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Assays to detect circulating tumor DNA (ctDNA) have multiple clinically important applications in management of multiple types of gastrointestinal cancers. Different methodologies of ctDNA detection have varying sensitivities and potential applications in different contexts. For patients with localized cancers treated for curative intent, ctDNA detection is associated with prognosis in multiple cancer types, and persistent detection of ctDNA after surgical resection is highly concerning for minimal residual disease (MRD) and forebodes impending radiographic and clinical recurrence. CtDNA assays for comprehensive genomic profiling enable genotyping of cancers in the absence of tumor tissue data, and longitudinal testing can also characterize clonal evolution and emergence of putative resistance mechanisms upon treatment with targeted agents. These applications have proven instructive in patients with HER2-amplified gastric and esophageal cancers and in patients with FGFR2 fusion cholangiocarcinomas. In this review, we summarize data supporting the role of ctDNA as a novel predictive and prognostic biomarker and potential impacts on current management of patients with pancreatic, gastroesophageal, and hepatobiliary cancers.

PURPOSE Pembrolizumab significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors but is not well studied in the neoadjuvant space. METHODS This is a phase II open-label, single-center trial of localized unresectable or high-risk resectable MSI-H/dMMR tumors. Treatment is pembrolizumab 200 mg once every 3 weeks for 6 months followed by surgical resection with an option to continue therapy for 1 year followed by observation. To continue on study, patients are required to have radiographic or clinical benefit. The coprimary end points are safety and pathologic complete response. Key secondary end points are response rate and organ-sparing at one year for patients who declined surgery. Exploratory analyses include interrogation of the tumor immune microenvironment using imaging mass cytometry. RESULTS A total of 35 patients were enrolled, including 27 patients with colorectal cancer and eight patients with noncolorectal cancer. Among 33 evaluable patients, best overall response rate was 82%. Among 17 (49%) patients who underwent surgery, the pathologic complete response rate was 65%. Ten patients elected to receive one year of pembrolizumab followed by surveillance without surgical resection (median follow-up of 23 weeks [range, 0-54 weeks]). An additional eight did not undergo surgical resection and received less than 1 year of pembrolizumab. During the study course of the trial and subsequent follow-up, progression events were seen in six patients (four of whom underwent salvage surgery). There were no new safety signals. Spatial immune profiling with imaging mass cytometry noted a significantly closer proximity between granulocytic cells and cytotoxic T cells in patients with progressive events compared with those without progression. CONCLUSION Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of pathologic, radiographic, and endoscopic response, which has implications for organ-sparing strategies.

Background: Bone bruises are commonly seen on magnetic resonance imaging (MRI) in acute anterior cruciate ligament (ACL) injuries and can provide insight into the underlying mechanism of injury. There are limited reports that have compared the bone bruise patterns between contact and noncontact mechanisms of ACL injury. Purpose: To examine and compare the number and location of bone bruises in contact and noncontact ACL injuries. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Three hundred twenty patients who underwent ACL reconstruction surgery between 2015 and 2021 were identified. Inclusion criteria were clear documentation of the mechanism of injury and MRI within 30 days of the injury on a 3-T scanner. Patients with concomitant fractures, injuries to the posterolateral corner or posterior cruciate ligament, and/or previous ipsilateral knee injury were excluded. Patients were stratified into 2 cohorts based on a contact or noncontact mechanism. Preoperative MRI scans were retrospectively reviewed by 2 musculoskeletal radiologists for bone bruises. The number and location of the bone bruises were recorded in the coronal and sagittal planes using fat-suppressed T2-weighted images and a standardized mapping technique. Lateral and medial meniscal tears were recorded from the operative notes, while medial collateral ligament (MCL) injuries were graded on MRI. Results: A total of 220 patients were included, with 142 (64.5%) noncontact injuries and 78 (35.5%) contact injuries. There was a significantly higher frequency of men in the contact cohort compared with the noncontact cohort (69.2% vs 54.2%, P = .030), while age and body mass index were comparable between the 2 cohorts. The bivariate analysis demonstrated a significantly higher rate of combined lateral tibiofemoral (lateral femoral condyle [LFC] + lateral tibial plateau [LTP]) bone bruises (82.1% vs 48.6%, P < .001) and a lower rate of combined medial tibiofemoral (medial femoral condyle [MFC] + medial tibial plateau [MTP]) bone bruises (39.7% vs 66.2%, P < .001) in knees with contact injuries. Similarly, noncontact injuries had a significantly higher rate of centrally located MFC bone bruises (80.3% vs 61.5%, P = .003) and posteriorly located MTP bruises (66.2% vs 52.6%, P = .047). When controlling for age and sex, the multivariate logistical regression model demonstrated that knees with contact injuries were more likely to have LTP bone bruises (OR, 4.721 [95% CI, 1.147-19.433], P = .032) and less likely to have combined medial tibiofemoral (MFC + MTP) bone bruises (OR, 0.331 [95% CI, 0.144-0.762], P = .009) compared with those with noncontact injuries. Conclusion: Significantly different bone bruise patterns were observed on MRI based on ACL injury mechanism, with contact and noncontact injuries demonstrating characteristic findings in the lateral tibiofemoral and medial tibiofemoral compartments, respectively.

To evaluate the effect of duration of preoperative hip pain symptoms on outcomes in patients undergoing primary hip arthroscopy for the treatment of femoroacetabular impingement syndrome (FAIS).A systematic review of the literature was conducted with the following keywords: "hip arthroscopy," "outcomes," "femoroacetabular impingement," "duration," "symptoms," "time," "delay," "earlier," and "timing" was performed in PubMed and Cochrane in May 2022. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were used for this review. When available, article information including the author, study type, study period, and follow-up, demographics, preoperative duration of symptoms, surgical outcome tools, and secondary surgeries were recorded.Six studies including 3,298 hips were included in this systematic review. Five studies had minimum 2-year follow-up and one study had minimum 5-year follow-up. Femoroacetabular impingement (including subtypes cam and pincer impingement) was a surgical indication in all six studies, and the most common indication for surgery. All six studies reported patient-reported outcome scores (PROs). All studies conducted statistical analyses comparing the duration of symptoms' effect on outcomes and found superior outcomes in patients with shorter duration of symptoms prior to hip arthroscopy. In three studies, mHHS, HOS-ADL, HOS-SS and VAS-Satisfaction ranged from 79.1-82.6, 86.3-88.4, 75-75.5. and 75.3-82.5, respectively in cohorts with2-year duration of symptoms, compared to 72-77.7, 79.6-84, 65.0-66.7, and 69.7-75.3 in2-year cohort. Similarly, in one study the2-year duration group was reported to have a conversion to total hip arthroplasty rate of 0.6% and an overall secondary surgery rate of 0.9%, while the2-year duration group had a conversion to total hip arthroplasty rate of 6.4% and an overall secondary surgery rate of 10.1%.Patients with hip pain symptoms of less than 2 years before arthroscopic treatment of FAIS have better outcomes than those patients who had a longer duration of symptoms. However, significant improvements can still be expected regardless of time between onset of symptoms and surgery.Level IV, systematic review of Level III and Level IV studies.

A 75-year-old Caucasian woman presented with sudden-onset multifocal scotomas in her right eye's central vision for 1 day. There were subtle white intraretinal foveal lesions that correlated with patchy inner retinal hyperreflectivity on optical coherence tomography, suggestive of paracentral acute middle maculopathy. Initial cerebrovascular work-up was negative. Review of systems was positive for lethargy and jaw claudication. The sedimentation rate and c-reactive protein were elevated, but platelet count was normal. The patient was started on 60 mg oral prednisone daily and underwent bilateral temporal artery that confirmed the diagnosis of giant cell arteritis.

To report patient-reported outcomes (PROs) and survivorship following revision hip arthroscopy in patients aged ≥40 years and to compare these results with a propensity-matched primary hip arthroscopy control group.Data were prospectively collected and retrospectively reviewed for all patients who underwent revision hip arthroscopy between June 2008 and January 2019. Patients were included if they were ≥40 years of age at the time of surgery and had minimum 2-year follow-up for the modified Harris Hip Score, Nonarthritic Hip Score, Visual Analog Scale for pain, and the Hip Outcome Score-Sports Specific Subscale. Patients who had a previous hip condition, or those who lacked minimum 2-year follow-up, were excluded. The revision group was further analyzed by conducting a 1:1 propensity-matched sub-analysis to a primary hip arthroscopy control group based on age, sex, body mass index, and acetabular labrum articular disruption grade. Statistical significance was set at P.05.Eighty-nine hips (92.7% follow-up) were included, with 66.3% being females. The mean age, body mass index, and follow-up time were 49.4 ± 8.0 years, 26.6 ± 4.1, and 62.7 ± 38.5 months, respectively. Significant improvement in all PROs (P.001) was reported, and 71.8%, 58 74.4%, and 65.2% achieved the minimal clinically important difference for the modified Harris Hip Score, Nonarthritic Hip Score, and Hip Outcome Score-Sports Specific Subscale, respectively. Eighty-seven revision hips were successfully propensity-matched to 87 primary hips. Both groups reported similar improvement for all PROs, but the relative risk of conversion to total hip arthroplasty was 2.63 times greater (95% confidence interval 1.20-5.79) for the revision group.Patients aged ≥40 years who underwent revision hip arthroscopy reported significant improvement in all PROs at a mean follow-up of 62.7 months with favorable rates of achieving the minimal clinically important difference. When compared to the propensity-matched control group, both achieved similar rates of improvement, but the revision group was 2.63 times more likely to convert to total hip arthroplasty.III. case-control study.

Background: Few studies have compared outcomes, return to sport (RTS), and continuation of sport (CTS) after primary hip arthroscopic surgery between matched groups of male and female athletes with a minimum 5-year follow-up. Purpose: (1) To report minimum 5-year patient-reported outcome (PRO) scores as well as RTS and CTS rates for elite female athletes undergoing hip arthroscopic surgery for femoroacetabular impingement syndrome (FAIS) and (2) to compare clinical results with those of a matched control group of elite male athletes. Study Design: Cohort study; Level of evidence, 3. Methods: Data were prospectively collected and retrospectively reviewed for elite (collegiate or professional) female athletes who underwent primary hip arthroscopic surgery for FAIS between March 2009 and March 2016. Inclusion criteria were preoperative and minimum 5-year scores for the modified Harris Hip Score, Nonarthritic Hip Score, Hip Outcome Score–Sport Specific Subscale, and visual analog scale for pain. Exclusion criteria were Tönnis grade >1, hip dysplasia, previous ipsilateral hip surgery/conditions, and those unwilling to participate. Rates of achieving the minimal clinically important difference (MCID), Patient Acceptable Symptom State (PASS), and maximum outcome improvement satisfaction threshold (MOIST) were recorded in addition to RTS. CTS was also recorded and defined as athletes reporting continued sport activity at a minimum 5-year follow-up after initially reporting returning to sport. Elite female athletes were propensity matched in a 1:1 ratio to elite male athletes for comparison. Results: A total of 81 hips in elite female athletes that underwent primary hip arthroscopic surgery met the inclusion criteria, and follow-up was available for 65 hips (80.2%) at a mean of 67.6 ± 6.5 months, with a mean age of 24.3 ± 6.8 years. Female athletes demonstrated significant improvements in all recorded PRO scores; achieved the MCID, PASS, and MOIST at high rates; returned to sport at a rate of 80.4%; and continued sport at a rate of 97.1%. Female athletes demonstrated lower preoperative PRO scores compared with male athletes, but postoperative PRO scores; improvements in scores; rates of achieving the MCID, PASS, MOIST; and RTS and CTS rates were similar between female and male athletes. Conclusion: Elite female athletes undergoing primary hip arthroscopic surgery for FAIS demonstrated favorable PRO scores and high RTS and CTS rates at a minimum 5-year follow-up. These results were comparable with those of a propensity-matched control group of elite male athletes.

To report minimum 2-year follow-up patient-reported outcomes and return-to-sport (RTS) rates in athletes undergoing concomitant hip arthroscopy and periacetabular osteotomy (PAO) to treat acetabular dysplasia and intra-articular pathologies such as cam deformity and labral tears.We reviewed the data of consecutive athletes undergoing concomitant primary hip arthroscopy and PAO for acetabular dysplasia and cam deformity from November 2010 to December 2018. Patients were included in the study if they had the following preoperative and minimum 2-year postoperative scores: modified Harris Hip Score (mHHS), Nonarthritic Hip Score (NAHS), and Hip Outcome Score-Sport-Specific Subscale (HOS-SSS). The percentage of patients who achieved the minimal clinically important difference was recorded, in addition to RTS status.A total of 29 athletes (29 hips) were included, with a mean follow-up time of 34.1 ± 7.9 months, mean age of 26.0 ± 8.7 years, and mean body mass index of 23.7 ± 3.4. These athletes showed significant improvements in the mHHS, NAHS, and HOS-SSS from baseline to latest follow-up (P.001). The minimal clinically important difference was achieved at high rates for the mHHS (82.8%), NAHS (86.2%), and HOS-SSS (79.3%). Athletes who attempted to RTS successfully returned at a rate of 81.8%.Athletes undergoing concomitant hip arthroscopy and PAO showed significant improvements in patient-reported outcomes at minimum 2-year follow-up and had an RTS rate of 81.8%.Level IV, retrospective case series.

Background: The minimal clinically important difference (MCID), Patient Acceptable Symptom State (PASS), substantial clinical benefit (SCB), and maximum outcome improvement (MOI) satisfaction threshold for the Hip Outcome Score Sport-Specific Subscale (HOS-SSS) have not been established in athletes undergoing hip arthroscopy for femoroacetabular impingement syndrome (FAIS). Purpose: To determine threshold MCID, PASS, SCB, and MOI satisfaction threshold values for the HOS-SSS in athletes undergoing hip arthroscopy for FAIS at minimum 2–year follow–up. Study Design: Cohort study (Diagnosis); Level of evidence, 3. Methods: Anchor questions were administered to recreational, organized amateur, high school, college, and professional athletes who underwent primary hip arthroscopy for FAIS between May 2015 and March 2019. Patients were included if they were younger than 50 years, answered the anchor questions, and had preoperative and minimum 2–year follow–up for the HOS-SSS, modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), and visual analog scale (VAS) for pain. Exclusion criteria were Tönnis grade >1, hip dysplasia (lateral center–edge angle Results: A total of 225 athletes who underwent primary hip arthroscopy met the inclusion criteria. Of those athletes, 200 (88.9%) who had minimum 2–year follow–up and information regarding return to sport (RTS) were included. The cohort included 124 (62.0%) women and 76 (38.0%) men with a mean ± standard deviation age of 29.4 ± 10.4 years, body mass index of 25.6 ± 5.4, and follow–up of 29.5 ± 5.1 months. Athletes experienced significant improvements in HOS-SSS, mHHS, NAHS, and VAS from preoperative to latest postoperative follow–up ( P < .001), and mean satisfaction was 8.2. The RTS rate was 83.7%. ROC analysis determined that the PASS, MOI satisfaction threshold, SCB absolute score, SCB change score, and MCID (baseline/change score methods) for the HOS-SSS were 77.0, 44.6%, 92.7, 30.6, and 10.6, respectively, with athletes achieving thresholds at high rates (80.0%, 80.5%, 45.0%, 54.0%, and 79.5%, respectively). Conclusion: This study identified values for the HOS-SSS that can be used to define clinically meaningful outcomes in athletes after primary hip arthroscopy for FAIS. The PASS, MOI satisfaction threshold, SCB absolute score, SCB change score, and MCID for the HOS-SSS at minimum 2–year follow–up in athletes after primary hip arthroscopy were 77.0, 44.6%, 92.7, 30.6, and 10.6, respectively.

KRAS and NRAS mutations occur in 45% of colorectal cancers, with combined MAPK pathway and CDK4/6 inhibition identified as a potential therapeutic strategy. In the current study, this combinatorial treatment approach was evaluated in a co-clinical trial in patient-derived xenografts (PDX), and safety was established in a clinical trial of binimetinib and palbociclib in patients with metastatic colorectal cancer with RAS mutations. Across 18 PDX models undergoing dual inhibition of MEK and CDK4/6, 60% of tumors regressed, meeting the co-clinical trial primary endpoint. Prolonged duration of response occurred predominantly in TP53 wild-type models. Clinical evaluation of binimetinib and palbociclib in a safety lead-in confirmed safety and provided preliminary evidence of activity. Prolonged treatment in PDX models resulted in feedback activation of receptor tyrosine kinases and acquired resistance, which was reversed with a SHP2 inhibitor. These results highlight the clinical potential of this combination in colorectal cancer, along with the utility of PDX-based co-clinical trial platforms for drug development. Significance: This co-clinical trial of combined MEK-CDK4/6 inhibition in RAS mutant colorectal cancer demonstrates therapeutic efficacy in patient-derived xenografts and safety in patients, identifies biomarkers of response, and uncovers targetable mechanisms of resistance.

To report and compare, according to sex and age, minimum 2-and minimum 5-year patient-reported outcome scores (PROs) and survivorship in a large cohort of patients who underwent primary hip arthroscopy for femoroacetabular impingement syndrome (FAIS).Data from February 2008 to September 2018 were reviewed. Patients aged 60 and younger who underwent primary hip arthroscopy with minimum 2-year follow-up were included. Exclusion criteria were Tönnis grade1, hip dysplasia, previous hip conditions, or any labral treatment different than repair. Minimum 5-year PROs were also collected. All patients included were divided into groups by sex. For further analysis, males and females were stratified according to age:21 years old, 21-30 years old, 31-40 years old, 41-50 years old, and 51-60 years old.In total, 1,326 hips had minimum 2-year follow-up, including 860 (64.9%) females and 466 males (35.1%), with a mean age of 31.6 years (range, 12.8-60.9 years) and a mean follow-up of 58.7 ± 28.9 months. Of those, 772 had minimum 5-year follow-up, 515 females (66.7%), and 257 males (33.3%) with a mean age of 31.7 years (range, 13.1-60.7 years) and a mean follow-up of 78.5 ± 23.0 months. All patients showed significant improvements in PROs at minimum 2-and 5-year follow-up (P.001). Between sex analysis revealed comparable PROs at latest follow-up between females and males across any age group. Within sexes, and when sexes were combined, patients21 years old had significantly better outcomes compared to other age groups. There were more females21 years old that required revision arthroscopy than males21 years old (P = .015). Conversion to total hip arthroplasty (THA) showed no significant difference between sexes (P.05). Rates of THA were21 years (.8%), 21-30 years (2.1%), 31-40 years (4%), 41-50 years (8.9%), and 51-60 years (14.3%).Following primary hip arthroscopy for FAIS, all patients reported significant improvements in all PROs at minimum 2-and minimum 5-year follow-up, with females and males achieving similar success. Age affected outcomes, with patients under 21 years old reporting better scores regardless of sex. Although the conversion rate to THA was similar between the sexes, it was lower in the younger ages groups in both sexes.III, retrospective comparative observation trial.

Visual snow syndrome—characterised by flickering specks throughout the visual field and accompanied by other symptoms—can disrupt daily life and affects roughly 2% of the population. However, its neural bases remain mysterious, and treatments are lacking. Here we present a method to quickly and reliably eliminate the visual snow symptom for a period of time. Prolonged viewing of a visual stimulus can strongly reduce sensitivity to subsequent stimuli, and we tested whether such adaptation could affect visual snow. Participants with visual snow (total n = 27) viewed high-contrast dynamic noise patterns, resembling television static, and then judged the strength of the symptom. Visual snow was temporarily reduced in strength to the point that it was invisible in many conditions for most observers. The effect followed typical trends of adaptation for physical stimuli in normally sighted observers. Effect duration increased monotonically with duration of exposure to the adapter and it was specific to dynamic noise; adapting to a high contrast striped pattern had little effect on visual snow. Adaptation provides reliable experimental control over visual snow, and so is a promising tool for understanding its neural origins, developing diagnostic tests, and may also provide a basis for treatment.

Regorafenib is a tyrosine kinase inhibitor approved by the FDA for the treatment of patients with chemotherapy refractory metastatic colorectal cancer (mCRC). Regorafenib inhibits signaling through multiple receptors associated with angiogenesis, metastasis, and tumor immunity. Here, we report biomarker results from LCCC1029, a randomized, placebo-controlled, phase II trial of chemotherapy ± regorafenib in patients with second-line mCRC. A panel of 20 soluble protein biomarkers (termed the Angiome) was assessed in the plasma of 149 patients from the LCCC1029 trial both at baseline and along the treatment continuum. Baseline protein levels were analyzed for prognostic and predictive value for progression-free survival (PFS) and overall survival (OS). Changes in protein levels during treatment were analyzed for potential pharmacodynamic effects. Six markers (HGF, IL6, PlGF, VEGF-R1, OPN, and IL6R) were found to be prognostic for PFS. Nine markers (IL6, TIMP-1, PlGF, VCAM-1, ICAM-1, OPN, TSP-2, HGF, and VEGF-R1) were prognostic for OS. Higher baseline levels of OPN (Pintx = 0.0167), VCAM-1 (Pintx = 0.0216), and PDGF-AA (Pintx = 0.0435) appeared to predict for PFS benefit from regorafenib compared with placebo. VCAM-1 was also potentially predictive of OS benefit from regorafenib compared with placebo (Pintx = 0.0124). On-treatment changes of six markers reflected potential on-target effect of regorafenib. Consistent results were observed in an Italian cohort where 105 patients with late-stage mCRC received regorafenib monotherapy. The key findings of this study suggest that VCAM-1 may be a predictive biomarker for regorafenib benefit, while multiple protein markers may be prognostic of outcome in patients with mCRC.

Figure S1, consort diagram. Table S1, pts characteristics. Table S2, baseline levels. Table S3, prognostic markers. Table S4, adjusted prognostic markers. Table S5, early changes. Table S6, late changes at disease progression.