A balance focused biometric does not predict rehabilitation needs and outcomes following total knee arthroplasty.

BACKGROUND: Both length of hospital stay and discharge to a skilled nursing facility are key drivers of total knee arthroplasty (TKA)-associated spending. Identifying patients who require increased postoperative care may improve expectation setting, discharge planning, and cost reduction. Balance deficits affect patients undergoing TKA and are critical to recovery. We aimed to assess whether a device that measures preoperative balance predicts patients' rehabilitation needs and outcomes after TKA. METHODS: 40 patients indicated for primary TKA were prospectively enrolled and followed for 12 months. Demographics, KOOS-JR, and PROMIS data were collected at baseline, 3-months, and 12-months. Single-leg balance and sway velocity were assessed preoperatively with a force plate (Sparta Science, Menlo Park, CA). The primary outcome was patients' discharge facility (home versus skilled nursing facility). Secondary outcomes included length of hospital stay, KOOS-JR scores, and PROMIS scores. RESULTS: The mean preoperative sway velocity for the operative leg was 5.7 ± 2.7 cm/s, which did not differ from that of the non-operative leg (5.7 ± 2.6 cm/s, p = 1.00). Five patients (13%) were discharged to a skilled nursing facility and the mean length of hospital stay was 2.8 ± 1.5 days. Sway velocity was not associated with discharge to a skilled nursing facility (odds ratio, OR = 0.82, 95% CI = 0.27-2.11, p = 0.690) or longer length of hospital stay (b = -0.03, SE = 0.10, p = 0.738). An increased sway velocity was associated with change in PROMIS items from baseline to 3 months for global07 ("How would you rate your pain on average?" b = 1.17, SE = 0.46, p = 0.015) and pain21 ("What is your level of pain right now?" b = 0.39, SE = 0.17, p = 0.025) at 3-months. CONCLUSION: Preoperative balance deficits were associated with postoperative improvements in pain and function after TKA, but a balance focused biometric that measured single-leg sway preoperatively did not predict discharge to a skilled nursing facility or length of hospital stay after TKA making their routine measurement cost-ineffective.

Primary Total Hip Arthroplasty in Juvenile Idiopathic Arthritis: Survivorship After a Median Follow-Up of 12 Years.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory condition of childhood that frequently affects the hip. Total hip arthroplasty (THA) in JIA can be challenging due to the patient's young age, small proportion, complex anatomy, and bone loss. Outcome data are limited. METHODS: We reviewed prospectively collected data in 57 JIA patients (83 hips) who underwent THA between 1986 and 2020 by a single surgeon. The median patient age at surgery was 26 years (range, 14 to 62). Reoperation-free survival was assessed via the cumulative incidence function, accounting for the competing risk of death. Relationships between patient and implant factors and survivorship were evaluated by stratification of the cumulative incidence function and Gray's tests. Wilcoxon signed rank tests were used to assess the preoperative to latest postoperative change in patient-reported outcome measures. RESULTS: At a median (interquartile range) of 12 (4, 20) years of follow-up, 13 (16%) patients underwent reoperation, most commonly for polyethylene wear and osteolysis (7 hips). The estimated incidence of 10-year, 20-year, and 30-year revision (95% confidence interval) were 11.3% (4.5, 21.6%), 18.5% (8.9, 30.9%), and 40.6% (19.4, 60.9%), respectively. There were no differences in survival based on patient age, sex, implant fixation method, polyethylene type, or thickness. All patient-reported outcome measures improved from preoperative to latest follow-up. CONCLUSIONS: Primary THA is a durable and effective treatment for JIA patients with severe hip involvement and results in major improvements in pain and function. We did not identify any factors predictive of failure.

Why the Treatment Sequence Matters: Interplay Between Chemotherapy Cycles Received, Cumulative Dose Intensity, and Survival in Resected Early-stage Pancreas Cancer.

OBJECTIVE: To define the optimal threshold of perioperative chemotherapy completion and relative dose intensity (RDI) for patients with resected pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Many patients who undergo pancreatectomy for PDAC fail to initiate or complete recommended perioperative chemotherapy. The association between the amount of perioperative chemotherapy received and overall survival (OS) is not well-defined. METHODS: Single-institution analysis of 225 patients who underwent pancreatectomy for stage I/II PDAC (2010-2021). Associations between OS, chemotherapy cycles completed, and RDI were analyzed. RESULTS: Regardless of treatment sequence, completion of ≥67% of recommended cycles was associated with improved OS compared with no chemotherapy [median OS: 34.5 vs 18.1 months; hazard ratio (HR): 0.43; 95% CI: 0.25-0.74] and <67% of cycles (median OS: 17.9 months; HR: 0.39; 95% CI: 0.24-0.64). A near-linear relationship existed between cycles completed and the RDI received (ß = 0.82). A median RDI of 56% corresponded to the completion of 67% of cycles. Receipt of ≥56% RDI was associated with improved OS compared with no chemotherapy (median OS: 35.5 vs 18.1 months; HR: 0.44; 95% CI: 0.23-0.84) and <56% RDI (median OS: 27.2 months; HR: 0.44; 95% CI: 0.20-0.96). Neoadjuvant chemotherapy is associated with increased odds of receiving ≥67% of recommended cycles (odds ratio: 2.94; 95% CI: 1.45-6.26) and ≥56% RDI (odds ratio: 4.47; 95% CI: 1.72-12.50). CONCLUSIONS: Patients with PDAC who received ≥67% of recommended chemotherapy cycles or ≥56% cumulative RDI had improved OS. Neoadjuvant therapy was associated with increased odds of receiving ≥67% of cycles and ≥56% cumulative RDI and should be considered in all patients with resectable PDAC.

BioID reveals an ATG9A interaction with ATG13-ATG101 in the degradation of p62/SQSTM1-ubiquitin clusters.

ATG9A, the only multi-pass transmembrane protein among core ATG proteins, is an essential regulator of autophagy, yet its regulatory mechanisms and network of interactions are poorly understood. Through quantitative BioID proteomics, we identify a network of ATG9A interactions that includes members of the ULK1 complex and regulators of membrane fusion and vesicle trafficking, including the TRAPP, EARP, GARP, exocyst, AP-1, and AP-4 complexes. These interactions mark pathways of ATG9A trafficking through ER, Golgi, and endosomal systems. In exploring these data, we find that ATG9A interacts with components of the ULK1 complex, particularly ATG13 and ATG101. Using knockout/reconstitution and split-mVenus approaches to capture the ATG13-ATG101 dimer, we find that ATG9A interacts with ATG13-ATG101 independently of ULK1. Deletion of ATG13 or ATG101 causes a shift in ATG9A distribution, resulting in an aberrant accumulation of ATG9A at stalled clusters of p62/SQSTM1 and ubiquitin, which can be rescued by an ULK1 binding-deficient mutant of ATG13. Together, these data reveal ATG9A interactions in vesicle-trafficking and autophagy pathways, including a role for an ULK1-independent ATG13 complex in regulating ATG9A.

Single, Recurrent, Synchronous, and Metachronous Periprosthetic Joint Infections in Patients With Multiple Hip and Knee Arthroplasties.

BACKGROUND: The rate for periprosthetic joint infection (PJI) exceeds 1% for primary arthroplasties. Over 30% of patients who have a primary arthroplasty require an additional arthroplasty, and the impact of PJI on this population is understudied. Our objective was to assess the prevalence of recurrent, synchronous, and metachronous PJI in patients who had multiple arthroplasties and to identify risk factors for a subsequent PJI. METHODS: We identified 337 patients who had multiple arthroplasties and at least 1 PJI that presented between 2003 and 2021. The mean follow-up after revision arthroplasty was 3 years (range, 0 to 17.2). Patients who had multiple infected prostheses were categorized as synchronous (ie, presenting at the same time as the initial infection) or metachronous (ie, presenting at a different time as the initial infection). The PJI diagnosis was made using the MusculoSkeletal Infection Society (MSIS) criteria. RESULTS: There were 39 (12%) patients who experienced recurrent PJI in the same joint, while 31 (9%) patients developed PJI in another joint. Positive blood cultures were more likely in the second joint PJI (48%) compared to recurrent PJI (23%) or a single PJI (15%, P < .001). Synchronous PJI represented 42% of the second joint PJI cases (n = 13), while metachronous PJI represented 58% (n = 18). Tobacco users had 75% higher odds of metachronous PJI (odds ratio 1.75, 95% confidence interval: 1.1-2.9, P = .041). CONCLUSION: Over 20% of the patients with multiple arthroplasties and a single PJI will develop a subsequent PJI in another arthroplasty with 12% recurring in the initial arthroplasty and nearly 10% ocurring in another arthroplasty. Particular caution should be taken in patients who use tobacco, have bacteremia, or have Staphylococcus aureus isolation at time of their initial PJI. Optimizing the management of this high-risk patient population is necessary to reduce the additional burden of subsequent PJI. LEVEL OF EVIDENCE: Prognostic Level IV.

Digital dermatopathology: The time is now.

To continue to provide expert specialized care during the COVID-19 pandemic, our dermatopathology service transitioned to a secure virtual microscopy platform. In our experience, this digitally-enabled dermatopathology practice revealed myriad benefits, including an improved diagnostic workflow and increased access to teaching. Whole slide imaging (WSI) is a related system that digitizes glass slides with high resolution and has been clinically validated for primary diagnosis. While WSI requires an initial institutional investment, its benefits include expanded access to subspecialized expertise and collaborations, digital histopathologic data generation for research, unification of patient clinical and pathologic information, and archiving of educational resources. The switch to digitally-enabled remote dermatopathology at our institution and across the United States presents a rare opportunity to critically examine newly implemented systems and to develop permanent digital solutions, thereby taking a leap forward for the benefit of patient care, research, and medical education.

Riga-Fede Disease: A Case of Sublingual Trauma Not Associated With Abuse.

OBJECTIVES: The following case presents a pediatric patient with Riga-Fede disease (RFD), a rare disorder in children under 2 years of age characterized by sublingual ulceration of the tongue due to trauma from repeated rubbing against the primary teeth. Riga-Fede disease is well reported in dental literature but is relatively unknown to the general pediatric community. It can be confused with nonaccidental trauma (NAT) from forced feeding or other abusive trauma because it presents with injury of oral structures including the sublingual frenulum and often results in problems with growth. This case highlights the importance for physicians to recognize RFD as a source of isolated oral injury that is distinct from NAT. Although approximately 35 cases of RFD have been reported in the literature, this is the first case to describe the process of distinguishing this disease from child abuse. METHODS: We present a case of an 8-month-old female infant who presented with extensive injury of her ventral tongue from RFD who underwent a full workup for NAT. We review the literature for guidance on diagnosing RFD and discuss how to distinguish it from abuse. RESULTS: Infants with characteristic ulceration of the ventral tongue opposing new teeth and with no other medical, social, or developmental concerns do not need to undergo further workup. Clinical examination and thorough history are sufficient to make the diagnosis. CONCLUSIONS: Traumatic intraoral injury in nonmobile children is highly concerning for child abuse. However, RFD is a well described cause of sublingual ulceration in infants that is not associated with abuse.

Linear IgA Bullous Dermatosis Preceding the Diagnosis of Primary Sclerosing Cholangitis and Ulcerative Colitis: A Case Report.

Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering disorder seen in the pediatric and adult populations that is often linked to a medication, infection, or underlying gastrointestinal, hepatobiliary, or autoimmune disease. In this study, we describe the case of a 23-year-old white man whose presentation and diagnosis of LABD ultimately led to the discovery of underlying primary sclerosing cholangitis (PSC) and ulcerative colitis (UC). His dermatitis resolved with topical steroids and dapsone, and he is undergoing systemic treatment for his UC and PSC. This exceptional case further validates the association between LABD with UC, strengthens that with PSC, and underscores the importance of alerting clinicians to consider conducting a systemic workup in addition to thorough medication history on making the diagnosis of LABD.

Immediate Abdominal Pain after Placement of Thoracic Paddle Leads for Spinal Cord Stimulation: A Case Series.

BACKGROUND: Spinal cord stimulation (SCS) is a well-established treatment modality for chronic pain. Thoracic radiculopathy has been reported as a complication of SCS paddle lead implantation by several authors and commonly presents as abdominal pain. METHODS: We performed a search of all patients who underwent either placement of a new epidural paddle lead electrode or revision of an epidural paddle lead electrode for SCS in the thoracic region from January 2017 to January 2018. We then investigated all cases of immediate postoperative abdominal pain. RESULTS: We identified 7 patients who had immediate postoperative abdominal pain among 86 cases of epidural SCS procedures. Most patients were discharged on postoperative days 1-3. No patients required revisions or removals of their SCS for any reason. CONCLUSIONS: We conclude that the etiology of immediate postoperative abdominal pain after thoracic paddle lead implantation for SCS is most likely thoracic radiculopathy. We hypothesize that small, transient epidural hematomas could be the cause of this thoracic radiculopathy. We argue that all patients with immediate postoperative abdominal pain and no other neurologic deficits after thoracic paddle lead implantation for SCS should first be treated conservatively with observation and pain management.

Validation of Digital Pathology for Primary Histopathological Diagnosis of Routine, Inflammatory Dermatopathology Cases.

BACKGROUND: Digital pathology (DP) systems have been validated for routine, histopathological diagnosis by several investigators. The diagnostic matter in previous studies is composed mostly of neoplasms. However, in dermatopathology, inflammatory diseases constitute a greater proportion of cases and have been under-represented in this literature. Herein, we report the results of a prospective, DP side-by-side validation study comparing the histologic assessment of routine, clinical inflammatory dermatopathology cases by whole slide imaging (WSI) and traditional light microscopy (LM). METHODS: Glass slides were digitized at ×40 magnification. Two dermatopathologists rendered diagnoses digitally and immediately thereafter by light microscopy. Additional recuts, special, and immunohistochemical stains obtained during workup were scanned and evaluated similarly. Morphological features used to make diagnoses and appreciable differences in histology were recorded. RESULTS: A total of 332 slides representing 93 cases were examined, including 157 hematoxylin & eosin sections, 132 special stains, and 43 immunohistochemical slides. In total, 333 microscopic features important for rendering inflammatory diagnoses were identified. Two discrepant instances were noted wherein Gram-positive cocci were identified using traditional microscopy but not by DP (×40 scan). Eosinophils, melanin granules, and mucin were identified on both modalities but were noted to have different appearances. CONCLUSIONS: Our findings indicate that DP is sufficient for primary diagnosis in inflammatory dermatopathology. Higher magnification scanning may be required to identify submicron features, such as microorganisms. Subtle differences in image quality between these 2 modalities may contribute to varied histologic interpretations of which pathologists should be aware when validating clinical DP systems.

5-Hydroxymethylcytosine is a nuclear biomarker to assess biological potential in histologically ambiguous heavily pigmented melanocytic neoplasms.

BACKGROUND: 5-Hydroxymethylcytosine (5-hmC) is an epigenetic marker detectable through immunohistochemistry (IHC) that has been shown to distinguish benign nevi from melanoma with high sensitivity and specificity. The purpose of the study was to explore its diagnostic utility in a subset of histologically challenging, heavily pigmented cutaneous melanocytic neoplasms. METHODS: 5-hmC IHC was performed on 54 heavily pigmented melanocytic tumors. Semi-quantitative analysis of immunoreactivity was correlated with clinical, pathologic and follow-up data. RESULTS: Benign melanocytic neoplasms (4 of 4 blue nevi with epithelioid change; 12 of 12 combined nevi; 5 of 5 deep penetrating nevi, DPN) exhibited strong 5-hmC nuclear reactivity. Eight heavily pigmented blue nevus-like melanomas and 7 of 8 pigmented epithelioid melanocytomas (PEM) showed significant 5-hmC loss. Five of 7 atypical DPN cases and 8 of 10 melanocytic tumors of uncertain malignant potential (MELTUMP) showed low to intermediate 5-hmC immunoreactivity. These differences were statistically significant (P-value <.0001). CONCLUSIONS: Loss of 5-hmC may be helpful in differentiating benign, diagnostically challenging, heavily pigmented melanocytic tumors from those with malignant potential. The intermediate to low 5-hmC immunoreactivity in atypical DPNs, PEMs and so-called MELTUMP categories further underscores the need to consider these neoplasms as having some potential for lethal biological behavior.

Cutaneous Reactions to Targeted Therapy.

Over the past decade, numerous targeted therapeutic agents have become available for clinical use in the oncologic setting with the hopes of realizing personalized cancer treatment. These agents have achieved great improvements in clinical outcomes for patients suffering from solid and hematologic malignancies. However, adverse cutaneous reactions are among the most common toxicities observed in patients undergoing treatment with a targeted agent and can alter the overall clinical management strategy. For these reasons, the practicing dermatopathologist should be mindful of the breadth and depth of adverse cutaneous reaction patterns associated with this mechanistically diverse array of targeted agents.

Quantitative Assessment of Multiorgan Sequestration of Parasites in Fatal Pediatric Cerebral Malaria.

Children in sub-Saharan Africa continue to acquire and die from cerebral malaria, despite efforts to control or eliminate the causative agent, Plasmodium falciparum. We present a quantitative histopathological assessment of the sequestration of parasitized erythrocytes in multiple organs obtained during a prospective series of 103 autopsies performed between 1996 and 2010 in Blantyre, Malawi, on pediatric patients who died from cerebral malaria and controls. After the brain, sequestration of parasites was most intense in the gastrointestinal tract, both in patients with cerebral malaria and those with parasitemia in other organs. Within cases of histologically defined cerebral malaria, which includes phenotypes termed "sequestration only" (CM1) and "sequestration with extravascular pathology" (CM2), CM1 was associated with large parasite numbers in the spleen and CM2 with intense parasite sequestration in the skin. A striking histological finding overall was the marked sequestration of parasitized erythrocytes across most organs in patients with fatal cerebral malaria, supporting the hypothesis that the disease is, in part, a result of a high level of total-body parasite sequestration.

5-Hydroxymethylcytosine expression in metastatic melanoma versus nodal nevus in sentinel lymph node biopsies.

Sentinel lymph node biopsies are conducted to stage patients with newly diagnosed melanomas that have histopathological attributes conferring defined levels of metastatic potential. Because benign nevic cells may also form 'deposits' in lymph nodes (nodal nevus), the pathological evaluation for metastatic melanoma within sentinel lymph nodes can be challenging. Twenty-eight sentinel lymph node biopsy cases containing either metastatic melanoma (N=18) or nodal nevi (N=10) were retrieved from the archives of the Brigham and Women's Hospital, Department of Pathology (2011-2014). In addition, two sentinel lymph node cases that were favored to represent metastatic disease but whose histopathological features were viewed as equivocal, with melanoma favored, were also included. Dual labeling for the melanocyte lineage marker, MART-1, and the epigenetic marker, 5-hydroxymethylcytosine, a functionally significant indicator that has been shown to distinguish benign nevi from melanoma, was performed on all cases using immunohistochemistry and/or direct immunofluorescence. All (18 of 18) metastatic melanoma cases showed complete loss of 5-hydroxymethylcytosine nuclear staining in MART-1-positive cells, and all (10 of 10) nodal nevus cases demonstrated 5-hydroxymethylcytosine nuclear staining in MART-1-positive cells. In addition, 5-hydroxymethylcytosine staining confirmed the favored diagnoses of metastatic melanoma in the two 'equivocal' cases. Thus, 5-hydroxymethylcytosine may be a useful adjunctive marker to distinguish between benign nodal nevi and metastatic melanoma during the evaluation of sentinel lymph node biopsies for metastatic melanoma.

Homozygous ALOXE3 Nonsense Variant Identified in a Patient with Non-Bullous Congenital Ichthyosiform Erythroderma Complicated by Superimposed Bullous Majocchi's Granuloma: The Consequences of Skin Barrier Dysfunction.

Non-bullous congenital ichthyosiform erythroderma (NBCIE) is a hereditary disorder of keratinization caused by pathogenic variants in genes encoding enzymes important to lipid processing and terminal keratinocyte differentiation. Impaired function of these enzymes can cause pathologic epidermal scaling, significantly reduced skin barrier function. In this study, we have performed a focused, genetic analysis of a probrand affected by NBCIE and extended this to his consanguineous parents. Targeted capture and next-generation sequencing was performed on NBCIE associated genes in the proband and his unaffected consanguineous parents. We identified a homozygous nonsense variant c.814C>T (p.Arg272*) in ALOXE3 (NM_001165960.1) in the proband and discovered that his parents are both heterozygous carriers of the variant. The clinical manifestations of the proband's skin were consistent with NBCIE, and detailed histopathological assessment revealed epidermal bulla formation and Majocchi's granuloma. Infection with Trichophyton rubrum was confirmed by culture. The patient responded to oral terbinafine antifungal treatment. Decreased skin barrier function, such as that caused by hereditary disorders of keratinization, can increase the risk of severe cutaneous fungal infections and the formation of Majocchi's granuloma and associated alopecia. Patients with NBCIE should be alerted to the possible predisposition for developing dermatophytoses and warrant close clinical follow-up.

Melanoma epigenetics: novel mechanisms, markers, and medicines.

The incidence and mortality rates of cutaneous melanoma continue to increase worldwide, despite the deployment of targeted therapies. Recently, there has been rapid growth and development in our understanding of epigenetic mechanisms and their role in cancer pathobiology. Epigenetics--defined as the processes resulting in heritable changes in gene expression beyond those caused by alterations in the DNA sequence--likely contain the information that encodes for such phenotypic variation between individuals with identical genotypes. By altering the structure of chromatin through covalent modification of DNA bases or histone proteins, or by regulating mRNA translation through non-coding RNAs, the epigenome ultimately determines which genes are expressed and which are kept silent. While our understanding of epigenetic mechanisms is growing at a rapid pace, the field of melanoma epigenomics still remains in its infancy. In this Pathology in Focus, we will briefly review the basics of epigenetics to contextualize and critically examine the existing literature using melanoma as a cancer paradigm. Our understanding of how dysregulated DNA methylation and DNA demethylation/hydroxymethylation, histone modification, and non-coding RNAs affect cancer pathogenesis and melanoma virulence, in particular, provides us with an ever-expanding repertoire of potential diagnostic biomarkers, therapeutic targets, and novel pathogenic mechanisms. The evidence reviewed herein indicates the critical role of epigenetic mechanisms in melanoma pathobiology and provides evidence for future targets in the development of next-generation biomarkers and therapeutics.