancer treated at community centers.

INTRODUCTION: Psychosocial status contributes to overall quality of life (QOL) for patients with cancer as psychosocial distress is commonly seen in this population. We sought to describe the psychosocial needs of older adults with metastatic breast cancer (MBC) treated in the community. We evaluated the correlation between the patient's psychosocial status and the presence of other geriatric abnormalities in this patient population. MATERIALS AND METHODS: This is a secondary analysis of a completed study evaluating older adults (≥65 years) with MBC treated at community practices who received a geriatric assessment (GA). This analysis evaluated psychosocial factors collected during GA, including depression assessed by Geriatric Depression Scale (GDS), perceived social support (SS) assessed by Medical Outcomes Study Social Support Survey (MOS), and objective social supportassessed by demographic variables (living situation and marital status). Perceived SS was further subdivided into tangible social support (TSS) and emotional social support (ESS). Kruskal-Wallis tests, Wilcoxon tests, and Spearman's correlations were used to assess the relationship between psychosocial factors, patient characteristics, and geriatric abnormalities. RESULTS: One hundred older patients with MBC were enrolled and completed GA with a median age of 73 years (65-90). Almost half of the participants (47%) were either single, divorced, or widowed and 38% lived alone, demonstrating a significant number of patients with objective social support deficits. Patients with HER2+ or triple negative MBC had lower overall SS scores compared to patients with ER/PR+ or HER2- MBC (p = 0.033). Patients on fourth line of therapy were more likely to screen positive for depression compared to patients on earlier lines of therapy (p = 0.047). About half (51%) of the patients indicated at least one SS deficit on the MOS. A higher GDS and lower MOS score correlated with greater total GA abnormalities (p = 0.016). Evidence of depression correlated with poor functional status, decreased cognition, and a high number of co-morbidities (p < 0.005). Abnormalities in functional status, cognition, and high GDS are associated with lower ESS (p = 0.025,0.031,0.006 respectively). DISCUSSION: Psychosocial deficits are common among older adults with MBC treated in the community and are associated with the presence of other geriatric abnormalities. These deficits require a thorough evaluation and management to optimize treatment outcomes.

Distinguishing lipid-poor angiomyolipoma from renal carcinoma using tumor shape.

OBJECTIVES: To validate the "overflowing beer sign" (OBS) for distinguishing between lipid-poor angiomyolipoma (AML) and renal cell carcinoma, and to determine whether it improves the detection of lipid-poor AML when added to the angular interface sign, a previously-validated morphologic feature associated with AML. METHODS: Retrospective nested case-control study of all 134 AMLs in an institutional renal mass database matched 1:2 with 268 malignant renal masses from the same database. Cross-sectional imaging from each mass was reviewed and the presence of each sign was identified. A random selection of 60 masses (30 AML and 30 benign) was used to measure interobserver agreement. RESULTS: Both signs were strongly associated with AML in the total population (OBS: OR 17.4 95% CI 8.0-42.5, p < 0.001; angular interface: OR 12.6, 95% CI 5.9-29.7, p < 0.001) and the population of patients excluding those with visible macroscopic fat (OBS: OR 11.2, 95% CI 4.8-28.7, p < 0.001; angular interface: 8.5, 95% CI 3.7-21.1, p < 0.001). In the lipid-poor population, the specificity of both signs was excellent (OBS: 95.6%, 95% CI 91.9%-98%; angular interface: 95.1%, 95% CI 91.3%-97.6%). Sensitivity was low for both signs (OBS: 31.4%, 95% CI 24.0-45.4%; angular interface: 30.5%, 95% CI 20.8%-41.6%). Both signs showed high levels of inter-rater agreement (OBS 90.0% 95% CI 80.5 - 95.9; angular interface 88.6, 95% CI 78.7-94.9) Testing for AML using the presence of either sign in this population improved sensitivity (39.0%, 95% CI 28.4%-50.4%, p = 0.023) without significantly reducing specificity (94.2%, 95% CI 90%-97%, p = 0.2) relative to the angular interface sign alone. CONCLUSIONS: Recognition of the OBS increases the sensitivity of detection of lipid-poor AML without significantly reducing specificity.

Starting the Conversation: randomized pilot trial of an intervention to promote effective clinical communication about sexual health for gynecologic cancer survivors.

PURPOSE: Gynecologic cancer survivors often hesitate to raise sexual health concerns with their clinicians. We pilot tested Starting the Conversation (STC), a theory-guided intervention aimed at facilitating survivors' clinical communication about sexual health. METHODS: Survivors (N = 32) were randomized 2:1 to STC (23-min video and accompanying workbook grounded in social cognitive theory that provides information and skills training for communicating with providers about sexual concerns, and resource guide) or control (resource guide only). Feasibility was assessed through enrollment, retention, and intervention completion rates (benchmarks: 60%, 80%, 70%); acceptability was assessed through post-intervention program evaluations (benchmark: 75%). Preliminary effects were assessed for sexual health communication (self-reported after next clinic encounter), self-efficacy for clinical communication about sexual health (post-intervention and 2-month follow-up), and sexual activity and anxiety/depressive symptoms (2-month follow-up). RESULTS: All feasibility/acceptability benchmarks were surpassed; 76% enrolled, 97% retained, ≥ 95% used intervention materials, and 100% endorsed STC as acceptable. Positive STC effects were seen for increases in self-efficacy (Cohen's d's = 0.45 at post-intervention; 0.55 at follow-up). In STC, 35% and 45% of women raised or asked about sexual health concerns during the post-intervention clinic visit, respectively, versus 0 and 27% in the control arm. Other measures showed little change. CONCLUSIONS: Data support the STC intervention as feasible and acceptable, with promising effects for gynecologic cancer survivors' communication about sexual health concerns. Because sexual health communication is relevant across the treatment trajectory, we included both on-treatment and post-treatment survivors. While this may be a limitation, it could also enhance sample generalizability. A larger trial is needed to determine efficacy. IMPLICATIONS FOR CANCER SURVIVORS: Communication about sexual health is important yet lacking for cancer survivors. Patient-focused interventions may help address concerns and improve survivors' health outcomes.

Neoadjuvant Chemotherapy with Accelerated Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Patients with Muscle-invasive Bladder Cancer: A Retrospective Age-stratified Analysis on Safety and Efficacy.

BACKGROUND: The standard of care (SOC) for muscle-invasive bladder cancer (MIBC) includes cisplatin-based combination chemotherapy in the neoadjuvant setting followed by radical cystectomy. Older patients often do not receive SOC due to perceived toxicity concerns despite guideline-directed recommendations. OBJECTIVE: To characterize the safety and efficacy of neoadjuvant accelerated methotrexate, vinblastine, adriamycin, and cisplatin (aMVAC) in MIBC patients as a function of age. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was conducted in 186 MIBC patients treated at Fox Chase Cancer Center between January 1, 2002 and December 31, 2018. Adults with histologically proven muscle-invasive urothelial cancer were eligible. The exclusion criteria included nonurothelial histology, lack of muscularis propria invasion, and primary upper tract or metastatic disease. INTERVENTION: Neoadjuvant chemotherapy with aMVAC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients were stratified by age (<65, 65-74, and >75 yr old). Renal function was assessed at baseline and at time points after treatment. Clinicopathologic variables were compared between age groups to determine efficacy. RESULTS AND LIMITATIONS: There were no statistically significant differences in dose reductions, treatment interruptions, time to surgery, or adverse events when patients were stratified by age in univariate and multivariate analyses. Full safety data were not available due to the retrospective nature of the study. Baseline renal function was significantly worse among older patients, and the percent decline in creatinine clearance was greater with older age. We found comparable efficacy of aMVAC regardless of age. CONCLUSIONS: Accelerated MVAC was safe and demonstrated efficacy in MIBC irrespective of age in this single-center, retrospective study. Careful selection based on clinical variables, and not age, should identify patients able to receive neoadjuvant chemotherapy. PATIENT SUMMARY: We examined the feasibility of the standard cisplatin-based chemotherapy regimen given prior to surgery in patients with muscle-invasive bladder cancer. Elderly patients experienced a greater decline in kidney function with treatment but not more complications than younger patients and tolerated therapy with minimal dose changes, resulting in benefit regardless of age.

Real-world progression-free survival (rwPFS) and the impact of PD-L1 and smoking in driver-mutated non-small cell lung cancer (NSCLC) treated with immunotherapy.

PURPOSE: Prior data suggest driver-mutated NSCLC, especially EGFR and ALK tumors, poorly respond to immunotherapy. However, little research using real-world cohorts have been performed, nor is it clear whether PD-L1 and smoking history are predictive of outcomes in such tumors. This study assessed rwPFS in a large cohort with driver-mutated advanced NSCLC treated with single-agent PD-1/PDL-1 inhibitors. METHODS: Real-world data from 1746 patients were analyzed and rwPFS with immunotherapy was determined for EGFR, ALK, BRAF, and KRAS tumors. Kaplan-Meier curves characterized rwPFS and correlated with PD-L1 and smoking history. Comparisons were tested using log-rank. RESULTS: Median rwPFS and the percent progression-free at 12 months were greater among KRAS (3.3 months, 21.1%) and BRAF (3.6 months, 20.6%) as compared to EGFR (2.5 months, 8.1%) and ALK tumors (2.3 months, 11.2%). KRAS tumors with PD-L1 ≥ 1% had longer rwPFS than PD-L1 < 1% tumors (4.1 versus 3.2 months, p = 0.001). PD-L1 positivity did not predict rwPFS in EGFR, ALK, or BRAF tumors. However, a smoking history was associated with longer rwPFS in EGFR (2.6 versus 2.3 months, p = 0.048) and ALK tumors (3.0 versus 2.1 months, p = 0.049) as compared to no smoking history. CONCLUSION: Real-world PFS with immunotherapy was greater in KRAS and BRAF as compared to EGFR and ALK tumors. PD-L1 positivity was predictive in KRAS and not associated with rwPFS in other mutation types. While median rwPFS was short for EGFR and ALK tumors, small subsets were progression-free at 12 months. Better characterizing these subsets that benefit, along with developing strategies to overcome immunotherapy resistance in EGFR/ALK tumors are needed.