A selective CutMix approach improves generalizability of deep learning-based grading and risk assessment of prostate cancer.

The Gleason score is an important predictor of prognosis in prostate cancer. However, its subjective nature can result in over- or under-grading. Our objective was to train an artificial intelligence (AI)-based algorithm to grade prostate cancer in specimens from patients who underwent radical prostatectomy (RP) and to assess the correlation of AI-estimated proportions of different Gleason patterns with biochemical recurrence-free survival (RFS), metastasis-free survival (MFS), and overall survival (OS). Training and validation of algorithms for cancer detection and grading were completed with three large datasets containing a total of 580 whole-mount prostate slides from 191 RP patients at two centers and 6218 annotated needle biopsy slides from the publicly available Prostate Cancer Grading Assessment dataset. A cancer detection model was trained using MobileNetV3 on 0.5 mm × 0.5 mm cancer areas (tiles) captured at 10× magnification. For cancer grading, a Gleason pattern detector was trained on tiles using a ResNet50 convolutional neural network and a selective CutMix training strategy involving a mixture of real and artificial examples. This strategy resulted in improved model generalizability in the test set compared with three different control experiments when evaluated on both needle biopsy slides and whole-mount prostate slides from different centers. In an additional test cohort of RP patients who were clinically followed over 30 years, quantitative Gleason pattern AI estimates achieved concordance indexes of 0.69, 0.72, and 0.64 for predicting RFS, MFS, and OS times, outperforming the control experiments and International Society of Urological Pathology system (ISUP) grading by pathologists. Finally, unsupervised clustering of test RP patient specimens into low-, medium-, and high-risk groups based on AI-estimated proportions of each Gleason pattern resulted in significantly improved RFS and MFS stratification compared with ISUP grading. In summary, deep learning-based quantitative Gleason scoring using a selective CutMix training strategy may improve prognostication after prostate cancer surgery.

Cricopharyngomyotomy: Outcomes of flexible endoscopic management of small and medium sized Zenker's diverticulum.

BACKGROUND: Zenker's diverticulum (ZD) was historically treated with an open transcervical myotomy with diverticulectomy, but endoscopic approaches have gained popularity, though with little recent data. This study aimed to report flexible endoscopic cricopharyngomyotomy (FEC) outcomes, particularly in smaller diverticula. METHODS: Patients with ZD treated with FEC at a tertiary center were reviewed. Patients were grouped by diverticulum size: small (sZD)≤1.5 â€‹cm; medium (mZD) â€‹> â€‹1.5 â€‹cm. RESULTS: Of 30 patients, median age, BMI, sex, and comorbidities were similar between sZD (n â€‹= â€‹18) and mZD (n â€‹= â€‹12). Overall, 80.0 â€‹% had the procedure performed with a needle knife. Median number of clips for mucosotomy closure (5.0[5.0,6.0]vs.7.0[5.0,7.0]clips;p â€‹= â€‹0.051), operative time (59.5[51.0,75.0]vs.74.5[51.0,93.5]minutes;p â€‹= â€‹0.498), length-of-stay (1.0[1.0,1.0]vs.1.0[1.0,1.0]days;p â€‹= â€‹0.397), and follow-up (20.8[1.1,33.4]vs.15.6[5.4,50.4]months;p â€‹= â€‹0.641) were comparable. There were no postoperative leaks; incomplete myotomy occurred in one sZD, yielding a clinical success rate of 96.7 â€‹%. CONCLUSIONS: FEC has a high success rate for ZD and an advantage in small diverticula, difficult to treat with stapling or open technique.

A Phase 2 Multicenter Clinical Trial of Intraoperative Molecular Imaging of Lung Cancer with a pH-Activatable Nanoprobe.

PURPOSE: Intraoperative molecular imaging (IMI) uses tumor-targeted optical contrast agents to improve identification and clearance of cancer. Recently, a probe has been developed that only fluoresces when activated in an acidic pH, which is common to many malignancies. We report the first multicenter Phase 2 trial of a pH-activatable nanoprobe (pegsitacianine, ONM-100) for IMI of lung cancer. METHODS: Patients with suspected or biopsy-confirmed lung cancer scheduled for sublobar resection were administered a single intravenous infusion of pegsitacianine (1 mg/kg) one to three days prior to surgery. Intraoperatively, the patients underwent a white light thoracoscopic evaluation, and then were imaged with an NIR thoracoscope to detect tumor fluorescence. The primary study endpoint was the proportion of patients with a clinically significant event (CSE) which was defined as an intraoperative discovery during IMI that led to a change in the surgical procedure. Possible CSEs included (i) localizing the index lung nodule that could not be located by white light, (ii) identifying a synchronous malignant lesion, or (iii) recognizing a close surgical margin (< = 10 mm). Secondary endpoints were sensitivity, specificity, NPV, and PPV of pegsitacianine in detecting tumor-containing tissue. The safety evaluation was based on adverse event reporting, clinical laboratory parameters, and physical examinations. RESULTS: Twenty patients were confirmed as eligible and administered pegsitacianine. Most of the patients were female (n = 12 [60%]), middle-aged (mean age 63.4 years), and former smokers (n = 13 [65%], 28.6 mean pack years). Mean lesion size was 1.9 cm, and most lesions (n = 17 [85%]) were malignant. The most common histologic subtype was adenocarcinoma (n = 9). By utilizing IMI with pegsitacianine, one patient had a CSE in the detection of a close margin and another had localization of a tumor not detectable by traditional surgical means. Six of 19 (31.6%) malignant lesions fluoresced with mean tumor-to-background ratio (TBR) of 3.00, as compared to TBR of 1.20 for benign lesions (n = 3). Sensitivity and specificity of pegsitacianine-based IMI for detecting malignant tissue was 31.6% and 33.3%, respectively. Positive predictive value (PPV) and negative predictive value (NPV) of pegsitacianine-based IMI was 75% and 7.1%, respectively. Pegsitacianine-based imaging was not effective in differentiating benign and malignant lymph nodes. From a safety perspective, no drug-related serious adverse events occurred. Four patients experienced mild pegsitacianine-related infusion reactions which required discontinuing the study drug with complete resolution of symptoms. CONCLUSIONS: Pegsitacianine-based IMI, though well tolerated from a safety perspective, does not consistently label lung tumors during resection and does not provide significant clinical benefit over existing standards of surgical care. The biology of lung tumors may not be as acidic as other solid tumors in the body thereby not activating the probe as predicted.

Extra-articular proximal tibia fracture fixation with locked plating versus intramedullary nailing: A meta-analysis.

OBJECTIVES: This study compared outcomes of locked plating (LP) versus intramedullary nailing (IMN) techniques for treatment of extra-articular proximal-third tibia fractures. METHODS: Data Sources: PubMed, Ovid MEDLINE STUDY SELECTION: Studies were included if they compared LP and IMN fixation for proximal one third tibial shaft fractures without articular extension or with simple articular extension into the tibial plateau. Minimum 1 year of clinical and radiographic follow up was used. DATA EXTRACTION: Outcomes assessed included operative duration, postoperative knee range of motion (ROM), union outcomes (time to union, nonunion, malunion, delayed union), and incidence of postoperative complications (superficial and deep infection, secondary surgical intervention, compartment syndrome). DATA SYNTHESIS: Separate random-effects meta-analyses were conducted for each outcome. For categorical data, relative risks were used whereas the standardized mean difference was used for continuous variables, with corresponding 95 % confidence intervals. RESULTS: 7 studies were included reporting the outcomes of 319 patients treated with LP and 300 treated with IMN. IMN fixation had significantly shorter time to union (p = 0.049) and lower risk for superficial infection (p = 0.028). However, LP conferred a significantly lower risk for malunion (p = 0.017) and postoperative compartment syndrome (p = 0.018). CONCLUSION: IMN demonstrated significantly shorter time to union and lower risk of superficial infection when treating extra-articular proximal tibia fractures, while LP fixation demonstrated significantly lower risk for malunion and postoperative compartment syndrome. Although successful results can be achieved with good technique in LP and IMN fixation, a significant complication profile exists with these fractures regardless of construct choice. LEVEL OF EVIDENCE: Therapeutic Level III.

Statistical Analysis of Self-Reported Health Conditions in Cohort Studies: Handling of Missing Onset Age.

OBJECTIVE: This paper discusses methodological challenges in epidemiological association analysis of a time-to-event outcome and hypothesized risk factors, where age/time at the onset of the outcome may be missing in some cases, a condition commonly encountered when the outcome is self-reported. STUDY DESIGN AND SETTING: A cohort study with long-term follow-up for outcome ascer- tainment such as the Childhood Cancer Survivor Study (CCSS), a large cohort study of 5-year survivors of childhood cancer diagnosed in 1970-1999 in which occurrences and age at onset of various chronic health conditions (CHCs) are self-reported in surveys. Simple methods for handling missing onset age and their potential bias in the exposure-outcome association infer- ence are discussed. The interval-censored method is discussed as a remedy for handling this problem. The finite sample performance of these approaches is compared through Monte Carlo simulations. Examples from the CCSS include four CHCs (diabetes, myocardial infarction, osteoporosis/osteopenia, and growth hormone deficiency). RESULTS: The interval-censored method is usable in practice using the standard statisti- cal software. The simulation study showed that the regression coefficient estimates from the 'Interval censored' method consistently displayed reduced bias and, in most cases, smaller stan- dard deviations, resulting in smaller mean square errors, compared to those from the simple approaches, regardless of the proportion of subjects with an event of interest, the proportion of missing onset age, and the sample size. CONCLUSION: The interval-censored method is a statistically valid and practical approach to the association analysis of self-reported time-to-event data when onset age may be missing. While the simpler approaches that force such data into complete data may enable the standard analytic methods to be applicable, there is considerable loss in both accuracy and precision relative to the interval-censored method.

Race and Ethnicity, Socioeconomic Factors, and Epigenetic Age Acceleration in Survivors of Childhood Cancer.

Importance: Current research in epigenetic age acceleration (EAA) is limited to non-Hispanic White individuals. It is imperative to improve inclusivity by considering racial and ethnic minorities in EAA research. Objective: To compare non-Hispanic Black with non-Hispanic White survivors of childhood cancer by examining the associations of EAA with cancer treatment exposures, potential racial and ethnic disparity in EAA, and mediating roles of social determinants of health (SDOH). Design, Setting, and Participants: In this cross-sectional study, participants were from the St Jude Lifetime Cohort, which was initiated in 2007 with ongoing follow-up. Eligible participants included non-Hispanic Black and non-Hispanic White survivors of childhood cancer treated at St Jude Children's Research Hospital between 1962 and 2012 who had DNA methylation data. Data analysis was conducted from February 2023 to May 2024. Exposure: Three treatment exposures for childhood cancer (chest radiotherapy, alkylating agents, and epipodophyllotoxin). Main Outcomes and Measures: DNA methylation was generated from peripheral blood mononuclear cell-derived DNA. EAA was calculated as residuals from regressing Levine or Horvath epigenetic age on chronological age. SDOH included educational attainment, annual personal income, and the socioeconomic area deprivation index (ADI). General linear models evaluated cross-sectional associations of EAA with race and ethnicity (non-Hispanic Black and non-Hispanic White) and/or SDOH, adjusting for sex, body mass index, smoking, and cancer treatments. Adjusted least square means (ALSM) of EAA were calculated for group comparisons. Mediation analysis treated SDOH as mediators with average causal mediation effect (ACME) calculated for the association of EAA with race and ethnicity. Results: Among a total of 1706 survivors including 230 non-Hispanic Black survivors (median [IQR] age at diagnosis, 9.5 [4.3-14.3] years; 103 male [44.8%] and 127 female [55.2%]) and 1476 non-Hispanic White survivors (median [IQR] age at diagnosis, 9.3 [3.9-14.6] years; 766 male [51.9%] and 710 female [48.1%]), EAA was significantly greater among non-Hispanic Black survivors (ALSM = 1.41; 95% CI, 0.66 to 2.16) than non-Hispanic White survivors (ALSM = 0.47; 95% CI, 0.12 to 0.81). Among non-Hispanic Black survivors, EAA was significantly increased among those exposed to chest radiotherapy (ALSM = 2.82; 95% CI, 1.37 to 4.26) vs those unexposed (ALSM = 0.46; 95% CI, -0.60 to 1.51), among those exposed to alkylating agents (ALSM = 2.33; 95% CI, 1.21 to 3.45) vs those unexposed (ALSM = 0.95; 95% CI, -0.38 to 2.27), and among those exposed to epipodophyllotoxins (ALSM = 2.83; 95% CI, 1.27 to 4.40) vs those unexposed (ALSM = 0.44; 95% CI, -0.52 to 1.40). The association of EAA with epipodophyllotoxins differed by race and ethnicity (ß for non-Hispanic Black survivors, 2.39 years; 95% CI, 0.74 to 4.04 years; ß for non-Hispanic White survivors, 0.68; 95% CI, 0.05 to 1.31 years) and the difference was significant (1.77 years; 95% CI, 0.01 to 3.53 years; P for interaction = .049). Racial and ethnic disparities in EAA were mediated by educational attainment (

Neurocognitive outcomes and functional independence in adult survivors of childhood medulloblastoma diagnosed over three decades.

BACKGROUND: Treatment of childhood medulloblastoma has evolved to reduce neurotoxicity while improving survival. However, the impact of evolving therapies on late neurocognitive outcomes and adult functional independence remains unknown. METHODS: Adult survivors of childhood medulloblastoma (n=505; median[minimum-maximum] age, 29[18-46] years) and sibling controls (n=727; 32[18-58] years) from the Childhood Cancer Survivor Study completed surveys assessing neurocognitive problems and chronic health conditions (CHCs). Treatment exposures were categorized as historical (craniospinal irradiation [CSI]≥30 Gy, no chemotherapy), standard-risk (CSI>0 to <30 Gy +chemotherapy) and high-risk (CSI≥30 Gy +chemotherapy) therapy. Latent class analysis identified patterns of functional independence using employment, independent living, assistance with routine/personal care needs, driver's license, marital/partner status. Multivariable models estimated risk of neurocognitive impairment in survivors versus siblings and by treatment exposure group, and associations between neurocognitive impairment, CHCs, and functional independence. RESULTS: Survivors in each treatment exposure group had 4- to 5-fold elevated risk of impaired memory and task efficiency compared to siblings. Contemporary risk-based therapies did not confer lower risk compared to historical therapy. Survivors treated in the 1990s had higher risk of memory impairment (relative risk [RR] 2.24, 95% confidence interval [CI] 1.39-3.60) compared to survivors treated in the 1970s. Sensorimotor, hearing problems and seizures were associated with 33%-34%, 25-26% and 21%-42% elevated risk of task efficiency and memory impairment, respectively. Treatment-related CHCs and neurocognitive impairment were associated with non-independence. CONCLUSIONS: Despite treatment changes, long-term survivors of childhood medulloblastoma remain at risk for neurocognitive impairment, which was associated with CHCs. Neurocognitive surveillance after contemporary regimens is imperative.

Long-term outcomes among survivors of childhood osteosarcoma: A report from the Childhood Cancer Survivor Study (CCSS).

PURPOSE: Treatment strategies for osteosarcoma evolving between 1970 and 1999 improved 5-year survival and continue as standard of care today. This report evaluates the impact of these evolving therapies on long-term health outcomes. METHODS: Five-year survivors of childhood osteosarcoma in CCSS treated from 1970 to 1999 were evaluated for late (>5 years from diagnosis) mortality, chronic health conditions (CHCs), and health status using piecewise-exponential and logistical models. Comparisons were made between survivors and siblings without cancer, and among survivors examining historical and current standard chemotherapies (e.g., methotrexate/doxorubicin/cisplatin [MAP] vs. others), specific chemotherapy agents and surgical approaches (amputation vs. limb salvage [LS]). Models were evaluated adjusting for attained age, sex, race, ethnicity, and age at diagnosis. RESULTS: A total of 1257 survivors of osteosarcoma were followed on average for 24.4 years. Twenty-year all-cause late mortality was 13.3% (95% confidence interval [CI]: 11.7%-14.9%) overall and 11.7% (95% CI: 6.9%-16.5%) for the subset treated with MAP plus LS. Survivors were at higher risk of CHCs (rate ratio [RR] 3.7, 95% CI: 3.2-4.3) than the sibling cohort, most notably having more serious cardiac, musculoskeletal, and hearing CHCs. Within the survivor cohort, the risk of severe CHCs was twice as high with MAP versus no chemotherapy (RR 2.1, 95% CI: 1.3-3.4). Compared with primary amputation, serious musculoskeletal CHCs were higher after LS (RR 6.6, 95% CI: 3.6-13.4), without discernable differences in health status. CONCLUSION: Contemporary osteosarcoma therapy with MAP plus LS, while improving 5-year disease-free survival, continues to be associated with a high burden of late mortality, CHCs, and health status limitations.

Characterization of chronic pain, pain interference, and daily pain experiences in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.

ABSTRACT: Although survivors of childhood cancer are at an increased risk, little is known about the prevalence of chronic pain, associated interference, and daily pain experiences. Survivors (N = 233; mean age = 40.8 years, range 22-64 years; mean time since diagnosis = 32.7 years) from the Childhood Cancer Survivor Study completed pain and psychosocial measures. Survivors with chronic pain completed 2-week, daily measures assessing pain and psychological symptoms using mHealth-based ecological momentary assessment. Multivariable-modified Poisson and linear regression models estimated prevalence ratio estimates (PR) and mean effects with 95% confidence intervals (CI) for associations of key risk factors with chronic pain and pain interference, respectively. Multilevel mixed models examined outcomes of daily pain and pain interference with prior day symptoms. Ninety-six survivors (41%) reported chronic pain, of whom 23 (24%) had severe interference. Chronic pain was associated with previous intravenous methotrexate treatment (PR = 1.6, 95% CI 1.1-2.3), respiratory (PR = 1.8, 95% CI 1.2-2.5), gastrointestinal (PR = 1.6, 95% CI 11.0-2.3), and neurological (PR = 1.5, 95% CI 1.0-2.1) chronic health conditions, unemployment (PR = 1.4, 95% CI 1.0-1.9) and clinically significant depression and anxiety (PR = 2.9, 95% CI 2.0-4.2), as well as a diagnosis of childhood Ewing sarcoma or osteosarcoma (PR = 1.9, 95% CI 1.0-3.5). Higher pain interference was associated with cardiovascular and neurological conditions, unemployment and clinical levels of depression and/or anxiety, and fear of cancer recurrence. For male, but not female survivors, low sleep quality, elevated anxiety, and elevated depression predicted high pain intensity and interference the next day. A substantial proportion of childhood cancer survivors experience chronic pain and significant associated interference. Chronic pain should be routinely evaluated, and interventions are needed.

Negative urgency as a state-level process.

OBJECTIVE: Test whether global self-reports of urgency moderated the within-person associations of affect and impulsive behaviors. BACKGROUND: Negative urgency is a personality trait that is a risk factor for a range of psychopathology. Although it is assumed that global self-reports of urgency measure individual tendencies to act more impulsively in the face of negative emotions, evidence from ecological momentary assessment studies is mixed. METHOD: In this Registered Report, we used ecological momentary assessment data from a large sample of young adults (n = 496, age 18-22, 5 surveys per day for 40 days). RESULTS: All forms of momentary impulsivity were impaired in moments when people reported more intense negative emotions, but global self-reports of urgency did not explain individual differences in this association. Moreover, averaged affective states, rather than specific dimensions, affective circumplex, or appraisals, best predicted impulsive states. CONCLUSIONS: Results suggest that face-valid interpretations of global self-report of urgency are inaccurate, and it may be important to understand how some people come to understand themselves as high on urgency rather than assuming that people's self-reports of their motivations are accurate. Momentary experiences of emotions globally impact multiple weakly to moderately associated impulsive behaviors, and future research should seek to understand both when and for whom these associations are strongest.

A comparison between the measurement of quantum spatial correlations using qCMOS photon-number resolving and electron multiplying CCD camera technologies.

Cameras with single-photon sensitivities can be used to measure the spatial correlations between the photon-pairs that are produced by parametric down-conversion. Even when pumped by a single-mode laser, the signal and idler photons are typically distributed over several thousand spatial modes yet strongly correlated with each other in their position and anti-correlated in their transverse momentum. These spatial correlations enable applications in imaging, sensing, communication, and optical processing. Here we show that, using a photon-number resolving camera, spatial correlations can be observed after only a few 10s of seconds of measurement time, thereby demonstrating comparable performance with previous single photon sensitive camera technologies but with the additional capability to resolve photon-number. Consequently, these photon-number resolving technologies are likely to find wide use in quantum, low-light, imaging systems.

Comparative Trends in the Distribution of Prostate Cancer Stage at Diagnosis in the Department of Defense Cancer Registry and the Surveillance, Epidemiology, and End Results Data, 2004-2014.

INTRODUCTION: It has been demonstrated that there was an increase in later-stage prostate cancer (PCa) at diagnosis after the U.S. Preventive Services Task Force recommended against prostate-specific antigen screening for prostate cancer. However, the cancer characteristics at diagnosis within the equal-access Military Health System (MHS) during the period have not been described. In this study, we compared PCa stage at diagnosis and its trends between the military health care system and the general public and further compared the trends in tumor stage by race. MATERIALS AND METHODS: This study was based on nonidentifiable data from the U.S. Department of Defense's Central Cancer Registry (CCR) and the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. Patients diagnosed between 2004 and 2014 were included. The distributions of PCa stage at diagnosis over time were compared between the 2 populations. Comparisons were further conducted for White and Black patients, respectively. RESULTS: Among the 11,895 patients in the CCR and 544,142 patients in SEER, the majority of patients were diagnosed with stage I or II prostate cancer. However, the CCR had a larger proportion of early-stage tumors (stages I and II combined) with 84.3% vs. 80.0% of SEER patients. The proportion of late-stage tumors (stages III and IV combined) increased over time from 2008 for both populations and the proportion of early-stage tumors decreased for the general population. In terms of temporal distributions by race, the trends were the same between White and Black groups in the general population. In the MHS, the trends in the White patients were similar to those in the general population, but in the Black patients, the percentages of stages I and II at diagnosis continued to increase and those of stages III and IV decreased, differing from those in the general population. CONCLUSIONS: The MHS consistently diagnosed PCa at an earlier stage than the U.S. general population across all time periods evaluated in this study. Although similar trends were observed for White patients between both populations, the proportion of stages I and II at diagnosis increased from 2012 among Black patients in the MHS, which stands in sharp contrast to trends in the U.S. general population. Although the differences between the two populations may be associated with various factors, differences in accessibility to care and thus the use of prostate-specific antigen testing might play an important role.

Utility of bioselection with neoadjuvant chemotherapy for organ preservation in patients with T4 laryngeal cancer.

BACKGROUND: Neoadjuvant chemotherapy for induction selection of definitive treatment (IS) protocols have shown excellent outcomes for organ preservation and survival in patients with T3 laryngeal squamous cell carcinoma (LSCC). We seek to evaluate survival and organ preservation outcomes in T4 LSCC patients treated with IS protocols. METHODS: Retrospective cohort of advanced T3 and T4 LSCC patients who underwent IS protocols based upon potential for preserving a functional larynx. Patients received one neoadjuvant cycle of platinum-based chemotherapy with either 5-fluorouracil or docetaxel or with two cycles of platinum-based chemotherapy with docetaxel and a Bcl-2 inhibitor. Patients who achieved ≥ 50 % response as determined by radiographic review and/or endoscopic evaluation received definitive chemoradiation. Patients who had < 50 % response after IS underwent total laryngectomy (TL) followed by post-operative radiation +/- chemotherapy. RESULTS: Amongst T4 patients, 114 met inclusion criteria including 89 who underwent IS protocols and 25 who received an upfront TL. In total, 76.0 % of T3 patients and 71.9 % of T4 patients responded to IS and underwent definitive chemoradiation. There was no significant difference in hazard of death between T4 IS and T4 TL patients (HR: 0.9, p = 0.86). Among responders, there was no significant difference in 5-year laryngectomy-free survival (T3 - 59.6 %, T4 44.3 %, p = 0.15) or laryngeal preservation by T stage (T3 - 72.8 %, T4 - 73.0 %, p = 0.84). CONCLUSIONS: Select T4 patients may benefit from organ preservation using IS protocols with similar response rates to patients with T3 tumors, without compromising survival when compared to upfront TL.

Hepatic improvement within 27 days of avenciguat treatment in Child-Pugh A cirrhosis detected by an oral cholate challenge test.

New methods for measuring hepatic improvement in clinical trials and the clinic are needed. One new method, HepQuant SHUNT, detected dose-dependent improvements in hepatic function and portal physiology in the phase 1b study (NCT03842761) of avenciguat, an activator of soluble guanylyl cyclase that is being developed for the treatment of portal hypertension. Herein, we examined whether HepQuant Duo, an easy-to-administer test version, could similarly detect the effects of avenciguat. Twenty-three patients with Child-Pugh A cirrhosis and liver stiffness >15 kPa received either a placebo (n = 5) or a maximum twice-daily avenciguat dose of 1, 2, or 3 mg (n = 6 per group) for 28 days. The DuO test was performed at baseline and on days 11 and 27 in each subject. The test involved administering 40 mg of d4-cholate orally, measuring d4-cholate concentrations in serum at 20 and 60 minutes, and calculating portal hepatic filtration rate, disease severity index, portal-systemic shunting (SHUNT%), and hepatic reserve (HR%). Avenciguat demonstrated dose-dependent improvement in all test parameters. Changes from baseline in SHUNT% after 27 days' treatment were 0.1 ± 9.0% for placebo, 1.7 ± 5.5% for 1 mg twice-daily, -3.2 ± 2.7% for 2 mg twice-daily, and -6.1 ± 5.0% for 3 mg twice-daily (paired t test for change from baseline p = 0.98, 0.48, 0.04, and 0.03, respectively). The changes detected by HepQuant DuO were similar to those previously observed and reported for HepQuant SHUNT. The results support further study of avenciguat in treating portal hypertension and spotlight the utility of HepQuant DuO in the development of drug therapy for liver disease. HepQuant DuO facilitates the use of function testing to measure hepatic improvement in clinical trials and the clinic.

Deep learning model utilizing clinical data alone outperforms image-based model for hernia recurrence following abdominal wall reconstruction with long-term follow up.

BACKGROUND: Deep learning models (DLMs) using preoperative computed tomography (CT) imaging have shown promise in predicting outcomes following abdominal wall reconstruction (AWR), including component separation, wound complications, and pulmonary failure. This study aimed to apply these methods in predicting hernia recurrence and to evaluate if incorporating additional clinical data would improve the DLM's predictive ability. METHODS: Patients were identified from a prospectively maintained single-institution database. Those who underwent AWR with available preoperative CTs were included, and those with < 18 months of follow up were excluded. Patients were separated into a training (80%) set and a testing (20%) set. A DLM was trained on the images only, and another DLM was trained on demographics only: age, sex, BMI, diabetes, and history of tobacco use. A mixed-value DLM incorporated data from both. The DLMs were evaluated by the area under the curve (AUC) in predicting recurrence. RESULTS: The models evaluated data from 190 AWR patients with a 14.7% recurrence rate after an average follow up of more than 7 years (mean ± SD: 86 ± 39 months; median [Q1, Q3]: 85.4 [56.1, 113.1]). Patients had a mean age of 57.5 ± 12.3 years and were majority (65.8%) female with a BMI of 34.2 ± 7.9 kg/m2. There were 28.9% with diabetes and 16.8% with a history of tobacco use. The AUCs for the imaging DLM, clinical DLM, and combined DLM were 0.500, 0.667, and 0.604, respectively. CONCLUSIONS: The clinical-only DLM outperformed both the image-only DLM and the mixed-value DLM in predicting recurrence. While all three models were poorly predictive of recurrence, the clinical-only DLM was the most predictive. These findings may indicate that imaging characteristics are not as useful for predicting recurrence as they have been for other AWR outcomes. Further research should focus on understanding the imaging characteristics that are identified by these DLMs and expanding the demographic information incorporated in the clinical-only DLM to further enhance the predictive ability of this model.

Phase 2 Clinical Trial of VGT-309 for Intraoperative Molecular Imaging During Pulmonary Resection.

BACKGROUND: Advances in intraoperative molecular imaging (IMI) may improve surgical outcomes when resecting tumors in the lung. A single-center trial was conducted using VGT-309, a cathepsin-targeted near-infrared imaging agent that causes lung nodules to fluoresce during surgical resection. The end point of this phase 2 study was to evaluate the frequency that IMI with VGT-309 resulted in a clinically significant event (CSE): localization of pulmonary nodules, discovery of unsuspected additional cancers, or identification of positive margins. METHODS: Patients undergoing surgical resection for known or suspected cancer in the lung received VGT-309 (0.32 mg/kg) preoperatively. During the surgical procedure, localization and resection of the nodules were performed using standard surgical techniques. Near-infrared imaging was then used to localize nodules, seek occult lesions, and assess resection margins. Efficacy was measured by the frequency of CSEs. RESULTS: Of the 40 patients who underwent pulmonary resection with VGT-309, 17 (42.5%) had at least 1 CSE. Near-infrared imaging identified lesions not found by standard surgical methods in 16 patients, additional cancers not found by preoperative imaging in 1 patient, and margins within 5 mm of the closest staple line in 2 patients. VGT-309 performance was tested across a broad range of tumor types and commercial near-infrared imaging systems. VGT-309 appeared safe, well-tolerated, with no infusion reactions, and no drug-related serious adverse events. CONCLUSIONS: This phase 2 study demonstrated the utility of IMI with VGT-309 in localizing pulmonary nodules, recognizing synchronous lesions, and identifying positive margins. A multi-institutional study will further evaluate the efficacy of VGT-309.

Fixation or Revision for Periprosthetic Fractures: Epidemiology, New Trends, and Projections in the United States.

BACKGROUND: Periprosthetic fractures can be devastating complications after total joint arthroplasty (TJA). The management of periprosthetic fractures is complex, spanning expertise in arthroplasty and trauma. The purpose of this study was to examine and project trends in the operative treatment of periprosthetic fractures in the United States. METHODS: A large, public and private payer database was queried to capture all International Classification of Diseases, Tenth Revision (ICD-10) diagnosis codes for periprosthetic femoral and tibial fractures. Statistical models were created to assess trends in treatment for periprosthetic fractures and to predict future surgical rates. An alpha value of 0.05 was used to assess significance. A Bonferroni correction was applied where applicable to account for multiple comparisons. RESULTS: In this study, from 2016 to 2021, 121,298 patients underwent surgical treatment for periprosthetic fractures. There was a significant increase in the total number of periprosthetic fractures. The incidence of periprosthetic hip fractures rose by 38% and that for periprosthetic knee fractures rose by 73%. The number of periprosthetic fractures is predicted to rise 212% from 2016 to 2032. There was a relative increase in open reduction and internal fixation (ORIF) compared with revision arthroplasty for both periprosthetic hip fractures and periprosthetic knee fractures. CONCLUSIONS: Periprosthetic fractures are anticipated to impose a substantial health-care burden in the coming decades. Periprosthetic knee fractures are predominantly treated with ORIF rather than revision total knee arthroplasty (TKA), whereas periprosthetic hip fractures are predominantly treated with revision total hip arthroplasty (THA) rather than ORIF. Both periprosthetic knee fractures and periprosthetic hip fractures demonstrated increasing trends in this study. The proportion of periprosthetic hip fractures treated with ORIF relative to revision THA has been increasing. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Racial and Socioeconomic Disparities in Complex Abdominal Wall Reconstruction Referrals.

Background: Health disparities are pervasive in surgical care. Particularly racial and socioeconomic inequalities have been demonstrated in emergency general surgery outcomes, but less so in elective abdominal wall reconstruction (AWR). The goal of this study was to evaluate the disparities in referrals to a tertiary hernia center. Methods: A prospectively maintained hernia database was queried for patients who underwent open ventral hernia (OVHR) or minimally invasive surgical (MISR) repair from 2011 to 2022 with complete insurance and address information. Patients were divided by home address into in-state (IS) and out-of-state (OOS) referrals as well as by operative technique. Demographic data and outcomes were compared. Standard and inferential statistical analyses were performed. Results: Of 554 patients, most were IS (59.0%); 334 underwent OVHR, and 220 underwent MISR. IS patients were more likely to undergo MISR (OVHR: 45.6% vs. 81.5%, laparoscopic: 38.2% vs. 14.1%, robotic: 16.2% vs. 4.4%; p < 0.001) when compared to OOS referrals. Of OVHR patients, 44.6% were IS and 55.4% were OOS. Patients' average age and BMI, sex, ASA score, and insurance payer were similar between IS and OOS groups. IS patients were more often Black (White: 77.9% vs. 93.5%, Black: 16.8% vs. 4.3%; p < 0.001). IS patients had more smokers (12.1% vs. 3.2%; p = 0.001), fewer recurrent hernias (45.0% vs. 69.7%; p < 0.001), and smaller defects (155.7 ± 142.2 vs. 256.4 ± 202.9 cm2; p < 0.001). Wound class, mesh type, and rate of fascial closure were similar, but IS patients underwent fewer panniculectomies (13.4% vs. 34.1%; p < 0.001), component separations (26.2% vs. 51.4%; p < 0.001), received smaller mesh (744.2 ± 495.6 vs. 975.7 ± 442.3 cm2; p < 0.001), and had shorter length-of-stay (4.8 ± 2.0 vs. 7.0 ± 5.5 days; p < 0.001). There was no difference in wound breakdown, seroma requiring intervention, hematoma, mesh infection, or recurrence; however, IS patients had decreased wound infections (2.0% vs. 8.6%; p = 0.009), overall wound complications (11.4% vs. 21.1%; p = 0.016), readmissions (2.7% vs. 13.0%; p = 0.001), and reoperations (3.4% vs. 11.4%; p = 0.007). Of MISR patients, 80.9% were IS and 19.1% were OOS. In contrast to OVHR, MISR IS and OOS patients had similar demographics, preoperative characteristics, intraoperative details, and postoperative outcomes. Conclusion: Although there were no differences in referred patients for MISR, this study demonstrates the racial disparities that exist among our IS and OOS complex, open AWR patients. Awareness of these disparities can help clinicians work towards equitable access to care and equal referrals to tertiary hernia centers.