Follow-up biopsies identify high rates of persistent rejection in pediatric kidney transplant recipients after treatment of T cell-mediated rejection.

BACKGROUND: Incomplete resolution of T cell-mediated rejection (TCMR) after treatment may not be detected with serum creatinine monitoring and is associated with donor-specific antibodies and chronic rejection. We evaluate the utility of follow-up biopsies (FUB) to identify and characterize rates of persistent TCMR after treatment in pediatric kidney transplant patients. METHODS: Patients from two pediatric transplant centers performing standard of care FUB at 1.5-2 months after treatment for TCMR were included. FUB were evaluated for extent of rejection resolution (complete vs. incomplete) and grade. Clinical data at time of FUB and later were reported, where available. RESULTS: Fifty-eight patients underwent FUB, at mean of 1.7 months (SD 0.7) post-index biopsy. Rejection grade on index biopsy was Banff borderline (≥i1t1 and

Solitary Fibrous Tumor of Breast and Axilla: Clinicopathological Profile of Five Tumors With Comparison of Risk Stratification Models.

Introduction: Solitary fibrous tumor (SFT) is a fibroblastic tumor with malignant potential that is underpinned by a recurrent inv12(q13q13)-derived NAB2::STAT6 fusion. Breast and axilla are uncommon locations for this entity. Methods: Records of two academic institutions were electronically searched for breast and axillary SFTs. Clinical and pathologic data were reviewed. Literature review for breast or axillary SFTs was performed. Present study and previously reported tumors were stratified using five SFT risk models: original and modified Demicco metastatic risk, Salas local recurrence risk, Salas metastatic risk, and Thompson local recurrence risk. Results: Five patients with breast or axillary SFT were identified. Median age was 49 years, and median follow-up (available for four patients) was 82 months. Three patients showed no evidence of disease, and one developed recurrence. Literature review identified 58 patients with breast or axillary SFT. Median age was 54 years, and median follow-up (available for 35 patients) was 24 months. Thirty-one patients showed no evidence of disease, three developed recurrence, and one developed metastasis. Original and modified Demicco models and Thompson model showed the highest sensitivity; original and modified Demicco models and Salas metastatic risk model demonstrated the highest specificity. Kaplan-Meier models were used to assess recurrence-free probability (RFP). Original and modified Demicco models predicted RFP when stratified by "low risk" and "moderate/intermediate and high risk" tumor, though sample size was small. Conclusions: While many SFTs of breast and axilla remain indolent, a subset may develop recurrence and rarely metastasize. The modified Demicco risk model demonstrated optimal performance characteristics.

ERBB2 Amplification and HER2 Expression in Salivary Duct Carcinoma: Evaluation of Scoring Guidelines and Potential for Expanded Anti-HER2 Therapy.

Salivary duct carcinoma (SDC) is aggressive with limited therapeutic options. A subset of SDC display human epidermal growth factor receptor 2 (HER2) protein overexpression by immunohistochemistry, and some show ERBB2 gene amplification. Guidelines for HER2 scoring are not firmly established. Recent advances in breast carcinoma have established a role for anti-HER2 therapies in lesions with low HER2 expression lacking ERBB2 amplification. Delineating HER2 staining patterns in SDC is critical for evaluating anti-HER2 treatments. In total, 53 cases of SDC resected at our institution between 2004 and 2020 were identified. Androgen receptor (AR) and HER2 immunohistochemistry and ERBB2 fluorescence in situ hybridization were performed in all cases. AR expression was scored for percentage positive cells and categorized as positive (>10% of cells), low positive (1%-10%), or negative (<1%). HER2 staining levels and patterns were recorded, scored using 2018 ASCO/CAP guidelines, and categorized into HER2-positive (3+ or 2+ with ERBB2 amplification), HER2-low (1+ or 2+ without ERBB2 amplification), HER2-very low (faint staining in <10% of cells), or HER2-absent types. Clinical parameters and vital status were recorded. Median age was 70 years, with a male predominance. ERBB2-amplified tumors (11/53; 20.8%) presented at lower pT stages (pTis/pT1/pT2; P = .005, Fisher exact test) and more frequently had perineural invasion (P = .007, Fisher exact test) compared with ERBB2 nonamplified tumors; no other pathologic features differed significantly by gene amplification status. In addition, 2+ HER2 staining by 2018 ASCO/CAP criteria was most common (26/53; 49%); only 4 cases (8%) were HER2-absent status; 3+ HER2 staining was found in 9 tumors, and all were ERBB2 amplified. Six patients with HER2-expressing tumors received trastuzumab therapy, including 2 with ERBB2-amplified tumors. Overall survival and recurrence-free survival did not differ significantly based on ERBB2 status. This work suggests that 2018 ASCO/CAP guidelines for HER2 evaluation in breast carcinoma could be applied to SDC. Our findings also show broad overexpression of HER2 in SDC raising the possibility that more patients may benefit from anti-HER2-directed therapies.

Low-grade adenosquamous carcinoma of the breast: a clinical, morphological and immunohistochemical analysis of 25 patients.

AIMS: Due to its rarity and non-specific clinical and pathological features, low-grade adenosquamous carcinoma (LGASC) of the breast continues to pose diagnostic challenges. Unlike other triple-negative breast carcinomas, LGASC tends to have an indolent clinical behaviour. It is essential to recognise this lesion for accurate diagnosis and appropriate management. METHODS AND RESULTS: Twenty-five cases of LGASC were identified in our archives and collaborating institutes. Cases of LGASC with dominant coexisting other type carcinomas were excluded. We studied the clinical presentation, morphological features, patterns of the commonly used immunohistochemical stains and follow-up. In our cohort, LGASC was commonly located at the outer aspect of the breast and associated with intraductal papilloma. The morphology of LGASC is characterised by infiltrating small glands and nests with variable squamous differentiation. We also found cuffing desmoplastic (fibrolamellar) stromal change in 75% of patients and peripheral lymphocytic aggregates in 87.5% of patients. P63 and smooth muscle myosin (SMM) were the most common myoepithelial markers used to assist in diagnosis. P63 often stained peripheral tumour cells surrounding invasive glands (circumferential staining in 80% of the cases), mimicking myoepithelial cells. It also stained the small nests with squamous differentiation. However, SMM was negative in 63% of the cases. The vast majority of our cases were triple-negative; only a few had focal and weak expressions of ER and PR. One patient who did not have excision developed lymph node metastasis. Most patients underwent excision or mastectomy with negative margins as surgical treatment; there were no recurrences or metastases in these patients with clinical follow-ups up to 108 months. CONCLUSIONS: LGASC has some unique, although not entirely specific, morphological features and immunohistochemical staining patterns. Fibrolamellar stromal change, peripheral lymphocytic aggregates and variable staining of p63 and SMM are valuable features to facilitate the diagnosis.

[Translated article] Implementation of a rapid recovery protocol in total knee arthroplasty. A randomised controlled trial.

BACKGROUND: Rapid recovery (RP) in total knee arthroplasty may increase the functionality while reducing costs. The aim of this study is to prove the benefits of a rapid recovery programme compared to our classic protocol. PATIENTS AND METHODS: We performed a RCT (NCT03823573) in patients undergoing otal knee arthroplasty. Intervention group (RP protocol) received local infiltration of levo-bupivacaine in the periarticular tissue and supervized ambulation 4-6h after surgery. Control (C) group received a femoral nerve block with levo-bupivacaine, while a drain was used. Ambulation after its removal. All the patients completed an Oxford Knee Score prior to surgery and 6 months after discharge. An ecodoppler to assess the presence of deep vein thrombosis was made 1 month after discharge. Minimum follow-up was of 6 months. RESULTS: A total of 175 patients were included in the trial (92 patients in the control group, 83 patients in the RP group). There were no differences in sex, age, implanted prosthesis, haemoglobin drop, need for transfusion, range of motion on discharge (C: 82.6°, RP: 85°) and at the end of the follow-up (C: 105.1, RP: 106.6), Oxford knee score improvement (C: 17.5 points; RP: 19.3 points), patient satisfaction or re-admissions at the emergency department (C: 7.6%; RP: 10.8%). Significancy was found on time of ischaemia (C: 81.29min; RP: 85.35min; p=.03), need for morphine shots (C: 19.7%; RP: 38.6%; p=.007), hospital stay (C: 3.84 days; RP: 2.54 days, p<.0001) and time until ambulation (C: 2.46 days; RP: 0.23 days; p<.0001). CONCLUSION: Rapid recovery protocols can reduce hospital stay without increasing complications or need for re-admission.

Spatial interplay of lymphocytes and fibroblasts in estrogen receptor-positive HER2-negative breast cancer.

In estrogen-receptor-positive, HER2-negative (ER+HER2-) breast cancer, higher levels of tumor infiltrating lymphocytes (TILs) are often associated with a poor prognosis and this phenomenon is still poorly understood. Fibroblasts represent one of the most frequent cells in breast cancer and harbor immunomodulatory capabilities. Here, we evaluate the molecular and clinical impact of the spatial patterns of TILs and fibroblast in ER+HER2- breast cancer. We used a deep neural network to locate and identify tumor, TILs, and fibroblasts on hematoxylin and eosin-stained slides from 179 ER+HER2- breast tumors (ICGC cohort) together with a new density estimation analysis to measure the spatial patterns. We clustered tumors based on their spatial patterns and gene set enrichment analysis was performed to study their molecular characteristics. We independently assessed the spatial patterns in a second cohort of ER+HER2- breast cancer (N = 630, METABRIC) and studied their prognostic value. The spatial integration of fibroblasts, TILs, and tumor cells leads to a new reproducible spatial classification of ER+HER2- breast cancer and is linked to inflammation, fibroblast meddling, or immunosuppression. ER+HER2- patients with high TIL did not have a significant improved overall survival (HR = 0.76, P = 0.212), except when they had received chemotherapy (HR = 0.447). A poorer survival was observed for patients with high fibroblasts that did not show a high level of TILs (HR = 1.661, P = 0.0303). Especially spatial mixing of fibroblasts and TILs was associated with a good prognosis (HR = 0.464, P = 0.013). Our findings demonstrate a reproducible pipeline for the spatial profiling of TILs and fibroblasts in ER+HER2- breast cancer and suggest that this spatial interplay holds a decisive role in their cancer-immune interactions.

Quality Issues in Diagnostic Immunohistochemistry in Breast Pathology.

Immunohistochemistry techniques have been incorporated into surgical pathology for nearly a half-century and have since become intimately intertwined with its practice. In the realm of breast pathology, immunohistochemistry serves several purposes, including providing crucial prognostic and predictive data. Among its other applications, assessment of stromal invasion and establishment of mammary origin are crucial from a diagnostic standpoint. In these regards, sole reliance on immunohistochemistry may lead to misdiagnosis. In this review, we highlight pitfalls of immunohistochemistry commonly encountered in the practice of breast pathology and emphasize the importance of careful histopathological evaluation.

Clinical and Pathologic Features Associated With Invasive Breast Carcinoma With 2018 American Society of Clinical Oncology/College of American Pathologists In Situ Hybridization Group 2 Results (Human Epidermal Growth Factor Receptor 2 [HER2]/Chromosome 17 Centromere [CEP17] Ratio ≥2.0 and Average HER2 Copy Number <4.0).

CONTEXT.­: The American Society of Clinical Oncology/College of American Pathologists updated the human epidermal growth factor receptor 2 (HER2) breast carcinoma testing guideline in 2018 to address issues from uncommon HER2 fluorescence in situ hybridization (FISH) results. Based on the 2013 American Society of Clinical Oncology/College of American Pathologists guideline, cases wherein the HER2/chromosome 17 centromere (CEP17) ratio of 2.0 or more with an average HER2 copy number of less than 4.0 were considered in situ hybridization (ISH) positive. Under the 2018 guideline, such cases are classified as ISH Group 2 and are no longer considered eligible for anti-HER2 therapy when the corresponding HER2 immunohistochemistry result is 0, 1+, or 2+. OBJECTIVE.­: To assess the clinical, pathologic, and treatment aspects of patients with ISH Group 2 results. DESIGN.­: We retrospectively reviewed HER2 FISH results at our center between January 2012 and December 2014 and identified and characterized cases with ISH Group 2 results. RESULTS.­: Thirty-nine cases with ISH Group 2 results from 39 patients were reviewed. Twenty of 39 (51%) patients received anti-HER2 therapy. Patients treated with HER2-targeted therapy were less likely to have hormone receptor-positive tumors, compared with patients without anti-HER2 treatment, though not significantly (P = .30). The only significant difference between the 2 patient groups was receipt of cytotoxic chemotherapy treatment (P < .001). Overall, clinical outcome was similar between the 2 groups (P > .99). CONCLUSIONS.­: This retrospective study with median follow-up of at least 6 years shows patients with ISH Group 2 tumors had similar clinical outcomes, irrespective of HER2-targeted therapy. Further analysis in the prospective setting would provide valuable data that would potentially inform clinical decision making.

Risk of malignancy associated with diagnostic categories of the proposed World Health Organization International System for Reporting Pancreaticobiliary Cytopathology.

BACKGROUND: The World Health Organization (WHO) has proposed an updated international classification system for reporting pancreaticobiliary cytology. Substantial changes to the prior Papanicolaou Society of Cytopathology (PSC) system have been recommended. Chiefly, the "neoplastic: benign" and "neoplastic: other" categories have been replaced by 2 new categories-"pancreatic neoplasia-low-grade" (PaN-Low) and "pancreatic neoplasia-high-grade" (PaN-High)-stratifying neoplastic mucinous cysts by cytological atypia. Low-grade malignancies are placed in the "malignant" category and benign serous cystadenoma in the "benign/negative" category. Risk of malignancy (ROM) associated with the diagnostic categories of the WHO system has yet to be defined. METHODS: All patients who underwent endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for a pancreatic lesion at a single institution from January 2016 to December 2016, prospectively classified using the PSC system, were reclassified using the WHO system. Absolute ROM was determined by histologic outcome and/or clinical follow-up of at least 6 months. RESULTS: A total of 334 EUS-FNA samples from 322 patients were reviewed and reclassified. Absolute ROM for the WHO system was 7.7% for "insufficient/inadequate/nondiagnostic" category, 1.0% for "benign/negative for malignancy," 28.0% for "atypical," 4.8% for "PaN-Low," 60.0% for "PaN-High," 100% for "suspicious for malignancy," and 100% for "malignant;" the absolute ROM for the same cohort using the PSC system was 7.7% for "nondiagnostic" category, 1.0% for "negative (for malignancy)," 28.0% for "atypical," 0.0% for "neoplastic: benign," 30.3% for "neoplastic: other," 100% for "suspicious (for malignancy)," and 100% for "positive or malignant." CONCLUSIONS: The WHO international system achieves improved stratification by associated ROM compared to the PSC system.

Papillary Breast Tumors: Continuing Controversies and Commentary on WHO's 2019 Criteria and Classification.

The category of papillary breast tumors includes a limited number of entities. Nonetheless, this relatively uncommon group of tumors seems to instigate a disproportionate degree of diagnostic disquiet. As a group, papillary breast tumors suffer from a relatively high rate of discordant interpretation. The latter is due to the inherent complexity of the lesions compounded by conflicting criteria as well as simmering controversies. For instance, "encapsulated" papillary carcinoma remains contentious with regards to whether these are noninvasive or not, and the assessment of the extent of the invasive versus noninvasive components in many solid papillary carcinomas can be problematic. The latest classification system of breast tumors enunciated by the World Health Organization (WHO), that is, Breast Tumors, which appeared in 2019, mainly sought to incorporate advances in basic and clinical sciences into diagnostic criteria for the entire spectrum of breast neoplasms-including papillary ones. The latter category of tumors is discussed at some length in Breast Tumors; however, it still appears to suffer from some lack of clarity in its subclassification. It is our intent in this communication to provide an overview of the controversies around papillary breast tumors, and offer comments on its coverage in Breast Tumors-so that any tangible or perceived ambiguities therein could be addressed in its next edition.

Implementation of a rapid recovery protocol in total knee arthroplasty. A randomized controlled trial. / Implantación de un protocolo de recuperación precoz en artroplastia total de rodilla. Ensayo clínico aleatorizado.

BACKGROUND: Rapid recovery (RP) in total knee arthroplasty may increase the functionality while reducing costs. The aim of this study is to prove the benefits of a rapid recovery program compared to our classic protocol. PATIENTS AND METHODS: We performed a RCT (NCT03823573) in patients undergoing otal knee arthroplasty. Intervention group (RP protocol) received local infiltration of levo-bupivacaine in the periarticular tissue and supervized ambulation 4-6h after surgery. Control (C) group received a femoral nerve block with levo-bupivacaine, while a drain was used. Ambulation after its removal. All the patients completed an Oxford Knee Score prior to surgery and 6 months after discharge. An ecodoppler to assess the presence of deep vein thrombosis was made one month after discharge. Minimum follow-up was of 6 months. RESULTS: A total of 175 patients were included in the trial (92 patients in the control group, 83 patients in the RP group). There were no differences in sex, age, implanted prosthesis, hemoglobin drop, need for transfusion, range of motion on discharge (C: 82.6°, RP: 85°) and at the end of the follow-up (C: 105.1, RP: 106.6), Oxford Knee Score improvement (C: 17.5 points; RP: 19.3 points), patient satisfaction or re-admissions at the emergency department (C: 7.6%; RP: 10.8%). Significancy was found on time of ischemia (C: 81.29min; RP: 85.35min; P=0.03), need for morphine shots (C: 19.7%; RP: 38.6%; P=0.007), hospital stay (C: 3.84 days; RP: 2.54 days, P<0.0001) and time until ambulation (C: 2.46 days; RP: 0.23 days; P<0.0001). CONCLUSION: Rapid recovery protocols can reduce hospital stay without increasing complications or need for re-admission.

Exploring the implications of the first COVID-19 lockdown on patients with melanoma: a national survey.

The impact of the COVID-19 pandemic upon care of malignant melanoma (MM) remains as yet poorly understood. We undertook a UK-wide national survey, in conjunction with a patient support group (Melanoma UK), to explore patient perceptions of the impact of the pandemic upon treatment and outpatient care of their MM. Our findings suggest that following the onset of COVID-19, a significant minority of treatments and appointments have been delayed, there has been a shift from face-to-face to virtual outpatient consultations and there may be a rise in psychological comorbidities in patients with MM. We would urge clinicians to consider mental health interventions as part of a holistic care package.

Economizing strabismus surgery: Using half the double-armed suture for horizontal muscles.

In a developing country like India, both availability and affordability of medical care are obstacles, leading to delay in seeking timely treatment. To reduce the cost incurred to the patients for strabismus surgery, we used half of a 6-0 polyglactin suture for performing common muscle weakening and strengthening procedures: a fixed and hang back recessions with plication and resection. We cut the 45-cm-long double-armed 6-0 polyglactin sutures in two halves, and with a modified approach, used one-half in each of two patients planned for monocular two horizontal muscles surgeries: fixed recession-plication and hang back recession-resection. By devising an intuitive manner of threading a single armed 22.5 cm suture we successfully carried out horizontal extraocular muscle surgeries on each of two patients of exotropia. We believe in the long run, this will reduce the cost to individual patients and sponsoring groups, and suggest that strabismus surgeons consider adopting this option.

p16 positive oropharyngeal small cell cancer: A case report.

Extra-pulmonary small cell carcinomas (EPSCC) are rare malignancies. Like small cell lung cancer (SCLC), they are aggressive malignancies with dismal prognosis. We here report a case of a middle-aged man who presented with odynophagia and cervical lymphadenopathy. Diagnostic workup confirmed the diagnosis of locally-advanced p16-positive oropharyngeal cancer (OPC) with a surprising histology of small cell cancer, suggesting a human papilloma virus (HPV)-related oropharyngeal cancer with small cell differentiation. HPV oropharynx infection is a well-known risk factor for squamous cell carcinoma of the oropharynx, but it is unknown if it may increase the risk of other OPC histology.

Interobserver Variation of PD-L1 SP142 Immunohistochemistry Interpretation in Breast Carcinoma: A Study of 79 Cases Using Whole Slide Imaging.

CONTEXT.­: The Ventana programmed death ligand-1 (PD-L1) SP142 immunohistochemical assay (IHC) is approved by the US Food and Drug Administration as the companion diagnostic assay to identify patients with locally advanced or metastatic triple-negative breast cancer for immunotherapy with atezolizumab, a monoclonal antibody targeting PD-L1. OBJECTIVE.­: To determine interobserver variability in PD-L1 SP142 IHC interpretation in invasive breast carcinoma. DESIGN.­: The pathology database was interrogated for all patients diagnosed with primary invasive, locally recurrent, or metastatic breast carcinoma on which PD-L1 SP142 IHC was performed from November 2018 to June 2019 at our institution. A subset of cases was selected using a computerized random-number generator. PD-L1 IHC was evaluated in stromal tumor-infiltrating immune cells using the IMpassion130 trial criteria, with positive cases defined as immunoreactivity in immune cells in 1% or more of the tumor area. IHC was interpreted on whole slide images by staff pathologists with breast pathology expertise. Interobserver variability was calculated using unweighted κ. RESULTS.­: A total of 79 cases were assessed by 8 pathologists. Interobserver agreement was substantial (κ = 0.727). There was complete agreement among all 8 pathologists in 62% (49 of 79) of cases, 7 pathologists or more in 84% (66 of 79) of cases, and 6 pathologists or more in 92% (73 of 79) of cases. In 4% (3 of 79) of cases, all of which were small biopsies, pathologists' interpretations were evenly split between scores of positive and negative. CONCLUSIONS.­: The findings show substantial agreement in PD-L1 SP142 IHC assessment of breast carcinoma cases among 8 pathologists at a single institution. Further study is warranted to define the basis for discrepant results.