Neoadjuvant short-course radiotherapy followed by camrelizumab and chemotherapy in locally advanced rectal cancer (UNION): early outcomes of a multicenter randomized phase III trial.

BACKGROUND: Neoadjuvant short-course radiotherapy (SCRT) followed by CAPOX and camrelizumab (a PD-1 monoclonal antibody) has shown potential clinical activity for locally advanced rectal cancer (LARC) in a phase II trial. This study aimed to further confirm the efficacy and safety of SCRT followed by CAPOX and camrelizumab compared to long-course chemoradiotherapy (LCRT) followed by CAPOX alone as neoadjuvant treatment for LARC. PATIENTS AND METHODS: In this randomized, phase III trial, patients with T3-4/N+ rectal adenocarcinoma were randomly assigned (1:1) to receive SCRT or long-course chemoradiotherapy (LCRT), followed by 2 cycles of camrelizumab and CAPOX or CAPOX alone, respectively. After surgery, each arm underwent either 6 cycles of camrelizumab and CAPOX, followed by up to 17 doses of camrelizumab, or 6 cycles of CAPOX. The primary endpoint was pathological complete response (pCR) rate (ypT0N0) assessed by a blinded independent review committee. Key secondary endpoints tested hierarchically were 3-year event-free survival (EFS) rate and overall survival (OS). RESULTS: Between July 2021 and March 2023, the intention-to-treat population comprised 113 patients in experimental arm and 118 patients in control arm, with surgery performed in 92% and 83.9%, respectively. At data cutoff (July 11, 2023), the pCR rate were 39.8% (95% CI, 30.7 to 49.5) in experimental arm compared to 15.3% (95% CI, 9.3 to 23.0) in control arm (difference, 24.6%; odds ratio, 3.7; 95% CI, 2.0 to 6.9; p < 0.001). In each arm, surgical complication rates were 40.0% and 40.8%, grade ≥ 3 treatment-related adverse events were 29.2% and 27.2%. 3-year EFS rate and OS continue to mature. CONCLUSIONS: In LARC patients, neoadjuvant SCRT followed by camrelizumab plus CAPOX demonstrated a significantly higher pCR rate than LCRT followed by CAPOX, with a well-tolerated safety profile. SCRT followed by camrelizumab and chemotherapy can be recommended as a neoadjuvant treatment modality for these patients.

Label-free differentiation of pancreatic pathologies from normal pancreas utilizing end-to-end three-dimensional multimodal networks on CT.

AIMS: To investigate the utilization of an end-to-end multimodal convolutional model in the rapid and accurate diagnosis of pancreatic diseases using abdominal CT images. MATERIALS AND METHODS: In this study, a novel lightweight label-free end-to-end multimodal network (eeMulNet) model was proposed for the rapid and precise diagnosis of abnormal pancreas. The eeMulNet consists of two steps: pancreatic region localization and multimodal CT diagnosis integrating textual and image data. A research dataset comprising 715 CT scans with various types of pancreas diseases and 228 CT scans from a control group was collected. The training set and independent test set for the multimodal classification network were randomly divided in an 8:2 ratio (755 for training and 188 for testing). RESULTS: The eeMulNet model demonstrated outstanding performance on an independent test set of 188 CT scans (Normal: 45, Abnormal: 143), with an area under the curve (AUC) of 1.0, accuracy of 100%, and sensitivity of 100%. The average testing duration per patient was 41.04 seconds, while the classification network took only 0.04 seconds. CONCLUSIONS: The proposed eeMulNet model offers a promising approach for the diagnosis of pancreatic diseases. It can support the identification of suspicious cases during daily radiology work and enhance the accuracy of pancreatic disease diagnosis. The codes and models of eeMulNet are publicly available at Rudeguy1/eeMulNet (github.com).

Cartilage compositional MRI-a narrative review of technical development and clinical applications over the past three decades.

Articular cartilage damage and degeneration are among hallmark manifestations of joint injuries and arthritis, classically osteoarthritis. Cartilage compositional MRI (Cart-C MRI), a quantitative technique, which aims to detect early-stage cartilage matrix changes that precede macroscopic alterations, began development in the 1990s. However, despite the significant advancements over the past three decades, Cart-C MRI remains predominantly a research tool, hindered by various technical and clinical hurdles. This paper will review the technical evolution of Cart-C MRI, delve into its clinical applications, and conclude by identifying the existing gaps and challenges that need to be addressed to enable even broader clinical application of Cart-C MRI.

Increasing Hip Arthroscopy Case Volume Is Associated With Increased Risk for Revision Surgery but Not Conversion to Total Hip Arthroplasty or 90-Day Hospitalizations: A Cross-Sectional Analysis of 468 Surgeons.

PURPOSE: To analyze the effects of surgeon-specific factors, including case volume, career duration, fellowship training, practice type, and region of practice, on rates of 2-year revision surgery, conversion to total hip arthroplasty (THA), and 90-day hospitalizations following hip arthroscopy. METHODS: The PearlDiver Mariner Database was used to query patients undergoing hip arthroscopy between 2015 and 2018. Surgeons performing these procedures were identified, and surgeon-specific demographics and variables were collected from publicly available data. Patients were followed for 2 years to assess for reoperations, including revision hip arthroscopy and conversion to THA, as well as 90-day hospitalizations, including emergency department visits and hospital readmissions. International Classification of Diseases, Tenth Revision codes were used to track the laterality of revision hip procedures. Associations between surgeon-specific factors and postoperative outcomes were assessed through univariate and multivariate analyses. RESULTS: In total, 20,834 patients underwent hip arthroscopy procedures by 468 surgeons. Multivariate analysis with logistic regression adjusted for patient-related factors (age, sex, obesity, Charlson Comorbidity Index, and smoking status) identified increasing surgeon case volume to be associated with increased risk for 2-year revision hip arthroscopy (P < .001), but not 2-year conversion to THA or 90-day hospitalizations. Nonsports medicine fellowship-trained surgeons were associated with greater risk for 2-year THA conversion (P < .001) and 90-day hospital readmissions (P < .01). Surgeons practicing in an academic setting demonstrated greater risk for 90-day hospital readmissions (P < .001). Surgeons practicing in the West region of the United States were more likely to incur 2-year revision hip arthroscopy procedures compared to surgeons in the South, Midwest or Northeast (P < .001). CONCLUSIONS: Increasing surgeon hip arthroscopy case volume is associated with an increased risk for 2-year revision hip arthroscopy but not conversion to THA or 90-day hospitalizations. Further, non-sports medicine fellowship-trained surgeons were associated with higher risk for 2-year THA conversion after hip arthroscopy. LEVEL OF EVIDENCE: Level III, retrospective cohort analysis.

No Differences in 2-Year Reoperation Rates for Meniscus Allograft Transplant With Concomitant Cartilage Restoration or Osteotomy: A National Database Study.

PURPOSE: To investigate reoperation rates after meniscus allograft transplant (MAT), comparing rates with and without concomitant articular cartilage and osteotomy procedures using a national insurance claims database. METHODS: We performed a retrospective cohort study of patients who underwent MAT from 2010 to 2021 with minimum 2 year follow-up using the PearlDiver database. Using Current Procedural Terminology (CPT) and International Classification of Diseases (ICD) codes, we identified patients who underwent concomitant procedures including chondroplasty or microfracture, cartilage restoration defined as osteochondral graft or autologous chondrocyte implantation (ACI), or osteotomy. Univariate logistic regressions identified risk factors for reoperation. Reoperations were classified as knee arthroplasty, interventional procedures, or diagnostic or debridement procedures. RESULTS: 750 patients were included with an average age of 29.6 years (interquartile range 21.0-36.8) and average follow-up time was 5.41 years (SD: 2.51). 90-day, 2-year, and all-time reoperation rates were 1.33%, 14.4%, and 27.6% respectively. MAT with cartilage restoration was associated with increased reoperation rate at 90 days (OR: 4.88; 95% CI: 1.38-19.27; p=.015), however there was no significant difference in reoperation rates at 2 years or to the end of follow-up. ACI had increased reoperation rates at 90 days (OR: 6.95; 95% CI: 1.45-25.96; p=.006), with no difference in reoperation rates 2 years post-operatively or to the end of follow-up. Osteochondral autograft and allograft were not associated with increased reoperation rates. CONCLUSION: 14.4% of patients in our cohort had a reoperation within 2 years of MAT. Nearly one in four patients undergoing MAT had concomitant cartilage restoration, showing that it is commonly performed on patients with articular cartilage damage. Concomitant osteochondral autograft, osteochondral allograft, chondroplasty, microfracture and osteotomy were not associated with any significant difference in reoperation rates. ACI was associated with increased reoperation rates at 90 days, but not later.

Concomitant Medial Collateral Ligament Injury Increases the Risk of Revision Anterior Cruciate Ligament Reconstruction.

PURPOSE: To compare rates of revisions between patients with isolated ACL reconstruction to those who had concomitant MCL injuries managed either operatively or non-operatively at time of index ACL reconstruction (ACLR). METHODS: The PearlDiver-Mariner Database was queried for all patients who underwent ACLR between 2016-2020 using laterality-specific International Classification of Diseases, Tenth Revision (ICD-10) and Current Procedural Terminology (CPT) codes. Patients were included if they were ages 15 or higher and had a minimum of 2 years follow-up after index ACLR. Patients were then divided into cohorts by presence or absence of concomitant MCL injury. The cohort of concomitant MCL injuries was further subdivided into those with MCL injuries managed non-operatively, with MCL repair, or with MCL reconstruction at time of index ACLR. Multivariate regression was performed between cohorts to evaluate for factors associated with revision ACLR. RESULTS: We identified 47,306 patients with isolated ACL injuries and 10,846 with concomitant MCL and ACL injuries. 93% of patients with concomitant MCL injuries had their MCL treated non-operatively; however, the annual proportion of patients being surgically managed for their MCL injury increased by 70% from 2016-2020. Concomitant MCL injury patients had higher odds of undergoing revision ACLR compared to patients with isolated ACL injuries (OR:1.50, 95%CI: 1.36-1.66, p<0.001). Amongst patients with concomitant MCL injuries, surgically managed patients had higher risk of revision ACLR compared to non-operatively managed MCL injuries (OR:1.39, 95%CI:1.01-1.86, p=0.034). CONCLUSIONS: Despite an increase in operatively managed concomitant MCL injuries, the majority of concomitant MCL injuries are still managed non-operatively at time of ACLR. Patients with concomitant MCL injury, particularly those managed operatively, at the time of ACLR are at increased risk of requiring revision ACLR compared to those with isolated ACL injuries.

Incidence, risk factors, and complications of acromial stress fractures after reverse total shoulder arthroplasty.

BACKGROUND: An acromial stress fracture (ASF) is an uncommon complication after reverse total shoulder arthroplasty (RTSA) that can have severe clinical consequences on shoulder function. Although patient-specific factors have been identified to influence the risk of ASF, it is unclear whether modifying these factors can minimize risk. Moreover, there is limited information on the treatment outcomes of these fractures. Therefore, the purpose of this study was to determine modifiable risk factors for ASFs and the complication and revision rates of conservatively and operatively managed ASFs. METHODS: The PearlDiver database was queried to identify a cohort of patients who underwent RTSA with minimum 2-year follow-up. Current Procedural Terminology and International Classification of Diseases codes were used to compare the demographic characteristics, comorbidities, and medication use of patients with and without ASFs. Surgical complication and revision rates were compared between operatively and conservatively treated fractures. RESULTS: The overall incidence of ASFs was 1.4%. Patient-specific factors that were independently associated with the occurrence of an ASF included osteoporosis, rheumatologic disease, shoulder corticosteroid injection within 3 months before surgery, and chronic oral corticosteroid use. Among patients with osteoporosis, the initiation of physical therapy within 6 weeks after surgery also increased the risk of ASF. Patients who underwent surgical treatment of ASFs had a revision arthroplasty rate of 7.0% compared to a rate of 3.2% among those with conservatively managed fractures. CONCLUSION: ASFs are infrequent complications that can occur after RTSA. Preoperative factors that affect the quality of bone independently increase the fracture risk. Moreover, this risk can be minimized by avoiding shoulder corticosteroid injections 3 months before surgery and delaying physical therapy exercises among patients with osteoporosis. Surgical fixation of these fractures should be reserved for instances when conservative management has failed given high rates of infection, instability, and revision shoulder arthroplasty.

[Effectiveness of minimally invasive surgery in the treatment of pancreatic acinar cell carcinoma].

Objective: To explore the effectiveness of minimally invasive surgical treatment for pancreatic acinar cell carcinoma (PACC). Methods: Six patients with PACC diagnosed in Peking University Third Hospital from January 2010 to September 2022 were retrospectively selected. Preoperative evaluation was performed on whether the lesions were eligible for surgery, including whether radical resection of liver metastases could be performed. Laparoscopic or Da Vinci robot-assisted resection was performed on six patients, and spleen retention was determined according to the original lesions and the relationship with peripheral blood vessels and tissues, while simultaneous resection was performed on cases of peripheral organ tissue invasion. The patients' basic information, preoperative general conditions, preoperative diagnosis and tumor stage, minimally invasive surgery methods, postoperative complications, pathological results, tumor stage and follow-up data were collected and analyzed to explore the effectiveness of minimally invasive surgery. Results: Among the six patients, four were males and two were females, with the age of 25-69 years. Five patients had abdominal pain and distension before surgery, five patients had tumors located at the tail of the pancreatic body, and one patient had tumors located at the head of the pancreas. Preoperative imaging (enhanced CT and MRI) was performed to measure the tumor diameter (2.8-10.0 cm). Tumor markers were elevated in two patients before surgery, and six patients underwent surgery through laparoscopy or robotic platform. No complications such as postoperative pancreatic fistula and bleeding were clinically relevant during and after surgery. There were two cases with concurrent or heterochronous liver metastasis, two cases with lymph node metastasis and nodular metastasis, four cases with tumor invasion of surrounding organs (stomach, spleen or duodenum), and three cases with vascular cancer thrombi. The follow-up time of the six patients was 12 to 165 months, and one patient underwent three operations due to postoperative liver metastasis and residual pancreatic recurrence, and the results were satisfactory. All the six patients survived at the last follow-up. Conclusions: PACC is prone to invade the surrounding organs, and has a large tumor diameter. Radical surgery for PACC can be completed through minimally invasive surgery, and satisfactory oncology prognosis can be obtained. In addition, some PACC patients with recurrence and metastasis can still be treated by surgery.

[Risk prediction and function evaluation by T-cell epitope model and expression model of HLA-DPB1 mismatching in unrelated-donor hematopoietic stem cell transplantations].

Objective: To evaluate the risk prediction and assessment function of HLA-DPB1 T-cell epitope (TCE) model and expression model in human leukocyte antigen (HLA)-matched unrelated hematopoietic stem cell transplantation (MUD-HSCT) with HLA-DPB1 mismatching. Methods: A total of 364 (182 pairs) potential MUD-HSCT donors and recipients confirmed by HLA high-resolution typing in Shaanxi Blood Center from 2016 to 2019 were analyzed retrospectively. Of the 182 recipients, there were 121 males and 61 females with an average age of (26.3±14.2) years. Of the 182 donors, there were 148 males and 34 females with an average age of (33.7±7.5) years. Polymerase chain reaction-sequence-based typing (PCR-SBT), next-generation sequencing (NGS) and polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSO) based on LABScan®3D platform were used for high-resolution typing of HLA-A, B, C, DRB1, DQB1, DPB1 gene, and PCR-SBT was used for single nucleotide polymorphism (SNP) typing. TCE model and expression model were used to predict and evaluate the HLA-DPB1 mismatch pattern and acute graft-versus-host-disease (aGVHD) risk. Results: A total of 26 HLA-DPB1 alleles and their 3'-UTR rs9277534 SNP genotypes were detected in this study population, and two new alleles HLA-DPB1*1052∶01 and HLA-DPB1*1119∶01 were found and officially named. The overall mismatch rate of HLA-DPB1 in MUD-HSCT donors and recipients was 90.66% (165/182). In TCE model, the HLA-DPB1 mismatch rates of permissible mismatch (PM) and non-permissible mismatch (non-PM) were 47.80% (87/182) and 42.86% (78/182), respectively. The non-PM in GvH direction was 13.73% (25/182), and which in HvG direction was 29.12% (53/182). A total of 73 pairs of donors and recipients in TCE model met the evaluation criteria of expression model. Among of TCE PM group, recipient DP5 mismatches accounted for 34.25% (25/73) were predicted as aGVHD high risk according to expression model. For the TCE non-PM group, both the recipient DP2 mismatches of 6.85% (5/73) and recipient DP5 mismatches of 10.86% (8/73) were predicted to be at high risk for aGVHD. Risk prediction by TCE model and expression model was 27.27% concordant and 16.97% unconcordant. Conclusions: TCE model and expression model are effective tools to predict aGVHD risk of MUD-HSCT. Comprehensive application of the two models is helpful to the hierarchical assessment of HSCT risk.

[Clinical characteristics and associated factors of mild cognitive impairment in patients with common cardiovascular diseases].

Objective: To analyze the clinical characteristics of patients with common cardiovascular diseases (CVD, including hypertension, coronary heart disease, atrial fibrillation, and heart failure) combined with mild cognitive impairment (MCI) and explore the potential risk factors of MCI in patients with CVD. Methods: A total of 2 294 patients with common cardiovascular diseases who met the criteria at Cardiology Medical Center in Beijing Anzhen Hospital, Capital Medical University, from June 1, 2021, to January 5, 2022, were retrospectively included. The patients were divided into the normal cognitive function group (1 107 cases) and the MCI group (1 187 cases). Demographic information and CVD status were collected. The information of cognitive function were collected using the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE) scales. The difference between normal cognitive function and MCI were compared and analyzed. The logistic regression analysis was used to explored risk factors of MCI in CVD patients. Results: A total of 2 294 patients aged (60.6±10.4) years were included, among whom there were 29.99% (688 cases) females. Compared with patients in the normal cognitive function group, patients in the MCI group were older [ (57.9±11.4) vs (63.1±8.9) years old, P<0.001], with a higher proportion of women [26.47% (293 cases) vs 33.28% (395 cases), P<0.001]; there was a higher proportion of patients suffering from hypertension in the MCI group [59.62% (660 cases) vs 64.62% (767 cases), P=0.014ï¼½, and more components of CVD [(1.68±0.62) vs (1.74±0.65) components, P=0.017]. The risk factors of MCI in patients with common CVD were increased age, increased depression score, combined with hypertension, and ≥3 common components of CVD, with OR (95%CI) of 1.043 (1.032-1.054), 1.021 (1.004-1.037), 1.151 (1.142-3.439), and 1.137 (1.023-1.797), respectively (all P values <0.05). Increasing education level was observed to be associated with reduced risk of MCI with OR (95%CI) of 0.319 (0.271-0.378) (P<0.05). Conclusions: The incidence of MCI was high in CVD patients. The risk factors of MCI in CVD patients included hypertension and≥3 common components of CVD.

[Relationship between maternal and fetal ERAP-1 gene polymorphism and pre-eclampsia].

Objective: To investigate the relationship between the polymorphism of endoplasmic reticulum aminopeptidase 1 (ERAP-1) gene and the occurrence of pre-eclampsia (PE). Methods: A case-control study was conducted in Beijing Obstetrics and Gynecology Hospital from October 2018 to October 2021. A total of 51 PE pregnant women with onset gestational age<34 weeks were selected as the PE group, and 48 normal pregnant women during the same period were selected as the control group. Venous blood samples were collected from the pregnant women before delivery and umbilical cord within 5 minutes after delivery. Single nucleotide polymorphisms (SNP) of ERAP-1 gene in the pregnant women and their fetus were detected by next-generation sequencing. Univariate analysis and multivariate logistic regression analysis were used to analyze all the SNP loci and alleles detected in the two groups, and the significant SNP were screened. Results: (1) A total of 13 target SNP loci of maternal ERAP-1 gene were selected by univariate analysis. Among them, the frequency distribution of genotypes at 96096828, 96121524, 96121715, 96122260 and 96122281 showed statistically significant differences between PE group and control group (all P<0.05). Multivariate logistic regression analysis showed that the risk of PE in pregnant women with TC genotype at locus 96121524 was 2.002 times higher than those with TT genotype (95%CI: 0.687-5.831, P=0.020). (2) A total of 4 target SNP loci of ERAP-1 gene in fetal were selected by univariate analysis, and there was no statistical significance in gene polymorphism of the 4 loci between PE group and control group (all P>0.05). Multivariate logistic regression analysis showed that the risk of PE in fetus with genotype AA at locus 96121406 was 0.236 times that of fetus with genotype GG (95%CI: 0.055-1.025, P=0.016). Conclusion: ERAP-1 gene with TC genotype at 96121524 in the mother and GG genotype at 96121406 in the fetus might be related to the incidence of PE.

[Expression changes of RNA m6A regulators in mouse cerebellum affected by hypobaric hypoxia stimulation].

Objective: To investigate the role of RNA m6A methylation in mediating cerebellar dysplasia through analyzing the phenotypes of the mouse cerebella and the expression of several key m6A regulators upon hypobaric hypoxia treatment. Methods: Five-day old C57/BL6 mice were exposed to hypobaric hypoxia for 9 days. The status of mouse cerebellar development was analyzed by comparing the body weights, brain weights and histological features. Immunostaining of cell-type-specific markers was performed to analyze the cerebellar morphology. Real-time PCR, Western blot and immunohistochemical staining were performed to detect the expression of key m6A regulators in the mouse cerebella. Results: Compared with the control, the body weights, brain weights and cerebellar volumes of hypobaric hypoxic mice were significantly reduced (P<0.01). The expression of specific markers in different cells, including NeuN (mature neuron), Calbindin-D28K (Purkinje cell) and GFAP (astrocyte), was decreased in hypobaric hypoxic mouse cerebella (P<0.01), accompanied with disorganized cellular structure. The expression of methyltransferase METTL3 was significantly down-regulated in the cerebella of hypobaric hypoxic mice (P<0.05). Conclusions: Hypobaric hypoxia stimulation causes mouse cerebellar dysplasia, with structural abnormalities in mature granular neurons, Purkinje cells and astrocytes. Expression of METTL3 is decreased in hypobaric hypoxic mice cerebellum compared with that of normobaric normoxic mice, suggesting that its mediated RNA m6A methylation may play an important role in hypobaric hypoxia-induced mouse cerebellar dysplasia.

[The value of quantitative flow ratio in the hemodynamic evaluation of myocardial bridge].

Objective: To explore the application value of quantitative flow ratio (QFR) in the hemodynamic evaluation of myocardial bridge and to preliminarily evaluate the correlation and related influencing factors between deformation quantitative flow ratio (D-QFR) and QFR. Methods: This is a cross-sectional study. Patients with CAG-confirmed simple myocardial bridge of the middle anterior descending coronary artery from June 2012 to June 2022 at the Air Force Medical Center were retrospectively included in this study. Systolic stenosis of mural coronary arteries (MCA) and myocardial bridge length were measured using quantitative coronary angiography. The patients were divided into mild stenosis group (<50% systolic stenosis) and moderate-to-severe stenosis group (≥50% systolic stenosis) according to the Nobel grading criteria. At different time periods (systolic and diastolic), the QFR values were measured at 3 locations (1 to 2 cm before the MCA entrance, the middle segment of the MCA, and 1 to 2 cm after the MCA exit), denoted as QFRa, QFRb, and QFRc, respectively, and the D-QFR values, incorporating vessel deformation information, were recorded. The MCA distal QFR≤0.8 in either stage was defined as an abnormal QFR value. QFR values were compared between the two groups at different locations and within each group. Factors associated with abnormal QFR values were analysed using multifactorial logistic regression. Spearman rank correlation analysis was used to examine the correlation between D-QFR values and systolic and diastolic QFR values.Multiple linear regression was used to analyse the factors associated with D-QFR. Results: A total of 83 patients were enrolled, including 58 males, aged (57.1±13.1) years. There were 48 cases in the mild stenosis group and 35 cases in the moderate-to-severe stenosis group, and the differences in systolic and diastolic QFRb and QFRc values between the two groups were statistically significant (all P<0.05). Within-group comparisons showed the values of QFRb and QFRc in the systolic phase were lower than those in the diastolic phase; QFRb and QFRc were both lower than QFRa during the same period (all P<0.05). Multifactorial logistic regression analysis showed that MCA systolic stenosis (OR=1.225, 95%CI 1.093-1.372, P<0.001) was an influential factor for abnormal QFR. D-QFR values were positively correlated with both systolic and diastolic QFR values (correlation coefficients were 0.849 and 0.675, respectively, both P<0.01). Multiple linear regression analysis showed that D-QFR values were negatively correlated with age (ß=-0.208, P=0.029), systolic stenosis (ß=-0.500, P<0.001), and myocardial bridge length (ß=-0.211, P=0.036). Conclusions: The QFR values in middle and distal of myocardial bridge decrease. The systolic stenosis rate of myocardial bridge is an important factor affecting QFR value. D-QFR is positively correlated with both systolic and diastolic QFR values. Age, myocardial bridge systolic stenosis rate and length are factors influencing the D-QFR values.

Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial.

BACKGROUND: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T. PATIENTS AND METHODS: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing. RESULTS: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response. CONCLUSIONS: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.

Prediction of plan adaptation in head and neck cancer proton therapy using clinical, radiographic, and dosimetric features.

PURPOSE: Because proton head and neck (HN) treatments are sensitive to anatomical changes, plan adaptation (re-plan) during the treatment course is needed for a significant portion of patients. We aim to predict re-plan at plan review stage for HN proton therapy with a neural network (NN) model trained with patients' dosimetric and clinical features. The model can serve as a valuable tool for planners to assess the probability of needing to revise the current plan. METHODS AND MATERIALS: Mean beam dose heterogeneity index (BHI), defined as the ratio of the maximum beam dose to the prescription dose, plan robustness features (clinical target volume (CTV), V100 changes, and V100 > 95% passing rates in 21 robust evaluation scenarios), as well as clinical features (e.g., age, tumor site, and surgery/chemotherapy status) were gathered from 171 patients treated at our proton center in 2020, with a median age of 64 and stages from I-IVc across 13 HN sites. Statistical analyses of dosimetric parameters and clinical features were conducted between re-plan and no-replan groups. A NN was trained and tested using these features. Receiver operating characteristic (ROC) analysis was conducted to evaluate the performance of the prediction model. A sensitivity analysis was done to determine feature importance. RESULTS: Mean BHI in the re-plan group was significantly higher than the no-replan group (p < .01). Tumor site (p < .01), chemotherapy status (p < .01), and surgery status (p < .01) were significantly correlated to re-plan. The model had sensitivities/specificities of 75.0%/77.4%, respectively, and an area under the ROC curve of .855. CONCLUSION: There are several dosimetric and clinical features that correlate to re-plans, and NNs trained with these features can be used to predict HN re-plans, which can be used to reduce re-plan rate by improving plan quality.

Ceruloplasmin regulating fibrosis in orbital fibroblasts provides a novel therapeutic target for Graves' orbitopathy.

PURPOSE: In diagnosing the pathogenesis of Graves' orbitopathy (GO), there is a growing interest in fibrosis generated by orbital fibroblasts (OFs); nevertheless, the involvement of ceruloplasmin (CP) in OFs remains unknown. METHODS: Differentially expressed genes (DEGs) were identified through bioinformatic analysis. OFs were isolated from orbital tissue and identified with immunofluorescent staining. The levels of DEGs were validated in GO tissue samples and TGF-ß-challenged OFs, and CP was selected for the following laboratory investigations. CP overexpression or knockdown was achieved, and cell viability and fibrosis-associated proteins were investigated to assess the cell phenotype and function. Signaling pathways were subsequently investigated to explore the mechanism of CP function in OFs. RESULTS: CP and cathepsin C (CTSC) are two overlapped DEGs in GSE58331 and GSE105149. OFs were isolated and identified through fibrotic biomarkers. CP and CTSC were downregulated in GO tissue samples and TGF-ß-challenged OFs. CP overexpression or knockdown was achieved in OFs by transducing a CP overexpression vector or small interfering RNA against CP (si1-CP or si2-CP) and verified using a qRT-PCR. CP overexpression inhibited cell viability and reduced the levels of α-SMA, vimentin, fibronectin, and collagen I, whereas CP knockdown exerted opposite effects on OFs. CP overexpression inhibited the phosphorylation of Smad3, Erk1/2, p38, JNK, and AKT; conversely, CP knockdown exerted opposite effects on the phosphorylation of factors mentioned above. CONCLUSION: CP was downregulated in GO and suppressed the expression of fibrosis-associated proteins in both GO and normal OFs. CP might serve as a promising therapeutic agent in the treatment regimens for GO.

Utilization of Autologous Chondrocyte Implantation in the Knee Is Increasing While Reoperation Rates Are Decreasing Despite Increasing Preoperative Comorbidities.

PURPOSE: The primary purpose of this study was to assess the use of autologous chondrocyte implantation (ACI) procedures in the knee during last decade, and the secondary aims of the study were to determine reoperation rates after ACI and to identify associated risk factors. METHODS: A retrospective cohort study from 2010-2020 was performed using the PearlDiver database. The database was queried for the Current Procedural Terminology (CPT) code for ACI performed in any knee location, including the patellofemoral and tibiofemoral joints. Reoperation was defined as interventional knee procedures or total knee arthroplasty after ACI. Reoperations were identified using CPT and International Classification of Diseases codes. Univariate and multivariate logistic regression were used to identify risk factors for reoperation. Significance was defined as P < .05. RESULTS: Among the 2010 patients included in this study, there were 90-day and overall reoperation rates of 2.24% and 30.4%, respectively, with an average follow up of 4.8 ± 3.3 years. The most common reoperations included chondroplasty, meniscectomy, and microfracture. There was an increased rate of ACI performed from 2017-2019 (5.53/100,000) compared to 2014-2016 (4.16/100,000; P < .001). ACI surgeries performed in 2017-2019 were associated with decreased risk of reoperation within 2 years relative to 2014-2016 (odds ratio [OR] = 0.70; 95% confidence interval [CI], 0.52-0.94; P = .019). In the entire ACI cohort, older age (OR = 1.07; 95% CI, 1.05-1.09; P < .001) and tobacco use (OR = 2.13; 95% CI, 1.06-3.94; P = .022) were associated with increased risk of conversion to arthroplasty. Male sex was associated with decreased overall reoperation rates (OR = 0.73; 95% CI, 0.60-0.89; P = .002). CONCLUSIONS: There has been increasing use of ACI in the knee with decreased risk of reoperation since 2017 and the introduction of matrix-associated autologous chondrocyte implantation. Older age and tobacco use were predictors of increased risk of conversion to arthroplasty. Male sex was associated with decreased risk of reoperation. LEVEL OF EVIDENCE: Level IV, retrospective cohort design; database study.

Pre-existing Mental Health Diagnoses Are Associated With Higher Rates of Postoperative Complications, Readmissions, and Reoperations Following Arthroscopic Rotator Cuff Repair.

PURPOSE: To investigate the association between preoperative mental health disorders and postoperative complications, readmissions, and ipsilateral revision procedures among patients undergoing arthroscopic rotator cuff repair (RCR). METHODS: A retrospective cohort study from 2010 to 2020 was performed using the PearlDiver database. Current Procedural Terminology and International Classification of Diseases codes were used to compare patients with and without mental health disorders who underwent arthroscopic RCR. Mental health disorders evaluated in this study include depressive disorder, major depressive disorder, major depressive affective disorder, bipolar disorder, dysthymic disorder, adjustment disorder, separation anxiety disorder, and posttraumatic stress disorder. Patients were matched at a 1:1 ratio based on age, sex, Charlson Comorbidity Index, body mass index, and tobacco use. Rates of complications and subsequent surgeries were compared between patients with and without a preoperative diagnosis of a mental health disorder. RESULTS: The 1-year preoperative prevalence of a mental health disorder from 2010 to 2020 was 14.6%. After 1:1 matching, patients with a mental health disorder who underwent arthroscopic RCR were nearly twice as likely to undergo a revision procedure (odds ratio 1.94, 95% confidence interval 1.76-2.14, P < .001) and more than twice as likely to experience conversion to shoulder arthroplasty (odds ratio 2.29, 95% confidence interval 1.88-2.80, P < .001) within 2 years of initial arthroscopy when compared with patients without a mental disorder. Patients with a mental disorder also experienced increased risk for 90-day readmission (1.9% vs 0%, P < .001) as well as multiple postoperative medical complications. CONCLUSIONS: Patients with pre-existing mental health diagnoses experience increased rates of 90-day postoperative complications and readmissions following arthroscopic RCR. In addition, patients with mental health diagnoses are more likely to undergo revision repair and conversion to shoulder arthroplasty within 2 years of the index procedure. LEVEL OF EVIDENCE: Level III.

Incidence of Venous Thromboembolism After Hip Arthroscopy Is Low With or Without Prophylaxis but Risk Factors Include Oral Contraceptive Use, Obesity, and Malignancy.

PURPOSE: To determine the incidence of and risk factors for symptomatic venous thromboembolism (VTE) after hip arthroscopy (HA) and thromboprophylaxis prescription utilization for this procedure. METHODS: The PearlDiver Mariner database was queried using Current Procedural Terminology codes to identify adult patients (aged ≥ 18 years) who underwent HA between 2010 and 2020. Patient demographic information, including age, oral contraceptive use, and medical comorbidities, as well as perioperative thromboprophylaxis utilization, was recorded using International Classification of Diseases codes and National Drug Codes. The incidence of postoperative VTE within 90 days was determined. Multivariate logistic regression was used to identify predictors of perioperative thromboprophylaxis utilization and risk factors for VTE. RESULTS: The queried records identified 60,181 patients who met the inclusion criteria. Of these patients, 367 (0.6%) experienced VTE, including deep venous thrombosis (0.5%) and/or pulmonary embolism (0.2%). Approximately 2.1% of patients used thromboprophylaxis, including aspirin (1.1%), low-molecular-weight heparin (0.9%), and oral factor Xa inhibitors (0.1%). Oral contraceptive pill use (adjusted odds ratio [aOR], 2.16; 95% confidence interval [CI], 1.34-3.46), obesity (aOR, 1.37; 95% CI, 1.05-1.79), and a history of malignancy (aOR, 1.69; 95% CI, 1.12-2.54) were associated with increased odds of experiencing VTE. Perioperative thromboprophylaxis (aOR, 0.52; 95% CI, 0.19-1.39) was not significantly associated with decreased odds of experiencing VTE. However, obesity (aOR, 1.17; 95% CI, 1.00-1.38) and hypertension (aOR, 1.17; 95% CI, 1.02-1.36) were associated with increased odds of thromboprophylaxis prescription utilization. CONCLUSIONS: Although the overall risk of symptomatic VTE after HA remains low, oral contraceptive use, obesity, and a history of malignancy are associated with increased odds of thromboembolic events within 90 days. Routine thromboprophylaxis after HA may not be indicated in all patients but can be considered based on patient-specific risk factors. LEVEL OF EVIDENCE: Level III, retrospective prognostic comparative trial.

Complications and re-operations after extensor mechanism repair surgery in a large cross-sectional cohort: females and tobacco-users at highest risk for adverse outcomes.

PURPOSE: There is little information on patients most at risk for poor outcomes following surgical repair of extensor mechanism tendon injuries. The purpose of this study is to provide an epidemiological overview of patients undergoing patellar or quadriceps tendon repair and to assess the incidence of postoperative complications, readmissions, and revision repairs among this population. METHODS: Retrospective data were obtained using the PearlDiver database for patellar tendon repair and quadriceps tendon repair patients between 2010 and 2020. Baseline demographics, incidences of 90-day readmissions and postoperative complications, and reoperation rates were collected for each group. Multivariate logistic regression was performed to assess the predictive power of each demographic variable on the incidence of postoperative complications and reoperations. RESULTS: In total, 1543 patients underwent patellar tendon repair and 601 underwent quadriceps tendon repair. Complications within 90-days were observed in 33.7% of patients with patellar tendon repair and 39.2% of patients with quadriceps tendon repair. Reoperation rates were 4.2% and 4.8% for patellar tendon repair and quadriceps tendon repair, respectively. Females in both patellar tendon repair and quadriceps tendon repair groups were at significantly higher risk for post-operative complications (patellar tendon repair OR 3.0, 95% CI 2.4-3.7; quadriceps tendon repair OR 2.9, 95% CI 1.9-4.6; p < 0.001 for both). Older age (p < 0.001), female gender (p < 0.001), CCI (p < 0.001), tobacco use (p < 0.001), and obesity (p < 0.01) were all predictors of experiencing at least one complication following patellar tendon repair. For quadriceps tendon repair, female gender (p < 0.001) and CCI (p < 0.001) were the strongest predictors of experiencing at least one complication, while older age, tobacco use, and obesity (p < 0.05 for all) were also significant independent predictors. CONCLUSION: Patellar tendon repair patients are younger on average than quadriceps tendon repair patients. Although females are less likely to sustain extensor mechanism ruptures compared to males, females are significantly more likely to have at least one complication after quadriceps or patellar tendon repair. These findings may be used by surgeons, patients, and payors to understand who is most at risk for adverse outcomes following extensor mechanism repair surgery, resulting in earlier intervention and counseling to reduce the likelihood of a poor outcome following extensor mechanism repair surgery. LEVEL OF EVIDENCE: Level III.