HCC EV ECG score: An extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma.

BACKGROUND AND AIMS: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC. APPROACH AND RESULTS: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations ( E pCAM + CD63 + , C D147 + CD63 + , and G PC3 + CD63 + HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort ( n  = 106) and an independent validation cohort ( n  = 72).Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99). CONCLUSION: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes.

Development and validation of a REcurrent Liver cAncer Prediction ScorE (RELAPSE) following liver transplantation in patients with hepatocellular carcinoma: Analysis of the US Multicenter HCC Transplant Consortium.

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22-1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04-1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35-1.73, p < 0.001), microvascular (HR = 2.37, 95%-CI, 1.87-2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41-4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29-2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54-3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.

Circulating Tumor Cell-Based Messenger RNA Scoring System for Prognostication of Hepatocellular Carcinoma: Translating Tissue-Based Messenger RNA Profiling Into a Noninvasive Setting.

Numerous studies in hepatocellular carcinoma (HCC) have proposed tissue-based gene signatures for individualized prognostic assessments. Here, we develop a novel circulating tumor cell (CTC)-based transcriptomic profiling assay to translate tissue-based messenger RNA (mRNA) signatures into a liquid biopsy setting for noninvasive HCC prognostication. The HCC-CTC mRNA scoring system combines the NanoVelcro CTC Assay for enriching HCC CTCs and the NanoString nCounter platform for quantifying the HCC-CTC Risk Score (RS) panel in enriched HCC CTCs. The prognostic role of the HCC-CTC RS was assessed in The Cancer Genome Atlas (TCGA) HCC cohort (n = 362) and validated in an independent clinical CTC cohort (n = 40). The HCC-CTC RS panel was developed through our integrated data analysis framework of 8 HCC tissue-based gene signatures and identified the top 10 prognostic genes (discoidin domain receptor tyrosine kinase 1 [DDR1], enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase [EHHADH], androgen receptor [AR], lumican [LUM], hydroxysteroid 17-beta dehydrogenase 6[HSD17B6], prostate transmembrane protein, androgen induced 1 [PMEPA1], tsukushi, small leucine rich proteoglycan [TSKU], N-terminal EF-hand calcium binding protein 2 [NECAB2], ladinin 1 [LAD1], solute carrier family 27 member 5 [SLC27A5]) highly expressed in HCC with low expressions in white blood cells. The panel accurately discriminated overall survival in TCGA HCC cohort (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.4-2.9). The combined use of the scoring system and HCC-CTC RS panel successfully distinguished artificial blood samples spiked with an aggressive HCC cell type, SNU-387, from those spiked with PLC/PRF/5 cells (P = 0.02). In the CTC validation cohort (n = 40), HCC-CTC RS remained an independent predictor of survival (HR, 5.7; 95% CI, 1.5-21.3; P = 0.009) after controlling for Model for End-Stage Liver Disease score, Barcelona Clinic Liver Cancer stage, and CTC enumeration count. Our study demonstrates a novel interdisciplinary approach to translate tissue-based gene signatures into a liquid biopsy setting. This noninvasive approach will allow real-time disease profiling and dynamic prognostication of HCC.

Optimal Timing of Administration of Direct-acting Antivirals for Patients With Hepatitis C-associated Hepatocellular Carcinoma Undergoing Liver Transplantation.

OBJECTIVE: To investigate the optimal timing of direct acting antiviral (DAA) administration in patients with hepatitis C-associated hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). SUMMARY OF BACKGROUND DATA: In patients with hepatitis C (HCV) associated HCC undergoing LT, the optimal timing of direct-acting antivirals (DAA) administration to achieve sustained virologic response (SVR) and improved oncologic outcomes remains a topic of much debate. METHODS: The United States HCC LT Consortium (2015-2019) was reviewed for patients with primary HCV-associated HCC who underwent LT and received DAA therapy at 20 institutions. Primary outcomes were SVR and HCC recurrence-free survival (RFS). RESULTS: Of 857 patients, 725 were within Milan criteria. SVR was associated with improved 5-year RFS (92% vs 77%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 92%, and 82%, and 5-year RFS of 93%, 94%, and 87%, respectively. Among 427 HCV treatment-naïve patients (no previous interferon therapy), patients who achieved SVR with DAAs had improved 5-year RFS (93% vs 76%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 93%, and 78% (P < 0.01) and 5-year RFS of 93%, 100%, and 83% (P = 0.01). CONCLUSIONS: The optimal timing of DAA therapy appears to be 0 to 3 months after LT for HCV-associated HCC, given increased rates of SVR and improved RFS. Delayed administration after transplant should be avoided. A prospective randomized controlled trial is warranted to validate these results.

Topical Scar Treatment Products for Wounds: A Systematic Review.

BACKGROUND: There is an increasing number of over-the-counter topical products that are said to prevent pathologic scar formation and improve scar cosmesis. However, robust clinical data are lacking to substantiate these claims and to guide selection of topical products. OBJECTIVE: To determine the effectiveness of topical scar management products, including silicone gel, Allium cepa onion extract, vitamin E, trolamine, and microporous tape. METHODS AND MATERIALS: A PubMed search (2005-2019) was performed to identify studies of topical scar management products. Randomized controlled trials (RCTs), quasi-RCTs, meta-analyses, and controlled clinical trials were included for analysis. RESULTS: A total of 34 trials were included in this study. Of the 16 trials investigating silicone gel sheets, numerous high-quality RCTs found that silicone gel sheets and silicone gels significantly improved scar outcomes. Only a limited number of studies supported the effectiveness of onion extract, vitamin E, trolamine, and microporous tape products. CONCLUSION: Silicone gel products are an effective noninvasive treatment to prevent formation of pathologic scars and improve mature scars. Further high-quality studies are needed to elucidate the long-term effectiveness of these therapies.

Pattern-Specific Loss of Desmoplakin I and II Immunoreactivity in Erythema Multiforme and its Variants: A Possible Aid in Histologic Diagnosis.

Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) comprise a family of mucocutaneous diseases associated with significant morbidity and mortality. Previous studies have confirmed the presence of autoantibodies to desmoplakin (Dp) I and II in patients with EM, SJS, and TEN. Truncated Dp production leads to characteristic changes visible on light microscopy: perinuclear clumping of keratin filaments and dyskeratotic keratinocyte. Based on these observations, the question arises as to whether a loss of Dp immunoreactivity in skin biopsies could serve as a diagnostic marker of EM, SJS, and TEN. This study analyzed Dp immunostaining patterns in 20 patients with EM or SJS/TEN. To assess the specificity of this approach, Dp immunostaining was also performed on specimens from patients with 5 potential histologic mimics of EM, SJS, and TEN. All of the samples from patients with EM, SJS, and TEN demonstrated absent or markedly diminished staining for Dp. A χ test demonstrated a statistically significant difference between the staining patterns in EM, SJS, and TEN and each of the other diagnostic groups that were investigated. This is the first report demonstrating statistically significant specificity of Dp staining patterns in EM/SJS/TEN as compared with other interface dermatitides.

Rapid response to treatment with thalidomide in an adolescent with generalized discoid lupus erythematosus.

Discoid lupus erythematosus (DLE) is the most common variant of cutaneous chronic lupus erythematosus (CLE). Sun protection, topical corticosteroids, and antimalarials constitute the first-line options for treatment. In refractory cases, alternative antimalarials, methotrexate, retinoids, and thalidomide have been utilized. We present a case of an adolescent patient with generalized DLE responding rapidly to thalidomide.

Characterizing and enhancing virus removal by protein A chromatography.

Protein A chromatography is an effective capture step to separate Fc-containing biopharmaceuticals from cell culture impurities but is generally not effective for virus removal, which tends to vary among different products. Previous findings have pointed to the differences in feedstocks to protein A, composed of the products and other cell culture-related impurities. To separate the effect of the feedstock components on virus removal, and understand why certain monoclonal antibody (mAb) products have low virus log reduction values (LRVs) across protein A chromatography, we investigated the partitioning of three types of viruses on Eshmuno® A columns. Using pure mAbs, we found that low LRVs were correlated with the presence of the particular mAb product itself, causing altered partitioning patterns. Three virus types were tested, and the trend in partitioning was the same for retrovirus-like particles (RVLPs) expressed in the cell substrate, and its model virus xenotropic murine leukemia virus (XMuLV), whereas slightly different for murine minute virus. These results were extended from previous observation described by Bach and Connell-Crowley (2015) studying XMuLV partitioning on MabSelect SuRe columns, providing further evidence using additional types of viruses and resin. Other product-specific cell culture impurities in harvested cell culture fluid played a lesser role in causing low LRVs. In addition, using high throughput screening (HTS) methods and Eshmuno® A resin plates, we identified excipients with ionic and hydrophobic properties that could potentially alleviate the mAb-induced LRV reduction, indicating that both ionic and hydrophobic interactions were involved. More excipients of such nature or combinations, once optimized, can potentially be used as load and/or wash additives to improve virus removal by protein A. We have demonstrated that HTS is a valuable tool for this type of screening, whether to gain deeper understanding of a mechanism, or to provide guidance during the optimization of protein A process with improved virus removal.

Closed Facebook™ groups and CME credit: a new format for continuing medical education.

BACKGROUND: The International Hernia Collaboration (IHC) is a closed Facebook™ group that allows international surgeons to post clinical questions and exchange transparent feedback with the intent to optimize patient outcomes. Despite the educational value of closed FB groups, CME credits have not been available to members. To determine feasibility of and user interest in earning CME credit through social media, the IHC piloted a series of expert lectures followed by an interactive Facebook Live session as a novel pathway offering CME credit. METHODS: Nine monthly lectures and Facebook Live sessions were presented. CME credit was offered for the final seven lectures. Participation in the form of views, comments, and likes was quantified by a Facebook analytics service and an engagement score, defined as [(the number of comments × 2) + (the number of reactions)], was calculated for each lecture and Facebook Live session. CME credit was obtained through a two-question quiz. RESULTS: Of 5400 + Facebook members of the IHC, an average of 1116 (20.4 ± 4.0%) viewed the live session event following each lecture (n = 9 events). The average Facebook engagement score for Facebook Live was 259 ± 75, a significant difference with the average Facebook engagement score on the IHC (40.8) over the same time period (p < 0.001). On average, 16 users [range 8-35, (n = 7 events)] claimed CME credit for each educational series. CONCLUSIONS: Closed Facebook groups can be a useful media to offer educational content and CME credit. The pilot IHC Lecture and Facebook Live series offering CME credit resulted in significantly more engagement amongst its members compared to other posts during the same time period. A small portion of participants qualified for CME credit. Future social media educational series may increase participants qualifying for CME by streamlining the interface to obtain CME credit.

Cabozantinib exposure-response analyses of efficacy and safety in patients with advanced hepatocellular carcinoma.

Cabozantinib, a multi-kinase inhibitor, is approved in the United States and European Union for treatment of patients with hepatocellular carcinoma following prior sorafenib treatment. In the Phase III CELESTIAL trial, hepatocellular carcinoma patients receiving cabozantinib showed longer overall survival (OS) and progression-free survival (PFS) than those receiving placebo. The approved cabozantinib (Cabometyx®) dose is 60 mg once daily with allowable dose modifications to manage adverse events (AE). Time-to-event Cox proportional hazard exposure-response (ER) models were developed to characterize the relationship between predicted cabozantinib exposure and the likelihood of various efficacy and safety endpoints. The ER models were used to predict hazard ratios (HR) for efficacy and safety endpoints for starting doses of 60, 40, or 20 mg daily. Statistically significant relationships between cabozantinib exposure and efficacy and safety endpoints were observed. For efficacy endpoints, predicted HR were lower for OS and PFS at 40 and 60 mg relative to the 20 mg dose: HR for death (OS) are 0.84 (40 mg) and 0.70 (60 mg); HR for disease progression/death (PFS) are 0.73 (40 mg) and 0.62 (60 mg). For safety endpoints, predicted HR were lower for palmar-plantar erythrodysaesthesia (PPE), diarrhea, and hypertension at 20 or 40 mg relative to the 60 mg dose: HR for PPE are 0.31 (20 mg) and 0.66 (40 mg); HR for diarrhea are 0.61 (20 mg) and 0.86 (40 mg); HR for hypertension are 0.46 (20 mg) and 0.76 (40 mg). The rate of dose modifications was predicted to increase in patients with lower cabozantinib apparent clearance. OS and PFS showed the greatest benefit at the 60 mg dose. However, higher cabozantinib exposure was predicted to increase the likelihood of AE and subsequent dose reductions appeared to decrease these risks.

Ketamine and norketamine stability in whole blood at ambient and 4°C conditions.

A study was implemented to describe the pharmacokinetics (PK) of ketamine (K) and its metabolite norketamine (NK) in critically ill adults. Conducting studies in these subjects is hindered by the immediate need to process and freeze samples obtained in a busy intensive care setting. The ability to store unprocessed samples at room temperature for an extended time period would overcome this barrier. Stability and blood to plasma partitioning of K and NK were investigated in whole blood for up to 120 h at room temperature and 4°C. Whole blood was spiked with K and NK (1000 ng/mL each). Blood samples were aliquoted at different time points (0-120 h), extracted and analyzed using a validated high-performance liquid chromatography tandem mass spectrometry assay. The study demonstrated the stability of both K and NK in whole blood up to 120 h. These in vitro studies suggest that the concentrations of K and NK measured in the PK samples are reliable. The established stability results were successfully employed to investigate K and NK pharmacology studies in critically ill adults.

Quantification of beam steering with an ionization chamber array.

Routine quality assurance for linear accelerators (linacs) usually involves verification of beam steering with a water scanning system. We established a beam steering procedure that uses a 2D ionization chamber array (ICA) and verified the equivalence of beam symmetry between the ICA and a water scanning system. The ICA calibration accuracy, reproducibility and stability were evaluated and the uncertainty in the measurement of beam symmetry due to the array calibration was examined. Forty-five photon beams and 80 electron beams across 7 Varian C-series and 4 TrueBeam linacs were steered in the radial and transverse directions using an ICA. After beam steering, profiles were re-measured using the ICA and in-water using a 3D Scanner (3DS). Beam symmetries measured with the ICA and 3DS were compared by (a) calculating the difference in point-by-point symmetry, (b) plotting the histogram distribution of the symmetry differences, and (c) comparing ICA and 3DS differences with their respective Varian symmetry protocol analysis. Array calibrations from five different occurrences (2012 to 2016) over six different beams reproduced within 0.5%. The uncertainty in beam symmetry was less than 0.5% due to the uncertainties in the array calibration. After all beams were steered using the ICA, the point-by-point symmetry differences between ICA and 3DS at the off-axis positions of 20% and 80% of field size for all beam profiles indicated that 95% of point-by-point symmetry comparisons agreed within 0.7%, and 100% agreed within 1.0%; after steering with the ICA 97.8% of photon beam profiles (88 of 90) and 97.5% of electron beam profiles (156 of 160) had symmetry within 1% when measured with the 3DS. All photon and electron beam profiles had symmetry within 1.1% and 1.2%, respectively, for profiles measured with the 3DS. Our data demonstrate that a calibrated ICA can be used to steer photon and electron beams achieving beam symmetry within 1% when re-measured with a 3D water scanning system.

Specific catalysis of asparaginyl deamidation by carboxylic acids: kinetic, thermodynamic, and quantitative structure-property relationship analyses.

Asparaginyl (Asn) deamidation could lead to altered potency, safety, and/or pharmacokinetics of therapeutic protein drugs. In this study, we investigated the effects of several different carboxylic acids on Asn deamidation rates using an IgG1 monoclonal antibody (mAb1*) and a model hexapeptide (peptide1) with the sequence YGKNGG. Thermodynamic analyses of the kinetics data revealed that higher deamidation rates are associated with predominantly more negative ΔS and, to a lesser extent, more positive ΔH. The observed differences in deamidation rates were attributed to the unique ability of each type of carboxylic acid to stabilize the energetically unfavorable transition-state conformations required for imide formation. Quantitative structure property relationship (QSPR) analysis using kinetic data demonstrated that molecular descriptors encoding for the geometric spatial distribution of atomic properties on various carboxylic acids are effective determinants for the deamidation reaction. Specifically, the number of O-O and O-H atom pairs on carboxyl and hydroxyl groups with interatomic distances of 4-5 Å on a carboxylic acid buffer appears to determine the rate of deamidation. Collectively, the results from structural and thermodynamic analyses indicate that carboxylic acids presumably form multiple hydrogen bonds and charge-charge interactions with the relevant deamidation site and provide alignment between the reactive atoms on the side chain and backbone. We propose that carboxylic acids catalyze deamidation by stabilizing a specific, energetically unfavorable transition-state conformation of l-asparaginyl intermediate II that readily facilitates bond formation between the γ-carbonyl carbon and the deprotonated backbone nitrogen for cyclic imide formation.

Evolution of hormonal therapy for prostate cancer.

BACKGROUND: Prostate cancer (PCa) is the most common malignancy after skin cancer in men in Australia. Its management varies according to tumour stage. Due to the significant dependence on androgen receptor signalling, agents that interfere with this pathway (most commonly medical castration in the form of androgen deprivation therapy [ADT]) are the mainstay treatment of advanced disease. OBJECTIVE: This review provides a contemporary update on ADT, with further discussion of emerging novel therapies for primary care. DISCUSSION: ADT is currently indicated for the treatment of metastatic prostate cancer, disease recurrence following attempted local curative therapy, as well as combined use with radiotherapy for intermediate/high-risk disease. There has been rapid development of new pharmaceuticals targeting the androgen receptor. These are reviewed historically with an emphasis placed on emerging therapies, their common side effects, and how to manage them in the general practice setting.

Non-operating room anesthesia workflow (NORA) implementation to improve start times in interventional radiology.

BACKGROUND: Non-OR Anesthesia (NORA) is rapidly becoming standard in many high-volume institutions and efficiency in these spaces has yet to be optimized. On-time first start percentage has been suggested to correlate with more efficient flow, and this correlation is established within the surgical space. PURPOSE: To investigate the effects of timetable targets on first case on-time first start percentage within a NORA setting. MATERIALS AND METHODS: A retrospective study of anesthesia-supported first start cases from October 2022 to April 2023 was performed to analyze the effect of timetable targets on on-time first-case starts for planned cases. Statistical analysis was calculated using Student's t-tests with statistical significance defined as p < 0.05. Additionally, analysis of variance was used to compare three or more groups, and Tukey Kramer was used to evaluate groups pairwise. RESULTS: One hundred twenty-four first start cases were included in the evaluation. After intervention with timetable targets, average patient arrival to the room time improved from 7:49 AM to 7:40 AM (p < 0.05) and procedure start time improved from 8:31 AM to 8:20 AM (p < 0.01). The percentage of procedure start times occurring prior to the goal time increased from 35 % to 58 % after the implementation (p < 0.05). With exception of Tuesdays (Anesthesia Late Start Day), on-time starts improved from 17 % to 48 % (p < 0.01) and sustained this improvement throughout the post-implementation period. CONCLUSION: Implementation of novel timetable targets yielded statistically significant improvement in first case start times. This improvement in efficiency and throughput results in increased room utilization, improved case throughput, and decreased block overrun times, all of which contribute toward increased revenues, decreased costs, and thus improved return on investment.

Sequential emergence and contraction of epithelial subtypes in the prenatal human choroid plexus revealed by a stem cell model.

Despite the major roles of choroid plexus epithelial cells (CPECs) in brain homeostasis and repair, their developmental lineage and diversity remain undefined. In simplified differentiations from human pluripotent stem cells, derived CPECs (dCPECs) displayed canonical properties and dynamic multiciliated phenotypes that interacted with Aß uptake. Single dCPEC transcriptomes over time correlated well with human organoid and fetal CPECs, while pseudotemporal and cell cycle analyses highlighted the direct CPEC origin from neuroepithelial cells. In addition, time series analyses defined metabolic (type 1) and ciliogenic dCPECs (type 2) at early timepoints, followed by type 1 diversification into anabolic-secretory (type 1a) and catabolic-absorptive subtypes (type 1b) as type 2 cells contracted. These temporal patterns were then confirmed in independent derivations and mapped to prenatal stages using human tissues. In addition to defining the prenatal lineage of human CPECs, these findings suggest new dynamic models of ChP support for the developing human brain.

Skin Metastasis of Low-Grade Ovarian Serous Carcinoma: A Case Report.

This case report, written with the assistance of ChatGPT, describes a rare manifestation of ovarian serous carcinoma that metastasized to the skin. A 30-year-old female with a history of stage IV low-grade serous ovarian carcinoma presented for evaluation of a painful nodule on her back. Physical examination demonstrated a round, firm, mobile subcutaneous nodule on the left upper back. An excisional biopsy was performed, and histopathologic examination was consistent with metastatic ovarian serous carcinoma. This case highlights the clinical presentation, histopathology, and treatment of cutaneous metastasis of serous ovarian carcinoma. Additionally, this case highlights the value and technique of using ChatGPT to assist in writing medical case reports including outlining, referencing, summarizing studies, and formatting citations.

Cabozantinib exposure-response analysis for the phase 3 CheckMate 9ER trial of nivolumab plus cabozantinib versus sunitinib in first-line advanced renal cell carcinoma.

PURPOSE: In the phase 3 CheckMate 9ER trial, intravenous nivolumab (240 mg every 2 weeks) plus oral cabozantinib (40 mg/day) improved progression-free survival (PFS) versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC). To support cabozantinib dosing with the combination, this exposure-response analysis characterized the relationship of cabozantinib exposure with clinical endpoints. METHODS: Dose modification was allowed with cabozantinib (holds and reductions) to manage adverse events (AEs). The population pharmacokinetics analysis was updated and used to generate individual predicted cabozantinib exposure measures. Kaplan-Meier plots and time-to-event Cox proportional hazard (CPH) exposure-response models characterized the relationship of cabozantinib exposure with PFS, dose modifications, and selected AEs. RESULTS: Kaplan-Meier plots showed no clear difference in PFS across cabozantinib exposure quartiles. Cabozantinib exposure did not significantly affect the hazard of PFS in the CPH base model nor in the final model. In contrast, baseline albumin and nivolumab clearance had a significant effect on PFS. There was no significant relationship between cabozantinib clearance and risk of dose modification, but a significant relationship was identified between cabozantinib exposure and Grade ≥ 1 palmar-plantar-erythrodysesthesia and Grade ≥ 3 diarrhea in the exposure-response analysis. CONCLUSION: To optimize individual cabozantinib exposure, these data support the dose modification strategies in CheckMate 9ER for cabozantinib in patients with advanced RCC when combined with nivolumab.