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Purpose of reviewTo review the recent updates in the management of cervical cancer across all stages of the disease.Recent findingsAfter decades of minor advances, the landscape in cervical cancer is now rapidly changing. Recent studies have reported across the cervical cancer spectrum and on different therapeutic modalities. First, less radical surgery in the assessment and management of patients with early-stage, low-risk disease has been shown to be a safe option with reduced morbidity. The role of checkpoint inhibitor therapy in combination with chemotherapy and radiation has demonstrated improved survival outcomes, moving immunotherapy to earlier lines of therapy. The options for systemic therapy continue to include checkpoint inhibitors as well as treatment with antibody drug conjugates (ADCs) in the recurrent setting. Additional research continues to focus on targeting biomarkers in this disease.SummaryIn this paper, we will review the practice-changing trials impacting early stage, locally advanced, and recurrent cervical cancer patients. Despite advances, the limited survival for these patients continues to highlight the need for access to preventive healthcare (vaccine/cytology) and clinical trials to continue to make advances.

Dilute povidone-iodine (polyvinylpyrrolidone iodine [PVP-I]) irrigation in spine surgery and total joint arthroplasty has seen a rapid and substantial increase in its use during the past decade. Yet, most surgeons do not know the chemistry and biochemistry that explain its efficacy in preventing infections. PVP-I forms a complex with molecular iodine (I2), facilitating the delivery of I2 to the membrane of the infectious organism. Here, PVP-I establishes an equilibrium between complexed and noncomplexed (free) I2 in the aqueous solution. The I2 acts at numerous cellular targets of infecting organisms augmenting its role as a biocidal molecule. The paradoxical increase in the concentration of I2 that occurs with dilution of PVP-I is a result of equilibrium kinetics and is associated with an enhanced antimicrobial activity. Cytotoxicity studies have yielded conflicting results, but most endorse diluted concentrations as being less damaging to tissues. Clinical studies have verified notable reductions in surgical site infections with a 3-minute soak of 0.35% dilute povidone-iodine irrigation. Guidelines from the World Health Organization, Centers for Disease Control and Prevention, and International Consensus Meeting on Musculoskeletal Infection support the use of prophylactic incisional wound irrigation with aqueous PVP-I to reduce and prevent surgical site infections.

BackgroundDespite recent advances in the biology of IDH-wildtype glioblastoma, it remains a devastating disease with median survival of less than 2 years. However, the molecular underpinnings of the heterogeneous response to the current standard-of-care treatment regimen consisting of maximal safe resection, adjuvant radiation, and chemotherapy with temozolomide remain unknown.MethodsComprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent glioblastoma specimens from 106 patients was performed to investigate the molecular evolution and cellular phenotypes underlying differential treatment responses.ResultsWhile TERT promoter mutation and CDKN2A homozygous deletion were early events during gliomagenesis shared by initial and recurrent tumors, most other recurrent genetic alterations (eg, EGFR, PTEN, and NF1) were commonly private to initial or recurrent tumors indicating acquisition later during clonal evolution. Furthermore, glioblastomas exhibited heterogeneous epigenomic evolution with subsets becoming more globally hypermethylated, hypomethylated, or remaining stable. Glioblastoma that underwent sarcomatous transformation had shorter interval to recurrence and were significantly enriched in NF1, TP53, and RB1 alterations and the mesenchymal epigenetic class. Patients who developed somatic hypermutation following temozolomide treatment had significantly longer interval to disease recurrence and prolonged overall survival, and increased methylation at 4 specific CpG sites in the promoter region of MGMT was significantly associated with this development of hypermutation. Finally, an epigenomic evolution signature incorporating change in DNA methylation levels across 347 critical CpG sites was developed that significantly correlated with clinical outcomes.ConclusionsGlioblastoma undergoes heterogeneous genetic, epigenetic, and cellular evolution that underlies prognostically different treatment responses.

ImportanceThe phase 3 randomized EMBARK trial evaluated enzalutamide with or without leuprolide in high-risk nonmetastatic hormone-sensitive prostate cancer. Eligibility relied on conventional imaging, which underdetects metastatic disease compared with prostate-specific membrane antigen-positron emission tomography (PSMA-PET).ObjectiveTo describe the staging information obtained by PSMA-PET/computed tomography (PSMA-PET/CT) in a patient cohort eligible for the EMBARK trial.Design, setting, and participantsThis post hoc, retrospective cross-sectional study included 182 patients from 4 prospective studies conducted from September 15, 2016, to September 27, 2021. All patients had recurrent prostate cancer after radical prostatectomy (RP), definitive radiotherapy (dRT), or salvage radiotherapy (SRT). Analysis was performed from January 2023 to July 2024.ExposuresPatients included had increasing prostate-specific antigen (PSA) levels greater than 1.0 ng/mL (after RP and SRT) or 2.0 ng/mL above the nadir value (after dRT), PSA doubling time of 9 months or less, and a serum testosterone level of 150 ng/dL or greater. Exclusion criteria were distant metastatic disease on radiographic imaging and prior hormonal or systemic therapy.Main outcomes and measuresStaging information obtained by PSMA-PET/CT in patients with nonmetastatic disease according to conventional imaging.ResultsFrom 2002 patients screened, 182 (median age at PET/CT scan, 69 years [IQR, 64-73 years]) were included. Median prescan PSA levels were 2.4 ng/mL (IQR, 1.4-4.8 ng/mL) after RP (n = 91), 6.9 ng/mL (IQR, 3.5-18.5 ng/mL) after dRT (n = 39), 2.6 ng/mL (IQR, 1.6-5.2 ng/mL) after RP and SRT (n = 52), and 2.8 ng/mL (IQR, 1.7-6.6 ng/mL) overall (n = 182). Results of PSMA-PET were positive in 80% of patients (73 of 91) after RP, 92% of patients (36 of 39) after dRT, 85% of patients (44 of 52) after RP and SRT, and 84% of patients (153 of 182) overall. PSMA-PET detected any distant metastatic disease (miTxNxM1) in 34% of patients (31 of 91) after RP, 56% of patients (22 of 39) after dRT, 60% of patients (31 of 52) after RP and SRT, and 46% of patients (84 of 182) overall. Polymetastatic disease (≥5 lesions) was found in 19% of patients (17 of 91) after RP, 36% of patients (14 of 39) after dRT, 23% of patients (12 of 52) after RP and SRT, and 24% of patients (43 of 182) overall.Conclusions and relevanceIn a cohort of patients with high-risk hormone-sensitive prostate cancer without evidence of metastatic disease by conventional imaging, PSMA-PET results were positive in 84% of patients, detected M1 disease stage in 46% of patients, and found polymetastatic disease (≥5 lesions) in 24% of patients, suggesting that patients' high-risk nonmetastatic hormone-sensitive prostate cancers are understaged by conventional imaging. The results challenge the interpretation of previous studies, such as the EMBARK trial, and support the evolving role of PSMA-PET for patient selection in clinical and trial interventions in prostate cancer. Further studies are needed to assess its independent prognostic value and use for treatment guidance.

SignificanceEliminating "persisters" before relapse is crucial for achieving durable treatment efficacy. This study provides a rationale for developing PRMT1-selective inhibitors to target cancer persisters and achieve more durable outcomes in oncogene-targeting therapies.

Management of refractory ventricular fibrillation (VF) in patients with implantable implantable cardioverter defibrillator (ICD) presents a therapeutic challenge. We present a case of pediatric refractory ventricular tachycardia (VT)/Torsade de Pointe managed effectively with bilateral stellate ganglion block (SGB) with a long-acting local anesthetic for 18 days as a bridge to more definitive surgical management.

Patients with metastatic pancreatic ductal adenocarcinoma survive longer if disease spreads to the lung but not the liver. Here we generated overlapping, multi-omic datasets to identify molecular and cellular features that distinguish patients whose disease develops liver metastasis (liver cohort) from those whose disease develops lung metastasis without liver metastases (lung cohort). Lung cohort patients survived longer than liver cohort patients, despite sharing the same tumor subtype. We developed a primary organotropism (pORG) gene set enriched in liver cohort versus lung cohort primary tumors. We identified ongoing replication stress response pathways in high pORG/liver cohort tumors, whereas low pORG/lung cohort tumors had greater densities of lymphocytes and shared T cell clonal responses. Our study demonstrates that liver-avid pancreatic ductal adenocarcinoma is associated with tolerance to ongoing replication stress, limited tumor immunity and less-favorable outcomes, whereas low replication stress, lung-avid/liver-averse tumors are associated with active tumor immunity that may account for favorable outcomes.

Current US clinical practice guidelines for advanced prostate cancer management contain recommendations based on high-level evidence from randomized controlled trials; however, these guidelines do not address the nuanced clinical questions that are unanswered by prospective trials but nonetheless encountered in day-to-day practice. To address these practical questions, the 2024 US Prostate Cancer Conference (USPCC 2024) was created to generate US-focused expert clinical decision-making guidance for circumstances in which level 1 evidence is lacking. At the second annual USPCC meeting (USPCC 2024), a multidisciplinary panel of experts convened to discuss ongoing clinical challenges related to 5 topic areas: biochemical recurrence; metastatic, castration-sensitive prostate cancer; poly [ADP-ribose] polymerase inhibitors; prostate-specific membrane antigen radioligand therapy; and metastatic, castration-resistant prostate cancer. Through a modified Delphi process, 34 consensus recommendations were developed and are intended to provide clinicians who manage prostate cancer with guidance related to the implementation of novel treatments and technologies. In this report, the authors review the areas of consensus identified by the USPCC 2024 experts and evaluate ongoing unmet needs regarding translational application of the current clinical evidence.

A 9.5-year-old male neutered domestic short-haired cat received two courses of postoperative, definitive-intent conformal radiation therapy (RT) for recurrent laryngeal adenocarcinoma (LACA). Adjuvant RT was prescribed (16 × 3.0 Gy, total 48 Gy) following incomplete resection. Following tumor recurrence and subsequent incomplete resection 31.5 months after the first course, a second course was prescribed (20 × 2.5 Gy, total 50 Gy). Acute and late adverse events were mild. No evidence of local recurrence was documented 42 months following the second course when the cat was euthanized for renal disease. This first report of long-term control in a cat with LACA supports further evaluation of surgery and definitive-intent RT.

Aim: A radio-pathomic machine learning (ML) model has been developed to estimate tumor cell density, cytoplasm density (Cyt) and extracellular fluid density (ECF) from multimodal MR images and autopsy pathology. In this multicenter study, we implemented this model to test its ability to predict survival in patients with recurrent glioblastoma (rGBM) treated with chemotherapy.Methods: Pre- and post-contrast T1-weighted, FLAIR and ADC images were used to generate radio-pathomic maps for 51 patients with longitudinal pre- and post-treatment scans. Univariate and multivariate Cox regression analyses were used to test the influence of contrast-enhancing tumor volume, total cellularity, mean Cyt and mean ECF at baseline, immediately post-treatment and the pre- and post-treatment rate of change in volume and cellularity on overall survival (OS).Results: Smaller Cyt and larger ECF after treatment were significant predictors of OS, independent of tumor volume and other clinical prognostic factors (HR = 3.23 × 10-6, p

Glioblastoma is immunologically cold and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrolizumab may improve survival. To increase the power of this observation, we enrolled an additional 25 patients with a primary endpoint of evaluating the cell cycle gene signature associated with neoadjuvant pembrolizumab and performed bulk-RNA seq on resected tumor tissue (NCT02852655). Neoadjuvant pembrolizumab was associated with suppression of cell cycle/cancer proliferation genes and upregulation of T-cell/interferon-related gene expression. This signature was unique to patients treated with neoadjuvant pembrolizumab and was an independent positive risk factor for survival. Our results demonstrate a clear pharmacodynamic effect of anti-PD1 therapy in glioblastoma and identify pathways that may mediate resistance. However, we did not confirm a survival benefit to neoadjuvant pembrolizumab in recurrent glioblastoma and our secondary endpoint of PFS-6 was 19.5% (95% CI: 9.29-41.2%) for the pooled neoadjuvant cohorts. Our new data suggests some patients may exhibit innate resistance to pre-surgical ICI and require other concomitant therapies to sensitize effectively.

BACKGROUND: Despite nearly 100% 5-year survival for localised prostate cancer, the survival rate for metastatic prostate cancer significantly declines to 32%. Thus, it is crucial to identify molecular indicators that reflect the progression from localised disease to metastatic prostate cancer. METHODS: To search for molecular indicators associated with prostate cancer metastasis, we performed proteomic analysis of rapid autopsy tissue samples from metastatic prostate cancer (N = 8) and localised prostate cancer (N = 2). Then, we utilised multiple independent, publicly available prostate cancer patient datasets to select candidates that also correlate with worse prostate cancer clinical prognosis. RESULTS: We identified 154 proteins with increased expressions in metastases relative to localised prostate cancer through proteomic analysis. From the subset of these candidates that correlate with prostate cancer recurrence (N = 28) and shorter disease-free survival (N = 37), we identified a 5-gene signature panel with improved performance in predicting worse clinical prognosis relative to individual candidates. CONCLUSIONS: Our study presents a new 5-gene signature panel that is associated with worse clinical prognosis and is elevated in prostate cancer metastasis on both protein and mRNA levels. Our 5-gene signature panel represents a potential modality for the prediction of prostate cancer progression towards the onset of metastasis.

Recurrent high-grade intracranial malignancies have a grim prognosis and uniform management guidelines are lacking. Re-irradiation is underused due to concerns about irreversible side effects. Pulsed-reduced dose rate radiotherapy (PRDR) aims to reduce toxicity while improving tumor control by exploiting dose-rate effects. We share our initial experience with temporally modulated pulsed proton re-irradiation (TMPPR), focusing on workflow, safety, feasibility, and outcomes for the first patient cohort. TMPPR was administered to patients with recurrent or progressive central nervous system malignancies using intensity modulated proton therapy with three fields. Patient and treatment data were collected, responses categorized using RANO assessment, and toxicities graded using CTCAE v5.0. Five patients received TMPPR between October 2022 and May 2023, with a median age of 54 years (Range: 32-72), and a median time from initial radiotherapy to re-RT of 23 months (Range 14-40). Treatment was completed without delay, with a median dose of 60 GyRBE in 30 fractions. Initial treatment response assessment showed complete (n = 1) or partial (n = 3) responses. Limited toxicity was observed, primarily grade 2 alopecia and one case of radiation necrosis graded at 2. This early experience demonstrates the feasibility of TMPPR delivery, highlighting the importance of prospective evaluations in the re-irradiation setting.

BACKGROUND: Despite advances in cancer care and detection, >65% of patients with squamous cell cancer of the head and neck (HNSCC) will develop recurrent and/or metastatic disease. The prognosis for these patients is poor with a 5-year overall survival of 39%. Recent treatment advances in immunotherapy, including immune checkpoint inhibitors like pembrolizumab and nivolumab, have resulted in clinical benefit in a subset of patients. There is a critical clinical need to identify patients who benefit from these antiprogrammed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors. METHODS: Here, we report findings from a multicenter observational study, PREDicting immunotherapy efficacy from Analysis of Pre-treatment Tumor biopsies (PREDAPT), conducted across 17 US healthcare systems. PREDAPT aimed to validate OncoPrism-HNSCC, a clinical biomarker assay predictive of disease control in patients with recurrent or metastatic HNSCC treated with anti-PD-1 immune checkpoint inhibitors as a single agent (monotherapy) and in combination with chemotherapy (chemo-immunotherapy). The test used RNA-sequencing data and machine learning models to score each patient and place them into groups of low, medium, or high. RESULTS: The OncoPrism-HNSCC prediction significantly correlated with disease control in both the monotherapy cohort (n=62, p=0.004) and the chemo-immunotherapy cohort (n=50, p=0.01). OncoPrism-HNSCC also significantly predicted progression-free survival in both cohorts (p=0.015 and p=0.037, respectively). OncoPrism-HNSCC had more than threefold higher specificity than programmed death-ligand 1 combined positive score and nearly fourfold higher sensitivity than tumor mutational burden for predicting disease control. CONCLUSIONS: Here, we demonstrate the clinical validity of the OncoPrism-HNSCC assay in identifying patients with disease control in response to anti-PD-1 immune checkpoint inhibitors. TRIAL REGISTRATION NUMBER: NCT04510129.

PURPOSE: AZD5991, a human MCL-1 inhibitor, was assessed for safety, tolerability, pharmacokinetics, and antitumor activity as monotherapy and in combination with venetoclax in patients with relapsed or refractory hematologic malignancies. PATIENTS AND METHODS: In the monotherapy cohort (n = 61), patients with hematologic malignancies received AZD5991 intravenously in escalating doses either once or twice weekly, following intrapatient dose escalation, during a 3-week cycle. In the combination cohort (n = 17), patients with acute myeloid leukemia and myelodysplastic syndrome received escalating doses of AZD5991 and venetoclax during either a 3- or 4-week cycle. Primary objectives were safety and maximum tolerated dose; secondary objectives included plasma pharmacokinetics and antitumor activity. RESULTS: The most common (≥30%) adverse events were diarrhea (59.0%), nausea (55.1%), and vomiting (47.4%). Four deaths occurred because of adverse events: cardiac arrest, sepsis, tumor lysis syndrome, and acute respiratory failure; only tumor lysis syndrome was related to AZD5991. Dose-limiting toxicities occurred in five patients. Three patients with myelodysplastic syndrome achieved an objective response: one marrow complete remission without hematologic improvement, one partial remission with AZD5991 monotherapy, and one marrow complete remission with AZD5991 + venetoclax. Asymptomatic elevations of troponin I or T were observed in eight (10.3%) patients. Post hoc retrospective analysis revealed elevated troponin T in 14/31 patients before any AZD5991 dose and in 54/65 patients after any AZD5991 dose at or after Cycle 1. No associations were found between elevated troponin and cardiovascular risk factors. CONCLUSIONS: Treatment with AZD5991 was associated with high incidence of laboratory troponin elevation and a low overall response rate.

BACKGROUND: Invasive lobular carcinoma (ILC) of the breast grows in a diffuse pattern, resulting in a high risk of positive margins at surgical resection. Oncoplastic approaches have been shown to reduce this risk, but concerns persist around the safety of immediate oncoplastic surgery for those with ILC. This study evaluated the short- and long-term oncologic outcomes of immediate oncoplastic surgery for patients with ILC. METHODS: This study retrospectively analyzed an institutional database of stages I to III ILC patients who underwent breast-conserving surgery (BCS) with or without immediate oncoplastic surgery (oncoplastic closure or oncoplastic reduction mammoplasty [ORM]). The study compared positive margin rates, rates of successful BCS, and recurrence-free survival (RFS) by type of surgery. RESULTS: For 494 patients the findings showed that the use of immediate ORM was associated with significantly lower odds of positive margins (odds ratio [OR], 0.34; 95 % confidence interval [CI], 0.17-0.66; p = 0.002). Both lumpectomy with oncoplastic closure and ORM were significantly associated with higher rates of successful BCS than standard lumpectomy (94.2 %, 87.8 %, and 73.9 %, respectively; p < 0.001). No difference in RFS was observed between those undergoing immediate oncoplastic surgery and those undergoing standard lumpectomy alone. CONCLUSIONS: The patients with stages I to III ILC who underwent immediate oncoplastic surgery had significant benefits including lower odds of positive margins and higher rates of successful BCS, with both types of immediate oncoplastic surgery showing similar RFS compared with lumpectomy alone. This supports the oncologic safety of immediate oncoplastic surgery for diffusely growing tumors such as ILC, providing it an ideal option for patients desiring BCS.

BACKGROUND: Invasive lobular carcinoma (ILC) is the second most common subtype of breast cancer. Although mammography is known to have low sensitivity for ILC, there are no data to guide the optimal surveillance after treatment. We explored surveillance strategies after breast-conserving surgery (BCS) for ILC and determined the proportion of imaging-detected recurrences versus interval cancers. METHODS: From an institutional database of 813 women, we retrospectively identified patients who underwent BCS for stage I-III ILC and subsequently had a recurrence. We categorized patients by surveillance strategy and determined the modality of recurrence detection. Interval cancer rates for local recurrences were compared across surveillance strategies using the Chi-square test. We evaluated overall survival with the log-rank test and a Cox proportional hazards model. RESULTS: We included 58 patients with ILC who had a recurrence after BCS. Of these, 22 (37.9%) had local recurrence, 27 (46.6%) had distant recurrence, and 9 (15.5%) had both local and distant recurrence. Most patients underwent routine mammographic surveillance (65.2%), with 19.6% having supplemental breast magnetic resonance imaging (MRI) and 15.2% having no surveillance. The interval cancer rate was significantly higher in the mammographic surveillance group compared with the MRI surveillance group (61.9% vs. 16.7%; p

PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a 40% recurrence rate, lacking effective prognostic biomarkers and surveillance methods. This prospective, multicenter, observational study aimed to evaluate circulating tumor DNA (ctDNA) as a biomarker for detecting MCC recurrence. METHODS: Plasma samples, clinical data, and imaging results were collected from 319 patients. A tumor-informed ctDNA assay was used for analysis. Patients were divided into discovery (167 patients) and validation (152 patients) cohorts. Diagnostic performance, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), was assessed. RESULTS: ctDNA showed high sensitivity, 95% (discovery; 95% CI, 87 to 99) and 94% (validation; 95% CI, 85 to 98), for detecting disease at enrollment, with corresponding specificities of 90% (95% CI, 82 to 95) and 86% (95% CI, 77 to 93). A positive ctDNA during surveillance indicated increased recurrence risk, with hazard ratios (HRs) of 6.8 (discovery; 95% CI, 2.9 to 16) and 20 (validation; 95% CI, 8.3 to 50). The PPV for clinical recurrence at 1 year after a positive ctDNA test was 69% (discovery; 95% CI, 32 to 91) and 94% (validation; 95% CI, 71 to 100), respectively. The NPV at 135 days after a negative ctDNA test was 94% (discovery; 95% CI, 90 to 97) and 93% (validation; 95% CI, 89 to 97), respectively. Patients positive for ctDNA within 4 months after treatment had higher rates of recurrence, with 1-year rates of 74% versus 21% (adjusted HR, 7.4 [95% CI, 2.7 to 20]). CONCLUSION: ctDNA testing exhibited high prognostic accuracy in detecting MCC recurrence, suggesting its potential to reduce frequent surveillance imaging. ctDNA also identifies high-risk patients who need more frequent imaging and may be best suited for adjuvant therapy trials.

BACKGROUND: In the phase 3 EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 study, cemiplimab significantly improved overall survival (OS) versus chemotherapy for patients with recurrent or metastatic cervical cancer who progressed after first-line platinum-based chemotherapy. We present a post hoc subgroup analysis of patients enrolled in Japan. METHODS: Patients were enrolled regardless of programmed cell death-ligand 1 status and randomized 1:1 to cemiplimab 350 mg intravenously every 3 weeks or investigators choice  single-agent chemotherapy for up to 96 weeks. Primary endpoint was OS. Key secondary endpoints were progression-free survival (PFS) and objective response rate (ORR). RESULTS: Overall, 608 patients were randomized, of whom 56 (9.2%) were in Japan (cemiplimab, n = 29; chemotherapy, n = 27). The median (range) duration of follow-up was 13.6 (6.0-25.3) versus 18.2 (6.0-38.2) months for patients in Japan and for the overall population, respectively. Median OS (95% confidence interval [CI]) was 8.4 (7.0-not evaluable) and 9.4 (5.4-14.9) months for cemiplimab versus chemotherapy (hazard ratio [HR]: 0.86; 95% CI: 0.43-1.68). Median PFS (95% CI) was 4.0 (1.4-8.2) versus 3.7 (1.8-4.2) months with cemiplimab and chemotherapy (HR: 0.90; 95% CI: 0.50-1.61), respectively. ORR was 17.2% for cemiplimab and 7.4% for chemotherapy (odds ratio, 2.47; 95% CI, 0.44-13.99). Incidence of treatment-emergent adverse events at any grade was 79.3% for cemiplimab and 100% for chemotherapy. Grade ≥3 adverse events were 37.9% versus 66.7% with cemiplimab and chemotherapy, respectively. DISCUSSION: While acknowledging limitations inherent to a small subgroup analysis, the HR of 0.86 observed in Japanese patients suggests an emerging survival benefit despite a 4.6-month shorter median duration of follow-up versus the overall study population.

TABLE OF CONTENTS INTRODUCTION 267 I. FRAMEWORKS FOR ENERGY (IN)JUSTICE 269 A. What Is Energy Justice? 270 B. Factors Impacting Energy Justice Outcomes 273 II. THE CALIFORNIA CONTEXT 275 A. [...]

TABLE OF CONTENTS I. INTRODUCTION 323 II. BACKGROUND ON MINING FOR TRANSITION MINERALS IN THE U.S. 331 A. Why the Domestic Push to Mine for Transition Minerals 331 B. Disproportionate [...]

The Supreme Court&apos;s 2007 decision in Massachusetts v. EPA marked the first time the Court had addressed the standing of states to sue the federal government in an environmental case. The Court&apos;s holding that Massachusetts, New York, and the other petitioners had standing to sue the Environmental Protection Agency for climate change-related harms established important precedent for lawsuits brought by states against the federal government. In this article, we examine environmental litigation over the past seventeen years in which federal courts have considered the Massachusetts standing holding--and the Court&apos;s instruction that states deserve "special solicitude" in the standing inquiry--in deciding whether states had demonstrated standing against the federal government. As was the case in Massachusetts, it is critical that states have the ability in our system of cooperative federalism to vindicate their rights (and the rights of their residents) in federal court. We discuss the different types of standing theories states have relied on to vindicate those rights, such as financial and quasi-sovereign injuries, and which ones have proven to be the most successful. We then highlight the recent effort to curb the well-established ability of states to use financial injury to establish standing against federal agencies, leading Justice Alito&apos;s admonition that the Court not treat states with "special hostility." We argue that states seeking to establish standing on financial injury grounds should not be held to a higher standard than other litigants in that showing, and we further discuss how states can rely more on quasi-sovereign interests in establishing standing in the event that standing based on financial injury is curtailed. In that vein, we revisit Massachusetts&apos;s discussion of quasi-sovereign interests, and conclude that--consistent with the grand bargain of federalism and the fundamental notion of parens patriae ("parent of the country")--a state should be able to sue the federal government where it is neglecting its duty under federal law to protect the health or welfare of the state&apos;s residents. Finally, we consider how courts have interpreted Massachusetts&apos;s instruction that states deserve special solicitude in the standing inquiry. Drawing on Massachusetts, we argue that, where states are suing the federal government to invoke the protections of federal law (including lawsuits brought by a state to protect the health and well-being of its residents), special solicitude is especially warranted., TABLE OF CONTENTS I INTRODUCTION 209 II THE EVOLUTION OF STATE STANDING IN MASSACHUSETTS v EPA 211 A Different Theories of State Standing 211 B State Standing in Massachusetts v [...]

ImportanceIn oncology randomized clinical trials, suboptimal access to best available care at recurrence (or relapse) may affect overall survival results.ObjectiveTo assess the proportion and the quality of postrecurrence treatment received by patients enrolled in US Food and Drug Administration (FDA) registration trials of systemic therapy in the adjuvant or neoadjuvant setting.Evidence reviewFor this systematic review, all trials leading to an FDA approval from January 2018 through May 2023 were obtained from the FDA website and drug announcements. Randomized clinical trials of an anticancer drug in the neoadjuvant or the adjuvant setting were included. Trials of supportive care treatment and treatments given in combination with radiotherapy were excluded. Information abstracted for each trial included tumor type, setting, phase, type of sponsor, reporting and assessment of postrecurrence, and overall survival data.FindingsA total of 14 FDA trials met the inclusion criteria. Postrecurrence data were not available in 6 of 14 registration trials (43%). Of the 8 remaining trials, postrecurrence treatment was assessed as suboptimal in 6 (75%). Overall, only 2 of 14 trials (14%) had data assessed as appropriate.Conclusions and relevanceThis systematic review found that 43% of randomized clinical trials of anticancer treatment in the adjuvant or neoadjuvant context failed to present any assessable postrecurrence treatment data. In instances in which these data were shared, postrecurrence treatment was suboptimal 75% of the time. The findings suggest that regulatory bodies should enforce rules stipulating that patients have access to the best standard of care at recurrence.

INTRODUCTION: Early neoplastic progression of Barretts esophagus (BE) is often treated with endoscopic therapy. Although effective, some patients are refractory to therapy or recur after apparent eradication of the BE. The goal of this study was to determine whether genomic alterations within the treated BE may be associated with persistent or recurrent disease. METHODS: We performed DNA sequencing on pre-treatment esophageal samples from 45 patients who were successfully treated by endoscopic therapy and did not recur as well as pre-treatment and post-treatment samples from 40 patients who had persistent neoplasia and 21 patients who had recurrent neoplasia. The genomic alterations were compared between groups. RESULTS: The genomic landscape was similar between all groups. Patients with persistent disease were more likely to have pre-treatment alterations involving the receptor tyrosine kinase pathway ( P = 0.01), amplifications of oncogenes ( P = 0.01), and deletions of tumor suppressor genes ( P = 0.02). These associations were no longer significant after adjusting for patient age and BE length. More than half of patients with persistent (52.5%) or recurrent (57.2%) disease showed pre-treatment and post-treatment samples that shared at least 50% of their driver mutations. DISCUSSION: Pre-treatment samples were genomically similar between those who responded to endoscopic therapy and those who had persistent or recurrent disease, suggesting there is not a strong genomic component to treatment response. Although it was expected to find shared driver mutations in pre-treatment and post-treatment samples in patients with persistent disease, the finding that an equal number of patients with recurrent disease also showed this relation suggests that many recurrences represent undetected minimal residual disease.

BACKGROUND: Sympathetic-mediated vasoconstriction from the superior cervical ganglion (SCG) is a significant contributor to cerebral vasospasm. Inhibition of the SCG has been shown to improve cerebral blood flow and reverse cerebral vasospasm in swine models. We evaluated the efficacy of a novel minimally invasive endovascular approach to target and pharmacologically inhibit the SCG, using a Micro-Infusion Device for transmural drug delivery. METHODS: Eight SCGs in four Yorkshire swine were surgically identified. After confirming appropriate sympathetic-mediated intracranial vasoconstriction response with SCG stimulation, an endovascular Micro-Infusion Device was used for transmural targeting of the SCG and delivery of 1.5-2 mL of 1% lidocaine-contrast mixture to the perivascular space. Digital subtraction angiography was obtained at: (1) baseline; (2) with SCG stimulation; and (3) after lidocaine delivery to the SCG using the Micro-Infusion Device with concurrent SCG stimulation. Vessel diameters were measured and compared. RESULTS: Endovascular transmural delivery of lidocaine to the SCG and carotid perivascular tissue using the Micro-Infusion Device successfully inhibited sympathetic-mediated vasoconstriction response. Measured vessel diameters after lidocaine delivery were comparable to baseline despite SCG stimulation. CONCLUSION: A novel endovascular technique of transmural delivery of lidocaine to the SCG and carotid artery perivascular tissues successfully inhibits the sympathetic input to the cerebral vasculature and modulates sympathetic-mediated cerebral vasospasm. These results suggest promising steps towards translation to potential clinical use for patients suffering from cerebral vasospasm.

PURPOSE: Minimal residual disease (MRD) detection can identify the recurrence in patients with colorectal cancer (CRC) following definitive treatment. We evaluated a plasma-only MRD assay to predict recurrence and survival in patients with metastatic CRC who underwent curative intent procedures (surgery and/or radiotherapy), with or without (neo)adjuvant chemotherapy. The primary objective of this study was to assess the correlation of postprocedure tumor cell-free DNA detection status with radiographic disease recurrence. EXPERIMENTAL DESIGN: Preprocedure and postprocedure longitudinal samples were collected from 53 patients and analyzed with a multiomic MRD assay detecting circulating tumor DNA (ctDNA) from genomic and epigenomic signals. Preprocedure and postprocedure ctDNA detection correlated with recurrence-free and overall survival (OS). RESULTS: From 52 patients, 230/233 samples were successfully analyzed. At the time of data cutoff, 36 (69.2%) patients recurred with median follow-up of 31 months. Detectable ctDNA was observed in 19/42 patients (45.2%) with ctDNA analyzed 3 weeks postprocedure. ctDNA detection 3 weeks postprocedure was associated with shorter median recurrence-free survival (RFS; HR, 5.27; 95% CI, 2.31-12.0; P < 0.0001) and OS (HR, 12.83; 95% CI, 3.6-45.9; P < 0.0001). Preprocedure ctDNA detection status was not associated with RFS but was associated with improved OS (HR, 4.65; 95% CI, 1.4-15.2; P = 0.0111). Undetectable ctDNA preprocedure had notable long-term OS, >90% 3 years postprocedure. CONCLUSIONS: In this cohort of oligometastatic CRC, detection of ctDNA preprocedure or postprocedure was associated with inferior outcomes even after accounting for known prognostic clinicopathologic variables. This suggests ctDNA may enhance current risk stratification methods helping the evaluation of novel treatments and surveillance strategies toward improving patient outcomes.

Glioblastoma (GBM) is the deadliest adult brain cancer. Under the current standard of care, almost all patients succumb to the disease and novel treatments are urgently needed. Recognizing that GBMs are addicted to cholesterol, past clinical trials have repurposed statins against GBM but failed. The purpose of this study was to test whether treatments that upregulate the cholesterol biosynthesis pathway in GBM would generate a metabolic vulnerability that can be exploited using statins and to determine the underlying mechanisms.Effects of radiotherapy and temozolomide or dopamine receptor antagonists on the mevalonate pathway in GBM were assessed in vitro and in vivo. The impact of statins on self-renewal of glioma stem cells and median survival was studied. Branches of the mevalonate pathway were probed to identify relevant effector proteins.Cells surviving combination treatments that converge in activating the immediate early response, universally upregulated the mevalonate pathway and increased stemness of GBM cells through activation of the Rho-GTPase Rac-1. Activation of the mevalonate pathway and Rac-1 was inhibited by statins, which led to improved survival in mouse models of glioblastoma when combined with radiation and drugs that target the glioma stem cell pool and plasticity of glioma cells.We conclude that a combination of dopamine receptor antagonists and statins could potentially improve radiotherapy outcome and warrants further investigation.SignificanceCombination therapies that activate the mevalonate pathway in GBM cells after sublethal treatment enhance self-renewal and migratory capacity through Rac-1 activation, which creates a metabolic vulnerability that can be further potentially exploited using statins.

Background: Treatment for refractory or relapsed primary CNS lymphoma (r/r PCNSL) is challenging. Salvage whole-brain radiation therapy (WBRT) is an option but has a short duration of disease control, so additional treatment modalities are warranted. Case: A 75-year-old female with r/r PCNSL who had multiple progressions after multiple lines of treatment underwent salvage WBRT. The patient received ibrutinib, a Brutons tyrosine kinase inhibitor, as maintenance therapy for 18 months following WBRT with the intention of increasing survival duration after salvage WBRT. She survived 81 months from diagnosis, including 57 months after completion of WBRT. Conclusion: This case presentation describes the experience of using ibrutinib as maintenance therapy in treating r/r PCNSL after salvage WBRT.

PurposeWe previously demonstrated the clinical significance of circulating tumor DNA (ctDNA) in patients with HER2-negative breast cancer receiving neoadjuvant chemotherapy (NAC). Here, we compared its predictive and prognostic value with cell-free DNA (cfDNA) concentration measured in the same samples from the same patients.Experimental design145 patients with hormone receptor (HR)-positive/HER2-negative and 138 triple-negative breast cancer (TNBC) with ctDNA data from a previous study were included in the analysis. Associations of serial cfDNA concentration with residual cancer burden (RCB) and distant recurrence-free survival (DRFS) were examined.ResultsIn TNBC, we observed a modest negative correlation between cfDNA concentration 3 weeks after treatment initiation and RCB, but none of the other timepoints showed significant correlation. In contrast, ctDNA was significantly positively correlated with RCB at all timepoints (all R > 0.3 and P < 0.05). In the HR-positive/HER2-negative group, cfDNA concentration did not associate with response to NAC, but survival analysis showed that high cfDNA shedders at pretreatment had a significantly worse DRFS than low shedders (hazard ratio, 2.12; P = 0.037). In TNBC, the difference in survival between high versus low cfDNA shedders at all timepoints was not statistically significant. In contrast, as previously reported, ctDNA at all timepoints was significantly correlated with DRFS in both subtypes.ConclusionsIn TNBC, cfDNA concentrations during therapy were not strongly correlated with response or prognosis. In the HR-positive/HER2-negative group, pretreatment cfDNA concentration was prognostic for DRFS. Overall, the predictive and prognostic value of cfDNA concentration was more limited than that of ctDNA.

Nearly all men with metastatic hormone-sensitive prostate cancer treated with intermittent androgen deprivation therapy (ADT) experience recurrence within 6 mo of testosterone recovery. We conducted a single-arm phase 2 trial to evaluate whether addition of dual androgen receptor pathway inhibitors (ARPIs) and metastasis-directed stereotactic body radiotherapy (SBRT) to intermittent ADT improves recurrence rates for men with between one and five nonvisceral, extrapelvic metastases on prostate-specific membrane antigen positron emission tomography/computed tomography after prior radical prostatectomy. Patients received 6 mo of androgen annihilation therapy (AAT; leuprolide, abiraterone acetate plus prednisone, and apalutamide) and metastasis-directed SBRT. The primary endpoint was the percentage of patients with prostate-specific antigen (PSA)

OBJECTIVE: The purpose of this study was to determine the in vitro effects of a single exposure of bupivacaine on the mechanical properties of bovine cartilage explants at 3 weeks. DESIGN: Femoral condyle articular cartilage explants were aseptically harvested from juvenile bovine stifle joints before being exposed to chondrogenic medium containing 0.50% (wt/vol) bupivacaine, 0.25% (wt/vol) bupivacaine, or no medication (control) for 1 hour. Explants were then washed and maintained in culture in vitro for 3 weeks before testing. Cell viability, tensile and compressive mechanical properties, histological properties, and biochemical properties were then assessed. RESULTS: Explants exhibited a dose-dependent decrease in mean tensile Youngs modulus with increasing bupivacaine concentration (9.86 MPa in the controls, 6.48 MPa in the 0.25% bupivacaine group [P = 0.048], and 4.72 MPa in the 0.50% bupivacaine group [P = 0.005]). Consistent with these results, collagen content and collagen crosslinking decreased with bupivacaine exposure as measured by mass spectrometry. Compressive properties of the explants were unaffected by bupivacaine exposure. Explants also exhibited a trend toward dose-dependent decreases in viability (51.2% for the controls, 47.3% for the 0.25% bupivacaine-exposed group, and 37.0% for the 0.50% bupivacaine-exposed group [P = 0.072]). CONCLUSIONS: Three weeks after 1-hour bupivacaine exposure, the tensile properties of bovine cartilage explants were significantly decreased, while the compressive properties remained unaffected. These decreases in tensile properties corresponded with reductions in collagen content and crosslinking of collagen fibers. Physicians should be judicious regarding the intra-articular administration of bupivacaine in native joints.

Intratumor heterogeneity underlies cancer evolution and treatment resistance, but targetable mechanisms driving intratumor heterogeneity are poorly understood. Meningiomas are the most common primary intracranial tumors and are resistant to all medical therapies, and high-grade meningiomas have significant intratumor heterogeneity. Here we use spatial approaches to identify genomic, biochemical and cellular mechanisms linking intratumor heterogeneity to the molecular, temporal and spatial evolution of high-grade meningiomas. We show that divergent intratumor gene and protein expression programs distinguish high-grade meningiomas that are otherwise grouped together by current classification systems. Analyses of matched pairs of primary and recurrent meningiomas reveal spatial expansion of subclonal copy number variants associated with treatment resistance. Multiplexed sequential immunofluorescence and deconvolution of meningioma spatial transcriptomes using cell types from single-cell RNA sequencing show decreased immune infiltration, decreased MAPK signaling, increased PI3K-AKT signaling and increased cell proliferation, which are associated with meningioma recurrence. To translate these findings to preclinical models, we use CRISPR interference and lineage tracing approaches to identify combination therapies that target intratumor heterogeneity in meningioma cell co-cultures.

BACKGROUND: Nearly one-third of patients with prostate cancer (PCa) experience biochemical recurrence (BCR) after primary definitive treatment. BCR increases the risk of distant metastasis and mortality in patients with prognostically unfavorable features. These patients are best managed with a tailored treatment strategy incorporating risk stratification using clinicopathological factors, next-generation imaging, and genomic testing. OBJECTIVE: This narrative review examines the utility of risk stratification for the management of patients with BCR in the context of clinical trial data, referencing the latest recommendations by European and US medical societies. METHODS: PubMed was searched for relevant studies published through May 21 2023 on treatment of patients with BCR after radical prostatectomy (RP) or external beam radiotherapy (EBRT). RESULTS: European and US guidelines support the risk-stratified management of BCR. Post-RP, salvage EBRT (with or without androgen deprivation therapy [ADT]) is an accepted treatment option for patients with BCR. Post-EBRT, local salvage therapies (RP, cryotherapy, high-intensity focused ultrasound, stereotactic body radiotherapy, and low-dose-rate and high-dose-rate brachytherapy) have demonstrated comparable relapse-free survival rates but differing adverse event profiles, short and long term. Local salvage therapies should be used for local-only relapses while ADT should be considered for regional or distant relapses. In practice, patients often receive ADT, with varying guidance for intermittent ADT vs. continuous ADT, due to consideration of quality-of-life effects. CONCLUSIONS: Despite a lack of consensus for BCR treatment among guideline associations and medical societies, risk stratification of patients is essential for personalized treatment approaches, as it allows for an informed selection of therapeutic strategies and estimation of adverse events. In lower-risk disease, observation is recommended while in higher-risk disease, after failed repeat local therapy, ADT and/or clinical trial enrollment may be appropriate. Results from ongoing clinical studies of patients with BCR should provide consensus for management.

BACKGROUND: Biochemical recurrence (BCR) following primary interventional treatment occurs in approximately one-third of patients with prostate cancer (PCa). Next-generation imaging (NGI) can identify local and metastatic recurrence with greater sensitivity than conventional imaging, potentially allowing for more effective interventions. This narrative review examines the current clinical evidence on the utility of NGI for patients with BCR. METHODS: A search of PubMed was conducted to identify relevant publications on NGI applied to BCR. Given other relevant recent reviews on the topic, this review focused on papers published between January 2018 to May 2023. RESULTS: NGI technologies, including positron emission tomography (PET) radiotracers and multiparametric magnetic resonance imaging, have demonstrated increased sensitivity and selectivity for diagnosing BCR at prostate-specific antigen (PSA) concentrations