Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) tumors have a nutrient-poor, desmoplastic, and highly innervated tumor microenvironment. Although neurons can release stimulatory factors to accelerate PDAC tumorigenesis, the metabolic contribution of peripheral axons has not been explored. We found that peripheral axons release serine (Ser) to support the growth of exogenous Ser (exSer)-dependent PDAC cells during Ser/Gly (glycine) deprivation. Ser deprivation resulted in ribosomal stalling on two of the six Ser codons, TCC and TCT, and allowed the selective translation and secretion of nerve growth factor (NGF) by PDAC cells to promote tumor innervation. Consistent with this, exSer-dependent PDAC tumors grew slower and displayed enhanced innervation in mice on a Ser/Gly-free diet. Blockade of compensatory neuronal innervation using LOXO-101, a Trk-NGF inhibitor, further decreased PDAC tumor growth. Our data indicate that axonal-cancer metabolic crosstalk is a critical adaptation to support PDAC growth in nutrient poor environments.

Distinguishing Clinical From Statistical Significances in Contemporary Comparative Effectiveness Research.

OBJECTIVE: To determine the prevalence of clinical significance reporting in contemporary comparative effectiveness research (CER). BACKGROUND: In CER, a statistically significant difference between study groups may or may not be clinically significant. Misinterpreting statistically significant results could lead to inappropriate recommendations that increase health care costs and treatment toxicity. METHODS: CER studies from 2022 issues of the Annals of Surgery , Journal of the American Medical Association , Journal of Clinical Oncology , Journal of Surgical Research , and Journal of the American College of Surgeons were systematically reviewed by 2 different investigators. The primary outcome of interest was whether the authors specified what they considered to be a clinically significant difference in the "Methods." RESULTS: Of 307 reviewed studies, 162 were clinical trials and 145 were observational studies. Authors specified what they considered to be a clinically significant difference in 26 studies (8.5%). Clinical significance was defined using clinically validated standards in 25 studies and subjectively in 1 study. Seven studies (2.3%) recommended a change in clinical decision-making, all with primary outcomes achieving statistical significance. Five (71.4%) of these studies did not have clinical significance defined in their methods. In randomized controlled trials with statistically significant results, sample size was inversely correlated with effect size ( r = -0.30, P = 0.038). CONCLUSIONS: In contemporary CER, most authors do not specify what they consider to be a clinically significant difference in study outcome. Most studies recommending a change in clinical decision-making did so based on statistical significance alone, and clinical significance was usually defined with clinically validated standards.

Superior Outcomes of Dual-Arterial Coronary Artery Bypass Grafting Are Maintained in the Veterans Health Administration.

INTRODUCTION: Controversy surrounds the long-term clinical benefit of coronary artery bypass grafting (CABG) using dual arterial grafts (DAGs) compared to single arterial grafts (SAGs). We investigated outcomes of DAG, using single internal thoracic artery and radial artery (DAG-RA) or bilateral internal thoracic artery grafts (DAG-BITA), compared to SAG, using the left internal thoracic artery and saphenous vein grafts, in the U.S. Veterans Health Administration (VA). METHODS: We conducted a cross-sectional study of U.S. Veterans undergoing isolated on-pump CABG between 2005 and 2015 at 44 VA medical centers. The primary composite outcome was first occurrence of a major adverse cardiac and cerebrovascular event (MACCE), comprised of death from any cause, myocardial infarction, stroke, or repeat revascularization. RESULTS: Among 25,969 Veterans undergoing isolated CABG, 1261 (4.9%) underwent DAG (66.8% DAG-RA and 33.2% DAG-BITA). Over a 5-y follow-up, DAG was associated with lower rates of all-cause death (adjusted hazard ratio [AHR] 0.70, 95% confidence interval [CI] 0.58-0.85), MACCE (AHR 0.80, 95% CI 0.71-0.91), and stroke (AHR 0.74, 95% CI 0.57-0.96) versus SAG. DAG-BITA was associated with lower rates of all-cause death (AHR 0.52, 95% CI 0.35-0.77) and MACCE (AHR 0.66, 95% CI 0.51-0.84) than SAG, while DAG-RA was associated with lower rates of all-cause death (AHR 0.79, 95% CI 0.64-0.99). CONCLUSIONS: In the VA, DAG was associated with improved long-term MACCE outcomes compared to SAG. These results suggest that the practice of DAG in the VA benefits Veterans and should be promoted further.

Norepinephrine transporter and vesicular monoamine transporter 2 tumor expression as a predictor of response to 131 I-MIBG in patients with relapsed/refractory neuroblastoma.

BACKGROUND: Prior studies suggest that norepinephrine transporter (NET) and vesicular monoamine transporter 2 (VMAT2) mediate meta-iodobenzylguanidine (MIBG) uptake and retention in neuroblastoma tumors. We evaluated the relationship between NET and VMAT2 tumor expression and clinical response to 131 I-MIBG therapy in patients with neuroblastoma. METHODS: Immunohistochemistry (IHC) was used to evaluate NET and VMAT2 protein expression levels on archival tumor samples (obtained at diagnosis or relapse) from patients with relapsed or refractory neuroblastoma treated with 131 I-MIBG. A composite protein expression H-score was determined by multiplying a semi-quantitative intensity value (0-3+) by the percentage of tumor cells expressing the protein. RESULTS: Tumor samples and clinical data were available for 106 patients, of whom 28.3% had partial response (PR) or higher. NET H-score was not significantly associated with response (≥PR), though the percentage of tumor cells expressing NET was lower among responders (median 80% for ≥PR vs. 90% for

Postoperative Troponin Levels in Children Undergoing Open Heart Surgery With and Without Coronary Intervention.

We aimed to characterize the ranges, temporal trends, influencing factors, and prognostic significance of postoperative troponin levels after congenital heart surgery. This single-center retrospective study included patients from 2006 to 2021 who had ≥ 1 postoperative troponin-T measurement collected within 96 h of congenital heart surgery (CHS). Patients were grouped as Anomalous Aortic Origin of the Coronary Artery-"AAOCA repair," or congenital heart surgery with "Other Coronary Interventions" other than AAOCA repair, or "No Coronary Intervention." In each group, information on concomitant surgery requiring one or more of the following-atriotomy, ventriculotomy, right ventricular muscle bundle resection, and/or septal myectomy-was collected. Clinical correlates of troponin values were analyzed in three postoperative windows: < 8, 8-24, and 24-48 h. The highest median [range] troponin levels (ng/mL) for the samples were 0.34 [0.06, 1.32] at < 8 h for "AAOCA repair," 1.35 [0.14, 12.0] at < 8 h for those undergoing CHS with "Other Coronary Interventions," and 0.87 [0.06, 25.1] at 8-24 h for those undergoing CHS with "No Coronary Interventions." Atriotomy was associated with higher median troponin levels in the AAOCA group at < 8 h (0.40 [0.31, 0.77] vs. 0.29 [0.17, 0.54], P = 0.043) and in the Other Coronary Intervention group at 8-24 h (1.67 [1.04, 2.63] vs. 0.40 [0.19, 1.32], P = 0.002). Patients experiencing major postoperative complications (vs. those who did not) had higher troponin levels in the AAOCA group as early as 8-24 h (0.36 [0.24, 0.57] vs. 0.21 [0.14, 0.33], P = 0.03). Similar findings were noted in the Coronary Intervention (2.20 [1.34, 3.90] vs. 1.11 [0.51, 2.90], P = 0.028) and No Coronary Intervention (2.2 [1.49, 15.1] vs. 0.74 [0.40, 2.34], P = 0.027) groups but earlier at < 8 h. In the AAOCA group, 2/18 (11%) troponin outliers experienced cardiac arrest in comparison to 0/80 (0%) non-outliers (P = 0.032). In the Other Coronary Intervention group, troponin outliers had longer median times to ICU discharge (10 vs. 4 days) and hospital discharge (21 vs. 10 days) (both P < 0.001). Postoperative troponin levels depend on a multitude of factors and may have prognostic value in patients undergoing congenital heart surgery with coronary interventions.

Perioperative risks associated with administration of andexanet alfa during emergency cardiac surgery with circulatory arrest.

This case report describes the perioperative course of a patient undergoing emergency repair of acute type A thoracic aortic dissection. Andexanet alfa was administered intraoperatively to obtain a dry operative field for right axillary artery exposure and cannulation. Andexanet alfa-induced heparin resistance resulted in cardiopulmonary bypass circuit and pericardial thrombosis requiring more than 400,000 units of unfractionated heparin and antithrombin III to overcome. Postoperatively, excessive chest tube output was observed secondary to protracted heparin rebound requiring continuous dosing of protamine. This case demonstrates the significant challenging perioperative, not just intraoperative, hazards associated with intraoperative andexanet alfa use during emergency cardiac surgery with cardiopulmonary bypass.

The Role of NCOA4-Mediated Ferritinophagy in Ferroptosis.

Nuclear receptor coactivator 4 (NCOA4) is a selective cargo receptor that mediates the autophagic degradation of ferritin, the cytosolic iron storage complex, in a process known as ferritinophagy. NCOA4-mediated ferritinophagy is required to maintain intracellular and systemic iron homeostasis and thereby iron-dependent physiologic processes such as erythropoiesis. Given this role of ferritinophagy in regulating iron homeostasis, modulating NCOA4-mediated ferritinophagic flux alters sensitivity to ferroptosis, a non-apoptotic iron-dependent form of cell death triggered by peroxidation of polyunsaturated fatty acids (PUFAs). A role for ferroptosis has been established in the pathophysiology of cancer and neurodegeneration; however, the importance of ferritinophagy in these pathologies remains largely unknown. Here, we review the available evidence on biochemical regulation of NCOA4-mediated ferritinophagy and its role in modulating sensitivity to innate and induced ferroptosis in neurodegenerative diseases and cancer. Finally, we evaluate the potential of modulating ferritinophagy in combination with ferroptosis inducers as a therapeutic strategy.

Right ventricular papillary muscle approximation to the septum as an adjunct technique during tricuspid valve repair in congenital heart surgery.

OBJECTIVE: Tricuspid regurgitation is often caused by leaflet splaying from displaced papillary muscles or ventricular dilatation. Traditional annuloplasty may not address this mechanism. The present study describes a single institution's experience using right ventricular papillary muscle approximation for tricuspid valve repair. METHODS: Right ventricular papillary muscle approximation consists of suturing the anterior papillary muscle to a point of the septum (septum or septal papillary muscle) that optimizes leaflet coaptation. We describe our technique and analyze clinical data of patients undergoing tricuspid valve repair with right ventricular papillary muscle approximation during congenital heart surgery between 2012 and 2021. RESULTS: Right ventricular papillary muscle approximation was performed as an adjunct procedure in 207 of 825 tricuspid valve repairs (25.1%). Discharge tricuspid regurgitation grade was mild tricuspid regurgitation or less in 153 patients (73.9%), and 140 patients (67.6%) had mild tricuspid regurgitation or less at a median latest follow-up of 3.2 years (interquartile range, 0.7-6.8). Thirty patients (14.5%) underwent 11 early tricuspid valve reinterventions (3 due to right ventricular papillary muscle approximation dehiscence) and 21 late tricuspid valve reinterventions. Estimated 5-year freedom from tricuspid valve reintervention was 84% (95% CI, 77.0-89.2). Systemic right ventricle physiology (odds ratio, 2.88, P = .048) and multiple mechanisms of tricuspid regurgitation (odds ratio, 7.35, P = .038) were significant predictors of tricuspid valve reintervention on multivariable analysis. CONCLUSIONS: Tricuspid valve repair with right ventricular papillary muscle approximation demonstrates acceptable short-term durability, but similar to other tricuspid valve repair strategies is less durable in patients with systemic right ventricle pressure and multiple mechanisms of tricuspid regurgitation. Right ventricular papillary muscle approximation is a safe and effective adjunct technique that should be considered in patients with tricuspid regurgitation caused by leaflet splaying from displaced papillary muscles or right ventricle dilatation.

Chronic Total Occlusions and Coronary Artery Bypass Grafting Outcomes.

OBJECTIVE: Investigate the association between the presence and grafting of chronic total occlusions (CTO) and coronary artery bypass grafting (CABG) outcomes. METHODS: This was a post hoc analysis of the REGROUP trial, which randomized veterans undergoing isolated on-pump CABG to endoscopic versus open vein harvest (2014-2017). Patients were stratified based on the presence of at least one CTO vessel (a 100% occluded coronary lesion for greater than or equal to 3 months), and according to whether all CTO vessels were bypassed. Rates of major cardiac adverse events (MACE) were compared. RESULTS: At least 1 CTO was present in 453/1,149 patients (39.4%). Over a median follow up of 4.7 years (interquartile range 3.84-5.45), MACE rates were 23.4% vs. 22.2% for the CTO vs. no CTO group, respectively (adjusted hazard ratio [AHR] 0.92, 95% CI 0.70-1.20). MACE rates for patients with complete CTO grafting vs. not were 23.1% vs. 25.0%, respectively (AHR 0.95, 95% CI 0.57-1.57) . In patients with right coronary dominance undergoing LAD grafting, bypassing a RCA CTO was associated with significantly lower rates of all-cause mortality (AHR 0.38, 95% CI 0.17-0.83). CONCLUSIONS: In this REGROUP trial subanalysis, neither CTO presence or complete grafting of CTO vessels were associated with significantly different rates of MACE. However, the finding of possible survival benefit among a subgroup of patients undergoing grafting of a dominant RCA CTO vessel alongside LAD grafting warrants additional study.

Off-label prescribing of immune checkpoint inhibitor therapy at a single pediatric cancer center.

BACKGROUND: Immune checkpoint inhibitors (ICI) have improved outcomes in a variety of adult cancers and are prescribed with increasing frequency across oncology. However, patterns of off-label use of ICI in pediatrics remain unclear. METHODS: This is a single-institution, retrospective cohort study evaluating off-label ICI use in pediatric and young adult patients with cancer treated at our institution from 2014 to 2022. Response was based on clinician assessment derived from clinical records. Immune-related adverse events (iRAEs) were classified according to CTCAE v5.0. RESULTS: We identified 50 unique patients treated with off-label ICI (28 with solid tumors, 20 with central nervous system (CNS) tumors, 2 with hematologic malignancies). At time of ICI initiation, only five patients (10%) had localized disease, and all but one patient was treated in the relapsed/refractory setting. All patients were treated with the FDA-approved weight-based dosing recommendations. Overall, there was disease control in 21 patients (42%), with best response including one complete response (melanoma), two partial responses (high-grade glioma, CNS nongerminomatous germ cell tumor), and 18 patients with stable disease. Forty-four patients (88%) eventually experienced disease progression. Among 22 patients (44%) experiencing iRAEs, 10 (20%) had a grade ≥3 irAE, 12 (24%) required corticosteroids, and 14 (28%) required ICI discontinuation. irAE occurrence was associated with significantly improved progression-free survival (HR 0.35; 95% CI: 0.18 to 0.68; p = 0.002) and overall survival (HR 0.33; 95% CI: 0.17 to 0.66; p = 0.002). CONCLUSIONS: At our institution, ICI was most commonly prescribed in the relapsed/refractory setting to patients with metastatic disease. The treatment was generally well-tolerated in the pediatric population. The overall response rate was low, and the majority of patients eventually experienced disease progression. A few patients, however, had durable treatment responses. Further studies are needed to identify which pediatric patients are most likely to benefit from ICI.

Do Complications After Pancreatoduodenectomy Have an Impact on Long-Term Quality of Life and Functional Outcomes?

Objective: Our aim was to assess whether complications after pancreatoduodenectomy (PD) impact long-term quality of life (QoL) and functional outcomes. Background: There is an increasing number of long-term post-PD survivors, but few studies have evaluated long-term QoL outcomes. Methods: The EORTC QLQ-C30 and QLQ-PAN26 questionnaires were administered to patients who survived >5 years post-PD. Clinical relevance (CR) was scored as small (5-10), moderate (10-20), or large (>20). Patients were stratified based on whether they experienced a complication during the index hospitalization. Results: Of 305 patients >5 years post-PD survivors, with valid contact information, 248 completed the questionnaires, and 231 had complication data available. Twenty-nine percent of patients experienced a complication, of which 17 (7.4%) were grade 1, 27 (11.7%) were grade 2, and 25 (10.8%) were grade 3. Global health status and functional domain scores were similar between both groups. Patients experiencing complications reported lower fatigue (21.4 vs 28.1, P < 0.05, CR small) and diarrhea (15.9 vs 23.1, P < 0.05, CR small) symptom scores when compared to patients without complications. Patients experiencing complications also reported lower pancreatic pain (38.2 vs 43.4, P < 0.05, CR small) and altered bowel habits (30.1 vs 40.7, P < 0.01, CR moderate) symptom scores. There was a lower prevalence of worrying (36.2% vs 60.5%, P < 0.05) and bloating (42.0% vs 56.2%, P < 0.05) among PD survivors with complications. Conclusions: Post-PD complication rates were not associated with long-term global QoL or functionality, and may be associated with less severe pancreas-specific symptoms.

Performance of left internal thoracic artery-left anterior descending artery anastomosis by residents versus attendings and coronary artery bypass grafting outcomes.

OBJECTIVES: Performance of a technically sound left internal thoracic artery to left anterior descending artery (LITA-LAD) anastomosis during coronary artery bypass grafting (CABG) is critically important. We used prospectively collected data from the multicentre, randomized REGROUP (Randomized Endograft Vein Perspective) trial to investigate CABG outcomes based on whether a resident or an attending surgeon performed the LITA-LAD anastomosis. METHODS: This was a post hoc subanalysis of the REGROUP trial, which randomized veterans undergoing isolated on-pump CABG to endoscopic versus open vein harvest from 2014 through 2017. The primary end point was major cardiac adverse events, defined as the composite of all-cause deaths, nonfatal myocardial infarctions or repeat revascularizations. RESULTS: Among 1,084 patients, 344 (31.8%) LITA-LAD anastomoses were performed by residents and 740 (68.2%), by attending surgeons. Residents (compared to attendings) operated on fewer patients with high tercile SYNTAX scores (22.1% vs 37.4%, P < 0.001), performed fewer multiarterial CABGs (5.2% vs 14.6%, P < 0.001) and performed more anastomoses to distal targets with diameters > 2.0 mm (19.0% vs 10.9%, P < 0.001) and non-calcified landing zones (25.1% vs 21.6%, P < 0.001). During a median observation time of 4.7 years (interquartile range 3.84-5.45), major cardiac adverse events occurred in 77 patients (22.4%) in the group treated by residents and 169 patients (22.8%) in the group treated by attendings (unadjusted HR 1.00; 95% confidence interval, 0.76-1.33; P = 0.99). Outcomes persisted on adjusted analyses. CONCLUSIONS: Based on this REGROUP trial subanalysis, under careful supervision and with appropriate patient selection, LITA-LAD anastomoses performed by the residents yielded clinical outcomes similar to those of the attendings.

Surgical debulking of large ventricular fibromas in children.

OBJECTIVE: This study aims to provide an update on the clinical presentation, diagnostic workup, operative strategies, and midterm outcomes in children undergoing ventricular fibroma resection. METHODS: Single-center, retrospective cohort study of patients undergoing ventricular fibroma resection between 2000 and 2023. RESULTS: Among 52 patients, median age at surgery was 2.0 years (interquartile range, 0.8-4.6) and median tumor volume index was 69 mL/m2 (interquartile range, 49-169). Tumor distorted the atrioventricular valve/subvalvar apparatus in 30 patients (58%) and abutted major epicardial coronary arteries in 41 patients (79%). Surgery was indicated for arrythmia (n = 45, 86%), symptoms (n = 14, 27%), or hemodynamic compromise (n = 11, 21%). Tumor was debulked in 34 patients (65%), including the last 21 patients. Concomitant atrioventricular valvuloplasty was performed in 18 patients and ventricular cavity closure in 15 patients (29%). During a median follow-up of 2.4 years (interquartile range, 0.8-6.2), there was no mortality, cardiac arrests, heart transplants, or single ventricle palliation. The 15-year risk of reoperation and clinical ventricular tachycardia/fibrillation was 6.7% (95% CI, 0-14.3) and 2.4% (95% CI, 0-7.2), respectively. On latest imaging, pre- and postdebulking left ventricular ejection fraction did not significantly differ (P = .069), whereas no patients had signs of outflow tract obstruction, inflow tract obstruction, or moderate or greater atrioventricular valve regurgitation. CONCLUSIONS: Large ventricular fibromas can be resected safely with appropriate surgical planning and an emphasis on debulking. Most children maintain left ventricular function and remain free of recurrent ventricular arrhythmias at follow-up. Extended follow-up is warranted to understand whether patients remain at risk for scar-based ventricular arrhythmias in the future.

A novel multimodal, intraoperative cognitive workload assessment of cardiac surgery team members.

OBJECTIVE: To characterize cognitive workload (CWL) of cardiac surgery team members in a real-world setting during coronary artery bypass grafting (CABG) surgery using providers' heart rate variability (HRV) data as a surrogate measure of CWL. METHODS: HRV was collected from the surgeon, anesthesiologist, perfusionist, and scrub nurse, and audio/video recordings were made during isolated, nonemergency CABG surgeries (n = 27). Eight surgical phases were annotated by trained researchers, and HRV was calculated for each phase. RESULTS: Significant differences in CWL were observed within a given role across surgical phases. Results are reported as predicted probability (95% confidence interval [CI]). CWL was significantly higher for anesthesiologists during "preparation and induction" (0.57; 95% CI, 0.42-0.71) and "anastomoses" (0.44; 95% CI, 0.30-0.58) compared to other phases, and the same held for nurses during the "opening" (0.51; 95% CI, 0.37-0.65) and "postoperative" (0.68; 95% CI, 0.42-0.86) phases. Additional significant differences were observed between roles within a given surgical phase. For example, surgeons had significantly higher CWL during "anastomoses" (0.81; 95% CI, 0.69-0.89) compared to all other phases, and the same was true of perfusionists during the "opening" (0.79; 95% CI, 0.66-0.88) and "prebypass preparation" (0.50; 95% CI, 0.36-0.64) phases. CONCLUSIONS: Our innovative analysis demonstrates that CWL fluctuates across surgical procedures by role and phase, which may reflect the distribution of primary tasks. This corroborates earlier findings from self-report measures. The data suggest that team-wide, peak CWL during a phase decreases from early phases of surgery through initiation of cardiopumonary bypass (CPB), rises during anastomosis, and decreases after termination of CPB. Knowledge of these trends could encourage the adoption of behaviors to enhance team dynamics and performance.

Ewing Sarcoma Drug Therapy: Current Standard of Care and Emerging Agents.

Ewing sarcoma is a translocation-associated sarcoma mainly impacting adolescents and young adults. The classic translocation (EWSR1::FLI1) leads to a fusion oncoprotein that functions as an aberrant transcription factor. As such, the oncogenic driver of this disease has been difficult to target pharmacologically and, therefore, the systemic therapies used to treat patients with Ewing sarcoma have typically been non-selective cytotoxic chemotherapy agents. The current review highlights recent clinical trials from the last decade that provide the evidence base for contemporary drug therapy for patients with Ewing sarcoma, while also highlighting novel therapies under active clinical investigation in this disease. We review recent trials that have led to the establishment of interval-compressed chemotherapy as an international standard for patients with newly diagnosed localized disease. We further highlight recent trials that have shown a lack of demonstrable benefit from high-dose chemotherapy or IGF-1R inhibition for patients with newly diagnosed metastatic disease. Finally, we provide an overview of chemotherapy regimens and targeted therapies used in the management of patients with recurrent Ewing sarcoma.

The Colocation Model in Community Cancer Care: A Description of Patient Clinical and Demographic Attributes and Referral Pathways.

PURPOSE: Cancer disparities are well documented among Black, Indigenous, and People of Color, yet little is known about the characteristics of programs that serve these populations. Integrating specialized cancer care services within community settings is important for addressing the needs of historically marginalized populations. Our National Cancer Institute-Designated Cancer Center initiated a clinical outreach program incorporating cancer diagnostic services and patient navigation within a Federally Qualified Health Center (FQHC) to expedite evaluation and resolution of potential cancer diagnoses with the goal of collaboration between oncology specialists and primary care providers in a historically marginalized community in Boston, MA. MATERIALS AND METHODS: Sociodemographic and clinical characteristics were analyzed from patients who were referred to the program for cancer-related care between January 2012 and July 2018. RESULTS: The majority of patients self-identified as Black (non-Hispanic) followed by Hispanic (Black and White). Twenty-two percent of patients had a cancer diagnosis. Treatment and surveillance plans were established for those with and without cancer at a median time to diagnostic resolution of 12 and 28 days, respectively. The majority of patients presented with comorbid health conditions. There was a high prevalence of self-reported financial distress among patients seeking care through this program. CONCLUSION: These findings highlight the wide spectrum of cancer care concerns in historically marginalized communities. This review of the program suggests that integrating cancer evaluation services within community-based primary health care settings offers promise for enhancing the coordination and delivery of cancer diagnostic services among historically marginalized populations and could be a method to address clinical access disparities.

NCOA4-Mediated Ferritinophagy Is a Pancreatic Cancer Dependency via Maintenance of Iron Bioavailability for Iron-Sulfur Cluster Proteins.

Pancreatic ductal adenocarcinomas (PDAC) depend on autophagy for survival; however, the metabolic substrates that autophagy provides to drive PDAC progression are unclear. Ferritin, the cellular iron storage complex, is targeted for lysosomal degradation (ferritinophagy) by the selective autophagy adaptor NCOA4, resulting in release of iron for cellular utilization. Using patient-derived and murine models of PDAC, we demonstrate that ferritinophagy is upregulated in PDAC to sustain iron availability, thereby promoting tumor progression. Quantitative proteomics reveals that ferritinophagy fuels iron-sulfur cluster protein synthesis to support mitochondrial homeostasis. Targeting NCOA4 leads to tumor growth delay and prolonged survival but with the development of compensatory iron acquisition pathways. Finally, enhanced ferritinophagy accelerates PDAC tumorigenesis, and an elevated ferritinophagy expression signature predicts for poor prognosis in patients with PDAC. Together, our data reveal that the maintenance of iron homeostasis is a critical function of PDAC autophagy, and we define NCOA4-mediated ferritinophagy as a therapeutic target in PDAC. SIGNIFICANCE: Autophagy and iron metabolism are metabolic dependencies in PDAC. However, targeted therapies for these pathways are lacking. We identify NCOA4-mediated selective autophagy of ferritin ("ferritinophagy") as upregulated in PDAC. Ferritinophagy supports PDAC iron metabolism and thereby tumor progression and represents a new therapeutic target in PDAC. See related commentary by Jain and Amaravadi, p. 2023. See related article by Ravichandran et al., p. 2198. This article is highlighted in the In This Issue feature, p. 2007.

Reimagining high-throughput profiling of reactive cysteines for cell-based screening of large electrophile libraries.

Current methods used for measuring amino acid side-chain reactivity lack the throughput needed to screen large chemical libraries for interactions across the proteome. Here we redesigned the workflow for activity-based protein profiling of reactive cysteine residues by using a smaller desthiobiotin-based probe, sample multiplexing, reduced protein starting amounts and software to boost data acquisition in real time on the mass spectrometer. Our method, streamlined cysteine activity-based protein profiling (SLC-ABPP), achieved a 42-fold improvement in sample throughput, corresponding to profiling library members at a depth of >8,000 reactive cysteine sites at 18 min per compound. We applied it to identify proteome-wide targets of covalent inhibitors to mutant Kirsten rat sarcoma (KRAS)G12C and Bruton's tyrosine kinase (BTK). In addition, we created a resource of cysteine reactivity to 285 electrophiles in three human cell lines, which includes >20,000 cysteines from >6,000 proteins per line. The goal of proteome-wide profiling of cysteine reactivity across thousand-member libraries under several cellular contexts is now within reach.

Defining and Targeting Adaptations to Oncogenic KRASG12C Inhibition Using Quantitative Temporal Proteomics.

Covalent inhibitors of the KRASG12C oncoprotein have recently been developed and are being evaluated in clinical trials. Resistance to targeted therapies is common and may limit long-term efficacy of KRAS inhibitors (KRASi). To identify pathways of adaptation to KRASi and predict drug combinations that circumvent resistance, we use mass-spectrometry-based quantitative temporal proteomics to profile the proteomic response to KRASi in pancreatic and lung cancer 2D and 3D cellular models. We quantify 10,805 proteins, representing the most comprehensive KRASi proteome (https://manciaslab.shinyapps.io/KRASi/). Our data reveal common mechanisms of acute and long-term response between KRASG12C-driven tumors. Based on these proteomic data, we identify potent combinations of KRASi with phosphatidylinositol 3-kinase (PI3K), HSP90, CDK4/6, and SHP2 inhibitors, in some instances converting a cytostatic response to KRASi monotherapy to a cytotoxic response to combination treatment. Overall, using quantitative temporal proteomics, we comprehensively characterize adaptations to KRASi and identify combinatorial regimens with potential therapeutic utility.