Neoadjuvant therapy leads to objective response in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is the second most common hepatic malignancy and has a poor prognosis. Surgical resection is the standard of care for patients with resectable disease, representing 30-40% of cases. Increasingly, neoadjuvant systemic therapy is being utilized in patients due to high-risk anatomic or biologic considerations. However, data on the clinical effect of this approach are limited. We performed a cohort study to evaluate the effect of neoadjuvant therapy in patients with oncologically high-risk iCCA. METHODS: iCCA patients (n = 181) between the years 2014-2020 were reviewed for clinical, histopathologic, treatment, and outcome-related data. Tumor regression grade was scored per CAP criteria for gastrointestinal carcinomas. RESULTS: 47 iCCA patients received neoadjuvant therapy and 72 did not. Neoadjuvant treatment led to objective response and tumor regression by CAP score. After adjustment for age, clinical stage, and tumor size, the outcomes of patients who had neoadjuvant therapy followed by surgery were not significantly different from those patients who had surgery first. DISCUSSION: In conclusion, neoadjuvant therapy in iCCA facilitated surgical care. The progression-free and overall survival for surgical patients with and without neoadjuvant therapy were not significantly different suggesting this approach needs further exploration as an effective treatment paradigm.

Prognostic Immunohistochemistry for Ki-67 and OTP on Small Biopsies of Pulmonary Carcinoid Tumors: Ki-67 Index Predicts Progression-free Survival and Atypical Histology.

Prognostic stratification of pulmonary carcinoids into "typical" and "atypical" categories requires examination of large tissue volume. However, there is a need for tools that provide similar prognostic information on small biopsy samples. Ki-67 and OTP immunohistochemistry have shown promising prognostic value in studies of resected pulmonary carcinoids, but prognostic value when using biopsy/cytology specimens is unclear. Ki-67 immunohistochemistry was performed on small biopsy/cytology specimens from pulmonary carcinoid tumors (n=139), and labeling index was scored via automated image analysis of at least 500 cells. OTP immunohistochemistry was performed on 70 cases with sufficient tissue and scored as positive or negative (<20% tumor nuclei staining). Higher Ki-67 index was associated with worse disease-specific progression-free survival (ds-PFS), with 3% and 4% thresholds having similarly strong associations with ds-PFS ( P <0.001, hazard ratio ≥11). Three-year ds-PFS was 98% for patients with Ki-67 <3% and 89% for patients with Ki-67≥3% ( P =0.0006). The optimal Ki-67 threshold for prediction of typical versus atypical carcinoid histology on subsequent resection was 3.21 (AUC 0.68). Negative OTP staining approached significance with atypical carcinoid histology ( P =0.06) but not with ds-PFS ( P =0.24, hazard ratio=3.45), although sample size was limited. We propose that Ki-67 immunohistochemistry may contribute to risk stratification for carcinoid tumor patients based on small biopsy samples. Identification of a 3% hot-spot Ki-67 threshold as optimal for prediction of ds-PFS is notable as a 3% Ki-67 threshold is currently used for gastrointestinal neuroendocrine tumor stratification, allowing consideration of a unified classification system across organ systems.

Breast Cancer Risk Perceptions Among Underserved, Hispanic Women: Implications for Risk-Based Approaches to Screening.

BACKGROUND: Understanding factors that shape breast cancer risk perceptions is essential for implementing risk-based approaches to breast cancer detection and prevention. This study aimed to assess multilevel factors, including prior screening behavior, shaping underserved, Hispanic women's perceived risk for breast cancer. METHODS: Secondary analysis of survey data from Hispanic women (N = 1325, 92% Spanish speaking, 64% < 50) enrolled in a large randomized controlled trial. Analyses were performed in two cohorts to account for the role of age on screening guideline recommendations (< 50 and 50 +). For each cohort, we examined differences in three common measures of perceived risk of breast cancer (percent lifetime, ordinal lifetime, comparative) by participant factors with chi-square or Kruskal-Wallis tests, as appropriate. Multivariate analyses examined the association between mammography history with percent perceived lifetime risk (outcome > 10 vs ≤ 10%). RESULTS: Overall, 75% reported a lifetime risk between 0 and 10%, 96% rated their ordinal risk as "not high," and 50% rated their comparative risk as "much lower." Women < 50 with a family history of breast cancer reported significantly higher levels of perceived risk across all three measures. Among women 50 + , those reporting lower levels of perceived risk were significantly more likely to be Spanish speaking. No significant association was observed between mammography history and percent lifetime risk of breast cancer. CONCLUSION: Factors shaping breast cancer risk perceptions differ by age. Prior screening may play less of role in constructing risk perceptions. Research is needed to develop culturally and linguistically appropriate strategies to improve implementation of risk-based screening.

A case-control autopsy series of liver pathology associated with novel coronavirus disease (COVID-19).

BACKGROUND: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for coronavirus disease 2019 (COVID-19) is most well-known for causing pulmonary injury, a significant proportion of patients experience hepatic dysfunction. The mechanism by which SARS-CoV2 causes liver injury is not fully understood. The goal of this study was to describe the hepatic pathology in a large cohort of deceased patients with COVID-19 as compared to a control group of deceased patients without COVID-19. METHODS: Consented autopsy cases at two institutions were searched for documentation of COVID-19 as a contributing cause of death. A group of consecutive consented autopsy cases during the same period, negative for SARS-CoV-2 infection, was used as a control group. The autopsy report and electronic medical records were reviewed for relevant clinicopathologic information. H&E-stained liver sections from both groups were examined for pertinent histologic features. Select cases underwent immunohistochemical staining for CD 68 and ACE2 and droplet digital polymerase chain reaction (ddPCR) assay for evaluation of SARS-CoV2 RNA. RESULTS: 48 COVID-19 positive patients (median age 73, M:F 3:1) and 40 COVID-19 negative control patients (median age 67.5, M:F 1.4:1) were included in the study. The COVID-19 positive group was significantly older and had a lower rate of alcoholism and malignancy, but there was no difference in other comorbidities. The COVID-19 positive group was more likely to have received steroids (75.6 % vs. 36.1 %, p < 0.001). Hepatic vascular changes were seen in a minority (10.6 %) of COVID-19 positive cases. When all patients were included, there were no significant histopathologic differences between groups, but when patients with chronic alcoholism were excluded, the COVID-19 positive group was significantly more likely to have steatosis (80.9 % vs. 50.0 %, p = 0.004) and lobular inflammation (45.7 % vs. 20.7 %, p = 0.03). Testing for viral RNA by ddPCR identified 2 of the 18 (11.1 %) COVID-19 positive cases to have SARS-CoV-2 RNA detected within the liver FFPE tissue. CONCLUSIONS: The most significant findings in the liver of COVID-19 positive patients were mild lobular inflammation and steatosis. The high rate of steroid therapy in this population may be a possible source of steatosis. Hepatic vascular alterations were only identified in a minority of patients and did not appear to play a predominant role in COVID-19 mediated hepatic injury. Low incidence of SARS-CoV-2 RNA positivity in liver tissue in our cohort suggests hepatic injury in the setting of COVID-19 may be secondary in nature.

Women 50 Years and Older With Negative Pap Test and Positive Human Papillomavirus Test for Genotypes Other Than 16 and 18-Follow-up Outcomes.

OBJECTIVE: A follow-up of women 50 years or older with concomitant positive high-risk human papillomavirus (HPV) genotypes other than 16 and 18 (hrHPVO) and negative Pap test (NILMPap) was conducted to better understand the implications of hrHPVO positivity on potential risk of developing significant high-grade lesions. MATERIAL AND METHODS: A retrospective review of 2014 cytology data of patients with co-testing (Pap test and HPV DNA) identified 85 women 50 years or older with NILMPap and hrHPVO+. RESULTS: Most patients (63) had repeat co-testing on next follow-up. Of these, 41 patients with persistent hrHPVO+ status, 3 developed cervical intraepithelial neoplasia 2 (CIN2), and 1 CIN3. Nineteen patients were followed with biopsies. Of these, 7 biopsies were abnormal, 5 of which showed low-grade (CIN1) and 2 high-grade (CIN3) histology; none progressed on further follow-up. Three patients were followed with Pap test only, all had NILMPap, and none progressed on further follow-up. In summary, of the 85 patients, 26 developed abnormal histology during follow-up, 6 of whom had high-grade histology (CIN2 and CIN3, 3 each).The 5-year risk of CIN1+ in this cohort was 43.8% and for CIN2+ was 12.3%. The risk of abnormal histology did not differ significantly by prior history of Pap tests, histology, and/or HPV results. CONCLUSIONS: A persistent positivity for hrHPVO indicated higher likelihood to develop a lesion, and this risk was not reduced for patients 50 and older compared with the published screening population risk.

Assessment of PD-L1, TROP2, and nectin-4 expression in penile squamous cell carcinoma.

OBJECTIVES: There is an unmet need for therapeutically relevant biomarkers for advanced penile squamous cell carcinoma (pSCC). Proposed immunohistochemistry (IHC)-based biomarkers include programmed death-ligand 1 (PD-L1), trophoblast cell-surface antigen 2 (TROP2), and nectin-4; however, there is a paucity of data pertaining to these biomarkers. Herein, we investigated the expression of PD-L1, TROP2, and nectin-4 in a well-annotated cohort of pSCCs. METHODS: A single-institution pathology archive was queried for patients who had a partial or total penectomy for pSCC between January 2000 and December 2022. Whole-slide sections were stained with antibodies against PD-L1 (22C3), TROP2, and nectin-4. Expression in tumor cells was quantified using H-scores (0-300). Associations between IHC expression, human papilloma virus (HPV) status, clinicopathologic findings, and outcome parameters were evaluated. RESULTS: This study included 121 patients. For PD-L1, the median combined positive and H-scores were 1 and 0, respectively; 32.7 % of the cases had an H-score>0. Compared to PD-L1-negative tumors, PD-L1-positive tumors had higher pT stage and grade. The median TROP2 and nectin-4 H-scores were 230 and 140, respectively, with high TROP2 and nectin-4, defined by an H-score>200, noted in 80.7 % and 10.9 % of cases, respectively. High-risk HPV-positive cases had higher TROP2 and nectin-4 scores compared to HPV-negative cases. Patients with high TROP2 expression had significantly more disease progression, and patients with high nectin-4 expression had significantly fewer deaths due to disease. CONCLUSIONS: High expression of TROP2 and nectin-4 in pSCC support evaluation of these markers as therapeutic targets pending validation of our findings.

Age-related histopathological findings in temporal arteries.

AIMS: Giant cell arteritis (GCA) is a systemic vasculitis affecting medium and large arteries in patients aged over 50 years. Involvement of temporal arteries (TA) can lead to complications such as blindness and stroke. While the diagnostic gold standard is temporal artery biopsy (TAB), comorbidities and age-related changes can make interpretation of such specimens difficult. This study aims to establish a baseline of TA changes in subjects without GCA to facilitate the interpretation of TAB. METHODS AND RESULTS: Bilateral TA specimens were collected from 100 consecutive eligible postmortem examinations. Subjects were divided into four age groups and specimens semiquantitatively evaluated for eccentric intimal fibroplasia, disruption and calcification of the internal elastic lamina (IEL), medial attenuation and degree of lymphocytic inflammation of the peri-adventitia, adventitia, media and intima. The individual scores of intimal fibroplasia, IEL disruption and medial attenuation were added to yield a 'combined score (CS)'. Seventy-eight 78 decedents were included in the final analysis following exclusion of 22 individuals for either lack of clinical information or inability to collect TA tissue. A total of 128 temporal artery specimens (50 bilateral from individual decedents, 28 unilateral) were available for examination. Intimal proliferation, IEL loss, IEL calcification and CS increased with age in a statistically significant fashion. Comparison of the oldest age group with the others showed statistically significant differences, although this was not uniformly preserved in comparison between the three youngest groups. CONCLUSION: Senescent arterial changes and healed GCA exhibit histological similarity and such changes increase proportionally with age. The CS demonstrates significant association with age overall and represents a potential avenue for development to 'normalise' TA biopsies from older individuals.

Performance of an Artificial Intelligence Model for Recognition and Quantitation of Histologic Features of Eosinophilic Esophagitis on Biopsy Samples.

We have developed an artificial intelligence (AI)-based digital pathology model for the evaluation of histologic features related to eosinophilic esophagitis (EoE). In this study, we evaluated the performance of our AI model in a cohort of pediatric and adult patients for histologic features included in the Eosinophilic Esophagitis Histologic Scoring System (EoEHSS). We collected a total of 203 esophageal biopsy samples from patients with mucosal eosinophilia of any degree (91 adult and 112 pediatric patients) and 10 normal controls from a prospectively maintained database. All cases were assessed by a specialized gastrointestinal (GI) pathologist for features in the EoEHSS at the time of original diagnosis and rescored by a central GI pathologist (R.K.M.). We subsequently analyzed whole-slide image digital slides using a supervised AI model operating in a cloud-based, deep learning AI platform (Aiforia Technologies) for peak eosinophil count (PEC) and several histopathologic features in the EoEHSS. The correlation and interobserver agreement between the AI model and pathologists (Pearson correlation coefficient [rs] = 0.89 and intraclass correlation coefficient [ICC] = 0.87 vs original pathologist; rs = 0.91 and ICC = 0.83 vs central pathologist) were similar to the correlation and interobserver agreement between pathologists for PEC (rs = 0.88 and ICC = 0.91) and broadly similar to those for most other histologic features in the EoEHSS. The AI model also accurately identified PEC of >15 eosinophils/high-power field by the original pathologist (area under the curve [AUC] = 0.98) and central pathologist (AUC = 0.98) and had similar AUCs for the presence of EoE-related endoscopic features to pathologists' assessment. Average eosinophils per epithelial unit area had similar performance compared to AI high-power field-based analysis. Our newly developed AI model can accurately identify, quantify, and score several of the main histopathologic features in the EoE spectrum, with agreement regarding EoEHSS scoring which was similar to that seen among GI pathologists.

Outcomes of Infliximab-Treated inflammatory bowel disease patients undergoing therapeutic drug monitoring with two different assays.

OBJECTIVES: There are multiple assays for infliximab (IFX) drug level (IFX-DL) and antibody to infliximab (ATI) measurement. The aims of this study are to examine the correlation and outcomes of IFX-DL and ATI in inflammatory bowel disease (IBD) patients, simultaneously measured with different methods in different institutions. DESIGN AND METHODS: Residual samples of IFX-treated IBD patients undergoing drug monitoring for IFX-DL and ATI, both measured by ECLIA (Esoterix Laboratories) were used to simultaneously quantify IFX-DL via LC-MS/MS and ATI via an in-house ECLIA (ih-ECLIA) (Mayo Clinic Laboratories). Comparisons of IFX-DL and ATI detection between the assays from different institutions were performed, along with a comparison between the assays by association of IFX-DL and ATI obtained by each method with clinical remission, endoscopic healing (EH) and normal serum C-reactive protein (CRP ≤ 8 mg/L). RESULTS: A total of 151 patients were included (median age, 32 years (range, 12-84); 45.7% female). The median IFX-DL was 7 mcg/mL (IQR: 1.3, 19.4) and 6 mcg/mL (IQR: 0.9, 20) via LC-MS/MS and ECLIA, respectively (Spearman correlation coefficient r = 0.97). ATI was detected in 13/142 (9.2%) via ih-ECLIA of whom 100% had IFX-DL < 5 mcg/mL by LC-MS/MS. ATI was positive in 39/151 (25.8%) via ECLIA, and 84.6% of positives had IFX-DL < 5 mcg/mL by ECLIA. Compared to ECLIA, the frequency of ATI detection via ih-ECLIA was lower in patients in clinical remission (7.3% vs 36.6%; p = 0.0005), those with normal CRP (5.9% vs. 20.0%; p = 0.0005), and in patients with EH (5.3% vs 18.4%; p = 0.03). CONCLUSIONS: IFX-DL was comparable between LC-MS/MS and ECLIA assays. Rate of ATI detection via ih-ECLIA was lower than ECLIA, which was more aligned with favorable clinical outcomes.

Artificial intelligence-based reticulin proportionate area - a novel histological outcome predictor in hepatocellular carcinoma.

AIMS: Reticulin stain is used routinely in the histological evaluation of hepatocellular carcinoma (HCC). The goal of this study was to assess whether the histological reticulin proportionate area (RPA) in HCCs predicts tumour-related outcomes. METHODS AND RESULTS: We developed and validated a supervised artificial intelligence (AI) model that utilises a cloud-based, deep-learning AI platform (Aiforia Technologies, Helsinki, Finland) to specifically recognise and quantify the reticulin framework in normal livers and HCCs using routine reticulin staining. We applied this reticulin AI model to a cohort of consecutive HCC cases from patients undergoing curative resection between 2005 and 2015. A total of 101 HCC resections were included (median age = 68 years, 64 males, median follow-up time = 49.9 months). AI model RPA reduction of > 50% (compared to normal liver tissue) was predictive of metastasis [hazard ratio (HR) = 3.76, P = 0.004, disease-free survival (DFS, HR = 2.48, P < 0.001) and overall survival (OS), HR = 2.80, P = 0.001]. In a Cox regression model, which included clinical and pathological variables, RPA decrease was an independent predictor of DFS and OS and the only independent predictor of metastasis. Similar results were found in the moderately differentiated HCC subgroup (WHO grade 2), in which reticulin quantitative analysis was an independent predictor of metastasis, DFS and OS. CONCLUSION: Our data indicate that decreased RPA is a strong predictor of various HCC-related outcomes, including within the moderately differentiated subgroup. Reticulin, therefore, may represent a novel and important prognostic HCC marker, to be further explored and validated.

Histologic and proteomic remodeling of the pulmonary veins and arteries in a porcine model of chronic pulmonary venous hypertension.

AIMS: In heart failure (HF), pulmonary venous hypertension (PVH) produces pulmonary hypertension (PH) with remodeling of pulmonary veins (PV) and arteries (PA). In a porcine PVH model, we performed proteomic-based bioinformatics to investigate unique pathophysiologic mechanisms mediating PA and PV remodeling. METHODS AND RESULTS: Large PV were banded (PVH, n = 10) or not (Sham, n = 9) in piglets. At sacrifice, PV and PA were perfusion labelled for vessel-specific histology and proteomics. The PA and PV were separately sampled with laser-capture micro-dissection for mass spectrometry. Pulmonary vascular resistance [Wood Units; 8.6 (95% confidence interval: 6.3, 12.3) vs. 2.0 (1.7, 2.3)] and PA [19.9 (standard error of mean, 1.1) vs. 10.3 (1.1)] and PV [14.2 (1.2) vs. 7.6 (1.1)] wall thickness/external diameter (%) were increased in PVH (P < 0.05 for all). Similar numbers of proteins were identified in PA (2093) and PV (2085) with 94% overlap, but biological processes differed. There were more differentially expressed proteins (287 vs. 161), altered canonical pathways (17 vs. 3), and predicted upstream regulators (PUSR; 22 vs. 6) in PV than PA. In PA and PV, bioinformatics indicated activation of the integrated stress response and mammalian target of rapamycin signalling with dysregulated growth. In PV, there was also activation of Rho/Rho-kinase signalling with decreased actin cytoskeletal signalling and altered tight and adherens junctions, ephrin B, and caveolae-mediated endocytosis signalling; all indicating disrupted endothelial barrier function. Indeed, protein biomarkers and the top PUSR in PV (transforming growth factor-beta) suggested endothelial to mesenchymal transition in PV. Findings were similar in human autopsy specimens. CONCLUSION: These findings provide new therapeutic targets to oppose pulmonary vascular remodeling in HF-related PH.

Arthroscopic Reduction of Bicruciate Tibial Avulsion Fractures: Lever Push Technique.

Combined anterior cruciate ligament and posterior cruciate ligament tibial avulsion fractures are rare knee injuries that are primarily seen in adults. Prompt surgical intervention is indicated for displaced fractures to restore knee stability. Arthroscopic techniques are now the preferred method for treating anterior tibial spine avulsion fractures with posterior cruciate ligament tibial avulsion fractures being treated arthroscopically or with open reduction and internal fixation methods. This Technical Note and accompanying video demonstrate an arthroscopically assisted repair of bicruciate tibial avulsion fractures using an arthroscopic lever push technique. Two sutures are passed through the anterior cruciate ligament and pulled down through two bone tunnels placed within the tibial fracture bed, and one suture is passed around the posterior cruciate ligament and pulled down through one bone tunnel passing from the anterior tibia to the tibial fracture bed. Our technique is simple and effective in reducing bicruciate tibial avulsion fractures to anatomic position.

Single-Nucleotide Polymorphism Array for Histologically Ambiguous Melanocytic Tumors.

Genome-wide copy number profiling by single-nucleotide polymorphism (SNP) array is increasingly employed in the clinical diagnostic workup of melanocytic tumors. We present our SNP array results on 675 melanocytic tumors, including 615 histologically ambiguous tumors evaluated by our institution's dermatopathology consultation service and a separate validation cohort of 26 known benign nevi and 34 known malignant melanomas. The total number of somatic copy number abnormalities, sub-chromosomal copy number abnormalities, regions of homozygosity, and abnormalities at disease-associated regions was significantly associated with a diagnosis of malignancy across disease categories. In our study, the number of copy number abnormalities was the factor that best discriminated between benign versus malignant diagnoses, confirming recent published research. Histologically ambiguous tumors had a range and spectrum of abnormalities, including recurrent 11p gains, copy state transitions over kinase genes, and 3p deletions overlapping BAP1 in neoplasms with Spitzoid morphology. Our data suggest that histologically ambiguous melanocytic neoplasms and early primary melanomas have a range of abnormalities that is intermediate between unambiguous benign or malignant melanocytic neoplasms. Careful technical review and an integrated diagnostic approach are essential for the accurate interpretation of SNP array results on histologically ambiguous melanocytic tumors.

Short- and Long-Term Biological Variability of Small Dense LDL, HDL3, and Triglyceride-Rich Lipoprotein Cholesterol.

BACKGROUND: Measurement of cholesterol within lipoprotein subfractions may aid in cardiovascular disease prediction. Simple, homogenous enzymatic assays for the direct measurement of lipoprotein subfractions have been developed to measure small dense low-density lipoprotein cholesterol (sdLDL-C), high-density lipoprotein-3 cholesterol (HDL3-C), and triglyceride-rich lipoprotein (TRL-C) cholesterol. The objective of this study was to determine biological variability for sdLDL-C, HDL3-C, and TRL-C in a healthy reference population to facilitate interpretation of these analytes. METHODS: Serum samples were collected from 24 healthy subjects (n = 14 female/10 male) daily for 3 days while non-fasting, and daily for 5 days, weekly for 4 weeks, and monthly for 6 months after overnight fasting. sdLDL-C, HDL3-C, and TRL-C cholesterol were measured by homogenous enzymatic assays. Sources of variability (between-subject, within-subject, and analytical) were calculated using random-effects regression models. Reference change value (RCV) and index of individuality (II) for each time period were determined from the variance components. RESULTS: Analytic variability (daily, weekly, and monthly CVA) was <3% for each analyte. Monthly within-subject variability (CVI) was 17.1% for sdLDL-C, 7.4% for HDL3-C, and 25.7% for TRL-C. Most of the monthly variation was attributed to between-subject variation for all 3 analytes. Overall RCVs for monthly measurements were 18.1 mg/dL for sdLDL-C, 6.1 mg/dL for HDL3-C, and 16.0 mg/dL for TRL-C. IIs were <0.6 for sdLDL-C and HDL3-C, and 0.81 for TRL-C. CONCLUSIONS: sdLDL-C, HDL3-C, and TRL-C showed moderate within-subject variability, but high between-subject variability, in a healthy reference population. Given the high individuality of each analyte, population-based reference intervals may be inadequate to detect clinically significant changes.

Sinonasal Mucosal Melanoma: Role of Tumor Proliferative Indices and Pathological Factors in Survival.

OBJECTIVE: The objective of this study is to determine the association of proliferation indices and pathologic biomarkers on overall and recurrence/metastasis-free survival (OS and RMFS) in patients with sinonasal mucosal melanoma (SNMM) and to assess the genetic mutational landscape of SNMM. METHODS: This is a retrospective cohort study of 45 SNMM patients without neoadjuvant therapy who underwent surgical therapy with curative intent and had tumor tissue available for histopathologic review, molecular analysis, and genetic mutational assessment. The OS and RMFS were assessed for associations with numerous tumor and patient-related factors. RESULTS: Among proliferative indices, higher Ki67 and mitotic rates were associated with worsened OS and RMFS (Ki67: p = 0.0007 and p < 0.0001; mitotic rate: p = 0.005 and p = 0.0009, respectively). The presence of brisk tumor-infiltrating lymphocytes (TILs) was associated with improved RMFS (p = 0.007) and the presence of lymphovascular invasion was associated with worsened OS and RMFS (p = 0.02 and p = 0.04, respectively). Patients with amelanotic tumors were more likely to have higher T-stage (p = 0.046), less likely to have brisk TILs (p = 0.02) and had worsened RMFS (p = 0.03). Patients on immunotherapy with tumor Ki67 < 40% had better 3-year OS compared to those with higher Ki67 index (p = 0.004). Actionable genetic mutations such as BRAF V600E are rare and present in only 1 of 20 patients tested. CONCLUSION: In SNMM patients, pathologic and proliferation markers such as Ki67, mitotic rate and brisk TILs are associated with survival and may be considered in future staging systems. Clinical response to immunotherapy appears to correlate with the Ki67 index. Given the distinct genetic profile of SNMM, targeted therapies against the MAPK kinase pathway have limited utility. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:2350-2358, 2022.

Subpectoral Biceps Tenodesis Using an All-Suture Anchor.

Long head biceps tendon pathology is a substantial contributor to anterior shoulder pain and often requires surgical intervention to offer a return to normal functionality. Surgical treatment options consist of both open and arthroscopic tenodesis or tenotomy of the long head biceps brachii. Several techniques exist for tenodesis and tenotomy of the biceps, although current debate continues regarding which surgical approach is the optimal intervention for symptomatic bicep pathology. In this technical note, we describe a subpectoral biceps tenodesis of the long head bicep tendon using an all-suture anchor. Our technique offers the advantages of using an all-suture anchor that incorporates a self-tensioning mechanism with direct visualization of the tendon during biceps tenodesis and anchor insertion.

CD117, BAP1, MTAP, and TdT Is a Useful Immunohistochemical Panel to Distinguish Thymoma from Thymic Carcinoma.

BACKGROUND: The morphologic distinction between thymic carcinomas and thymomas, specifically types B3, A, and occasionally micronodular thymomas with lymphoid stroma (MNTLS) can be challenging, as has also been shown in interobserver reproducibility studies. Since thymic carcinomas have a worse prognosis than thymomas, the diagnosis is important for patient management and treatment. This study aimed to identify a panel of immunohistochemical (IHC) markers that aid in the distinction between thymomas and thymic carcinomas in routine practice. MATERIALS AND METHOD: Thymic carcinomas, type A and B3 thymomas, and MNTLS were identified in an institutional database of thymic epithelial tumors (TET) (1963-2021). IHC was performed using antibodies against TdT, Glut-1, CD5, CD117, BAP1, and mTAP. Percent tumor cell staining was recorded (Glut-1, CD5, CD117); loss of expression (BAP1, mTAP) was considered if essentially all tumor cells were negative; TdT was recorded as thymocytes present or absent (including rare thymocytes). RESULTS: 81 specimens included 44 thymomas (25 type A, 11 type B3, 8 MNTLS) and 37 thymic carcinomas (including 24 squamous cell carcinomas). Using BAP1, mTAP, CD117 (cut-off, 10%), and TdT, 88.9% of thymic carcinomas (95.7% of squamous cell carcinomas) and 77.8% of thymomas could be predicted. Glut-1 expression was not found to be useful in that distinction. All tumors that expressed CD5 in ≥50% of tumor cells also expressed CD117 in ≥10% of tumor cells. In four carcinomas with homozygous deletion of CDKN2A, mTAP expression was lost in two squamous cell carcinomas and in a subset of tumor cells of an adenocarcinoma and was preserved in a lymphoepithelial carcinoma. CONCLUSION: A panel of immunostains including BAP1, mTAP, CD117 (using a cut-off of 10% tumor cell expression), and TdT can be useful in the distinction between thymomas and thymic carcinomas, with only a minority of cases being inconclusive.

Predictors of seroconversion after coronavirus disease 2019 vaccination.

BACKGROUND: Vaccine nonresponse during the coronavirus disease 2019 (COVID-19) pandemic has considerable individual and societal risks. OBJECTIVE: To investigate the clinical characteristics of patients with lack of seroconversion after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: Demographic and clinical data were collected from 805 patients who had validated antibody assays against the SARS-CoV-2 spike protein at least 14 days after completion of their COVID-19 vaccination. Clinical characteristics from patients with a negative (< 0.4 U/mL) antibody response were assessed and summarized. RESULTS: A total of 622 (77.3%) patients attained seroconversion as defined by a titer of greater than or equal to 0.4 U/mL, whereas 183 out of 805 (22.7%) patients exhibited no seroconversion after vaccination against SARS-CoV-2. Univariately, older age (P = .02) and male sex were associated with a lower likelihood of seroconversion (P = .003). Therapy with immunosuppressive drugs was noted in 93 (50.8%) of seronegative patients with most (n = 83/93, 89.2%) receiving ongoing immunosuppressive therapy at the time of vaccination. Among the 134 (73.2%) seronegative patients with immunodeficiency, 110 (82.1%) had primary immunodeficiency. Cancer (n = 128, 69.9%), B cell depletion therapy (n = 90/115, 78.3%), and immunosuppressant steroid use (n = 71/93 on immunosuppressants, 76.3%) were the other common characteristics among the vaccine nonresponders. More importantly, our study did not evaluate the actual efficacy of COVID-19 vaccination. CONCLUSION: Vaccine responses vary by age and sex, with men showing lower rates of seroconversion as compared with women. Primary immunodeficiency along with active malignancy and ongoing immunosuppression with steroids or B cell depletion therapy appeared to be the most common characteristics for those with a lack of vaccine seroconversion after COVID-19 vaccination.

Rehabilitation After Anterior Cruciate Ligament Injury: Review of Current Literature and Recommendations.

PURPOSE OF REVIEW: Anterior cruciate ligament reconstruction (ACLR) is a common surgical procedure with an estimated 120,000 cases performed in the USA each year. Physical therapy plays a critical role in the successful recovery of both surgically and non-surgically managed patients. Interestingly, ACL rehabilitation protocols vary greatly with little consensus among practitioners. Nonetheless, there has been agreement over the last decade to shift from conservative, standardized length protocols to more accelerated, individualized protocols that vary in length and modalities based on patient-specific findings and preferences. This review summarizes the most recent trends, opinions, and modalities in ACL rehabilitation research, with a specific focus on novel methods to treat the specific psychosocial needs of ACL deficient patients. RECENT FINDINGS: We found that new protocols emphasize early weight bearing, open kinetic chain (OKC) exercises, and other alternative modalities such as neuromuscular electrical stimulation and blood flow restriction. We also found a recent trend toward the use of clinical milestones to determine when a patient is ready for the next phase of a "step-up" rehabilitation program. One particularly nascent topic of research is the inclusion of methods to treat the psychosocial impacts of ACL injury, recovery, and the anxiety around return to sport. Rehabilitation strategy has become increasingly patient-dependent, and the new modalities being utilized are accelerating patient recovery. Return to sport is a particularly important factor for many ACLR patients, and recovery has an important psychological component that has only recently been addressed in the literature, with positive preliminary findings.

Multi-institutional development and validation of a novel histologic grading system for colonic graft-versus-host disease.

Graft-versus-host disease (GVHD) remains a major complication for patients who have undergone hematopoietic stem cell transplantation. The Lerner system is the most widely used histologic grading score for gastrointestinal GVHD but its clinic utility is debated. The aim of our study was to develop a novel histologic grading system for gastrointestinal GVHD that incorporates independent evaluation of both apoptotic counts and crypt destruction. Colonic biopsies taken to assess for GVHD were retrospectively assessed for: Crypt damage (No crypt dropout or ulceration-0; crypt dropout without ulceration-1; ulceration-2) and crypt apoptotic counts (No apoptosis-0; 1-6 apoptotic bodies per 10 contiguous crypts-1; >6apoptotic bodies per 10 contiguous crypts-2). The two scores were added together to get an overall grade (0-4). Alternative apoptotic cutoff points were examined. An apoptotic cutoff of >9 apoptotic bodies per 10 contiguous crypts marginally improved the area under the curve (AUC), but the AUCs from the resulting novel grade calculations were not significantly different (p = 0.10). Lerner grading was also applied. The study group consisted of an initial analysis cohort (n = 191) and a second validation cohort from a separate institution (n = 97). In the initial analysis cohort, our histologic grading system provided prognostic stratification for GVHD-related death within 6 months (p = 0.0004, AUC = 0.705). The Lerner system performed similarly in terms of providing prognostic stratification for GVHD-related death (p = 0.0001, AUC = 0.707). In the external validation cohort, our histologic grading system was not associated with GVHD-related death (p = 0.14, AUC = 0.621), but the Lerner system was associated with GVHD-related death (p = 0.048, AUC = 0.663). While our grading system may have some advantages compared to the Lerner system, due to lack of reproducibility we do not currently recommend widespread adoption of this system. Nonetheless, we present a standardized tool for assessing both apoptosis and crypt damage. Future studies assessing alternative histologic grading systems with external validation and further examination the lower apoptotic threshold for GVHD diagnosis are warranted.