Biomechanical and Histological Study of Retrieved LARS Synthetic Ligaments.

BACKGROUND: Synthetic grafts have been used for a number of years in anterior cruciate ligament (ACL) reconstruction surgery. One of the more recent additions to the stable of synthetic ligaments is the Ligament Augmentation and Reconstruction System (LARS) ligament. PURPOSE: To analyze the biomechanics and histology of LARS grafts retrieved due to failure of the device. STUDY DESIGN: Descriptive laboratory study. METHODS: A total of 22 LARS ligament grafts that were explanted from patients were sent for analysis. Five new, unused samples of the standard LARS ACL graft were also analyzed. Biomechanical testing was performed: ultimate tensile force, force versus displacement, and stress versus strain were recorded. Histopathological examination was performed looking for degree of fibrous tissue ingrowth as well as the presence of a foreign body reaction. RESULTS: Of the 22 grafts retrieved, 14 were used for ACL grafts, 1 for a lateral collateral ligament graft, 2 for medial collateral ligament grafts, 4 for gluteal tendon augmentation, and 1 for a supraspinatus augmentation. A severe foreign body reaction was found in 86% of the grafts (18/22) and a mild foreign body reaction in the remaining 14% (4/22). Tissue ingrowth was minimal in the majority of ACL grafts; the other grafts showed moderate tissue ingrowth. Maximal tensile force was significantly higher for the new ACL grafts (mean ± SD, 1667 ± 845 N) compared with the retrieved grafts (897 ± 395 N; P < .05). CONCLUSION: This study demonstrated that the vast majority of retrieved LARS artificial ligaments had a florid foreign body reaction. There was minimal tissue ingrowth in ACL grafts and moderate ingrowth in other grafts. Retrieved grafts had a decreased ultimate tensile force, which increased their risk of rupture. CLINICAL RELEVANCE: Surgeons should be cautious in choosing to use these grafts in reconstructive surgery for patients.

Diffuse large B cell lymphoma within an anal fistula: a case report with an intriguing possible aetiology.

Described is a case of diffuse large B cell lymphoma that presented within a typical fistula tract, possibly secondary to oxidative stress within the fistula tract itself and consequent malignant change rather than a fistula as a consequence of necrosis in a lymphoma. If so it would be unique in the world literature. A 42-year-old fitness instructor presented with a typical appearing left lateral anal fistula. Biopsy of the fistulous tract revealed B cell lymphoma, graded 1E. Although chemotherapy cured the lymphoma, surgical treatment by ligation of the inter-sphincteric fistula tract was required to heal the fistula. At 3-year follow-up, there has been no recurrence of the lymphoma or the fistula. Neoplasia arising secondary to oxidative stress within an anal fistula is a well-established phenomenon. Early diagnosis of rare conditions associated with anal fistula can only be accomplished by routine biopsy of every fistula tract.

The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer.

Adipogenesis associated Mth938 domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers. We uncover that AAMDC regulates the expression of several metabolic enzymes involved in the one-carbon folate and methionine cycles, and lipid metabolism. We show that AAMDC controls PI3K-AKT-mTOR signaling, regulating the translation of ATF4 and MYC and modulating the transcriptional activity of AAMDC-dependent promoters. High AAMDC expression is associated with sensitization to dactolisib and everolimus, and these PI3K-mTOR inhibitors exhibit synergistic interactions with anti-estrogens in IntClust2 models. Ectopic AAMDC expression is sufficient to activate AKT signaling, resulting in estrogen-independent tumor growth. Thus, AAMDC-overexpressing tumors may be sensitive to PI3K-mTORC1 blockers in combination with anti-estrogens. Lastly, we provide evidence that AAMDC can interact with the RabGTPase-activating protein RabGAP1L, and that AAMDC, RabGAP1L, and Rab7a colocalize in endolysosomes. The discovery of the RabGAP1L-AAMDC assembly platform provides insights for the design of selective blockers to target malignancies having the AAMDC amplification.

Learning to detect lymphocytes in immunohistochemistry with deep learning.

The immune system is of critical importance in the development of cancer. The evasion of destruction by the immune system is one of the emerging hallmarks of cancer. We have built a dataset of 171,166 manually annotated CD3+ and CD8+ cells, which we used to train deep learning algorithms for automatic detection of lymphocytes in histopathology images to better quantify immune response. Moreover, we investigate the effectiveness of four deep learning based methods when different subcompartments of the whole-slide image are considered: normal tissue areas, areas with immune cell clusters, and areas containing artifacts. We have compared the proposed methods in breast, colon and prostate cancer tissue slides collected from nine different medical centers. Finally, we report the results of an observer study on lymphocyte quantification, which involved four pathologists from different medical centers, and compare their performance with the automatic detection. The results give insights on the applicability of the proposed methods for clinical use. U-Net obtained the highest performance with an F1-score of 0.78 and the highest agreement with manual evaluation (κ=0.72), whereas the average pathologists agreement with reference standard was κ=0.64. The test set and the automatic evaluation procedure are publicly available at lyon19.grand-challenge.org.

Foreign Body Reaction Associated With Artificial LARS Ligaments: A Retrieval Study.

BACKGROUND: Artificial ligaments have been developed and used in the treatment of ligamentous injuries since the 1970s. The early generation of artificial ligaments showed promising short-term results but resulted in high rates of rupture and inflammatory reaction in the surrounding tissues. PURPOSE: To determine whether the use of Ligament Augmentation and Reconstruction System (LARS) ligaments is associated with the development of intra-articular foreign body reaction. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: LARS ligaments were explanted from 15 patients under 6 consultant orthopaedic surgeons at 8 surgical centers. Of these, 14 explanted samples were sent for macroscopic and histological analysis, with the 1 remaining sample sent for scanning electron microscopy, to assess for inflammatory change as well as the degree of fibrous tissue ingrowth. RESULTS: We observed a foreign body reaction in 10 of 14 explanted LARS ligaments. Seven samples demonstrated fibrous tissue ingrowth, with 5 producing only focal or incomplete ingrowth. The 2 samples with extensive fibrous coverage were completely free of any foreign body reaction, while all 5 remaining samples with only focal or partial fibrous ingrowth were associated with at least some degree of harmful immune response. CONCLUSION: The LARS ligament is still associated with a clinically significant degree of foreign body reaction despite the LARS Company's efforts to reduce complications through improved design. The development and completion of fibrous tissue ingrowth may work to reduce the occurrence of a foreign body reaction.

Taper Corrosion and Adverse Local Tissue Reactions in Patients with a Modular Knee Prosthesis.

BACKGROUND: Corrosion has been documented in modular knee implants, but it has not been related to negative patient outcomes. We performed an observational retrieval investigation of 13 Stryker Triathlon TS modular knee implants, 3 of which were revised because of osteolysis and adverse local tissue reactions secondary to fretting corrosion at the modular junctions. METHODS: Modular surfaces were examined for the presence and severity of corrosion, and factors that may influence the development of corrosion were investigated. Scanning electron microscopy and energy-dispersive x-ray spectroscopy were performed to evaluate implants with severe corrosion, and tissue samples were sent for histopathological analysis. RESULTS: Mild to severe corrosion was present in association with 62% of modular tibial components and 75% of modular femoral components. Although tibial corrosion was less prevalent than femoral corrosion, it occurred earlier and with greater severity. Scanning electron microscopy and energy-dispersive x-ray spectroscopy demonstrated the appearances of fretting and corrosion of the modular junctions. Histopathological analysis of specimens from the 3 patients with adverse local tissue reactions demonstrated severe reactions to metal debris, including 1 reaction that was consistent with an aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL). CONCLUSIONS: To our knowledge, ALVAL and pseudotumors have not previously been reported secondary to corrosion of modular knee replacements. The threaded taper design and the release of cobalt-chromium ions and/or debris are implicated in the occurrence of the adverse local tissue reactions, osteolysis, and soft-tissue damage that we observed in our investigation. Clinicians should be aware of this possible complication associated with modular knee implants. CLINICAL RELEVANCE: This article should raise clinician awareness of adverse local tissue reactions secondary to corrosion, potentially resulting in earlier recognition of this complication.

Erdheim-Chester disease associated with a novel, complex BRAF p.Thr599_Val600delinsArgGlu mutation.

BRAF mutation testing to determine eligibility for treatment with vemurafenib was performed on archival skin lesions of a 54-year-old patient diagnosed with Erdheim-Chester disease (ECD) in 1999. Sanger sequencing of DNA extracted from a 2008 skin lesion identified two non-contiguous base substitutions in BRAF, which were shown by next-generation sequencing (NGS) to be located in the same allele. Due to its long-standing duration, molecular evolution of disease was possible; however, both Sanger and NGS of a 2000 skin lesion were unsuccessful due to the poor quality of DNA. Finally, droplet digital PCR using a probe specific for this novel mutation detected the complex BRAF mutation in both the 2000 and 2008 lesions, indicating this case to be ECD with a novel underlying BRAF p.Thr599_Val600delinsArgGlu mutation. Although well at present, molecular modelling of the mutant BRAF suggests suboptimal binding of vemurafenib and hence reduced therapeutic effectiveness.

A comparison of the antemortem clinical diagnosis and autopsy findings for patients who die in the emergency department.

OBJECTIVES: In spite of advances in medical technology, there remains a high discrepancy rate between the antemortem clinical diagnosis and postmortem examination diagnosis for patients who die in hospitals. The aim of this study was to compare the clinical and postmortem examination diagnoses of patients who died in the emergency department (ED) of a tertiary hospital, and to analyze any discrepancy between them. METHODS: The study was a retrospective chart review of patients who died in the ED of a tertiary referral teaching hospital and a comparison of the antemortem diagnosis with the autopsy diagnosis. Any missed diagnosis was classified, according to the Goldman criteria, into major and minor missed diagnoses. RESULTS: A total of 59 patients were eligible for inclusion in the study. There was complete agreement between the antemortem diagnosis and the autopsy result in 51% of cases. The incidence of major missed diagnoses-where if the diagnosis had been known before the patient died, treatment may have been altered or survival may have been prolonged-was 7%. CONCLUSIONS: There is a significant discrepancy rate between the antemortem diagnosis and the autopsy diagnosis. However, in this study, serious missed diagnoses in which outcome may have been significantly altered are unusual among those who die in the ED of a tertiary referral hospital.

Eosinophilic cystitis: treatment with intravesical steroids and oral antihistamines.

This is a case of eosinophilic cystitis in a 56-year-old indigenous Australian woman who presented with urosepsis on the background of a urinary tract infection unresponsive to oral antibiotics. After resolution of the urosepsis, she had persisting urinary retention and a cystoscopy/bladder biopsy suggested eosinophilic cystitis. After 1 month of intravesical hydrocortisone and oral loratadine, repeat cystoscopy showed vast improvement in the bladder lesions. This case further strengthens the use of intravesical steroids and oral antihistamines for the management of eosinophilic cystitis.