Smallpox lesion characterization in placebo-treated and tecovirimat-treated macaques using traditional and novel methods.

Smallpox was the most rampant infectious disease killer of the 20th century, yet much remains unknown about the pathogenesis of the variola virus. Using archived tissue from a study conducted at the Centers for Disease Control and Prevention we characterized pathology in 18 cynomolgus macaques intravenously infected with the Harper strain of variola virus. Six macaques were placebo-treated controls, six were tecovirimat-treated beginning at 2 days post-infection, and six were tecovirimat-treated beginning at 4 days post-infection. All macaques were treated daily until day 17. Archived tissues were interrogated using immunohistochemistry, in situ hybridization, immunofluorescence, and electron microscopy. Gross lesions in three placebo-treated animals that succumbed to infection primarily consisted of cutaneous vesicles, pustules, or crusts with lymphadenopathy. The only gross lesions noted at the conclusion of the study in the three surviving placebo-treated and the Day 4 treated animals consisted of resolving cutaneous pox lesions. No gross lesions attributable to poxviral infection were present in the Day 2 treated macaques. Histologic lesions in three placebo-treated macaques that succumbed to infection consisted of proliferative and necrotizing dermatitis with intracytoplasmic inclusion bodies and lymphoid depletion. The only notable histologic lesion in the Day 4 treated macaques was resolving dermatitis; no notable lesions were seen in the Day 2 treated macaques. Variola virus was detected in all three placebo-treated animals that succumbed to infection prior to the study's conclusion by all utilized methods (IHC, ISH, IFA, EM). None of the three placebo-treated animals that survived to the end of the study nor the animals in the two tecovirimat treatment groups showed evidence of variola virus by these methods. Our findings further characterize variola lesions in the macaque model and describe new molecular methods for variola detection.

The Lymphoma Epidemiology of Outcomes cohort study: Design, baseline characteristics, and early outcomes.

To address the current and long-term unmet health needs of the growing population of non-Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States. The median age at diagnosis was 62 years (range, 18-99). Participants came from 49 US states and included 538 Black/African-Americans (AA), 822 Hispanics (regardless of race), 3386 women, 716 age <40 years, and 1513 rural residents. At study baseline, we abstracted clinical, pathology, and treatment data; banked serum/plasma (N = 5883, 76.0%) and germline DNA (N = 5465, 70.7%); constructed tissue microarrays for four major NHL subtypes (N = 1189); and collected quality of life (N = 5281, 68.3%) and epidemiologic risk factor (N = 4489, 58.0%) data. Through August 2022, there were 1492 deaths. Compared to population-based SEER data (2015-2019), LEO participants had a similar distribution of gender, AA race, Hispanic ethnicity, and NHL subtype, while LEO was underrepresented for patients who were Asian and aged 80 years and above. Observed overall survival rates for LEO at 1 and 2 years were similar to population-based SEER rates for indolent B-cell (follicular and marginal zone) and T-cell lymphomas, but were 10%-15% higher than SEER rates for aggressive B-cell subtypes (diffuse large B-cell and mantle cell). The LEO cohort is a robust and comprehensive national resource to address the role of clinical, tumor, host genetic, epidemiologic, and other biologic factors in NHL prognosis and survivorship.

Myeloid Proliferations Associated with Down Syndrome: Clinicopathologic Characteristics of Forty Cases from Five Large Academic Institutions.

INTRODUCTION: The incidence of myelodysplastic syndrome and acute myeloid leukemia is significantly increased in children with Down syndrome (DS). Within the revised 2016 WHO edition, these entities are jointly classified as myeloid leukemia associated with DS (ML-DS). Additionally, infants with DS may develop transient abnormal myelopoiesis (TAM) which is histomorphologically similar to ML-DS. While TAM is self-limiting, it is associated with an increased risk of subsequently developing ML-DS. Differentiating TAM and ML-DS is challenging but clinically critical. METHODS: We performed a retrospective review of ML-DS and TAM cases collected from five large academic institutions in the USA. We assessed clinical, pathological, immunophenotypical, and molecular features to identify differentiating criteria. RESULTS: Forty cases were identified: 28 ML-DS and 12 TAM. Several features were diagnostically distinct, including younger age in TAM (p < 0.05), as well as presentation with clinically significant anemia and thrombocytopenia in ML-DS (p < 0.001). Dyserythropoiesis was unique to ML-DS, as well as structural cytogenetic abnormalities aside from the constitutional trisomy 21. Immunophenotypic characteristics of TAM and ML-DS were indistinguishable, including the aberrant expression of CD7 and CD56 by the myeloid blasts. DISCUSSION: The findings of the study confirm marked biological similarities between TAM and ML-DS. At the same time, several significant clinical, morphological, and genetic differences were observed between TAM and ML-DS. The clinical approach and the differential diagnosis between these entities are discussed in detail.

Hyperammonemia in the Pediatric Emergency Department.

ABSTRACT: Hyperammonemia is a serious clinical condition associated with significant morbidity and mortality. In the pediatric population, this is often caused by urea cycle disorders, acute liver failure, or other less common underlying etiologies. Children and teens with hyperammonemia can have a broad range of clinical findings, including vomiting, respiratory distress, and changes in mental status. As ammonia levels worsen, this presentation can progress to respiratory failure, encephalopathy, cerebral edema, seizures, and death. Given the risk of neurologic damage, timely identification and management of hyperammonemia is critical and includes initial resuscitation, early consultation with subspecialists, and initiation of appropriate therapies. It is important for pediatric emergency medicine providers to understand the clinical findings, causes, diagnosis, and management of hyperammonemia because they play a key role in the provision of effective, multidisciplinary care of these patients.

Long-term outcomes of patients with conjunctival extranodal marginal zone lymphoma.

Comprehensive information on clinical features and long-term outcomes of primary conjunctival extranodal marginal zone lymphoma (PCEMZL) is scarce. We present a large single-institution retrospective study of 72 patients. The median age was 64 years, and 63.9% were female. Stage I was present in 87.5%. Radiation therapy (RT) alone was the most common treatment (70.8%). Complete response (CR) was 87.5%, and 100% in RT-treated patients. With a median follow-up of 6.7 years, relapse/progression and death occurred in 19.4% each, with one relapse within the RT field. The 10-year progression-free survival (PFS) and overall survival (OS) were 68.4% (95% CI 52.8%-79.8%) and 89.4% (95% CI 77.4%-95.2%), respectively. The 10-year rate for time to progression from diagnosis was 22.5% (95% CI 11.6%-35.7%). The 10-year PFS and OS of MALT-IPI 0 versus 1-2 were 83.3% versus 51.3%, (p = .022) and 97.6% versus 76.6%, (p = .0052), respectively. The following characteristics were associated with shorter survival: age > 60 years (PFS: HR = 2.93, 95% CI 1.08-7.95; p = .035, OS: HR = 9.07, 95% CI 1.17-70.26; p = .035) and MALT-IPI 1-2 (PFS: HR = 2.67, 95% CI 1.12-6.31; p = .027, OS: HR = 6.64, 95% CI 1.45-30.37; p = .015). CR following frontline therapy was associated with longer PFS (HR = 0.13, 95% CI 0.04-0.45; p = .001), but not OS. Using the Fine and Gray regression model with death without relapse/progression as a competing risk, RT and CR after frontline therapy were associated with lower risk of relapse (SHR = 0.34, 95% CI 0.12-0.96 p = .041 and SHR = 0.11, 95% CI 0.03-0.36; p < .001, respectively). Patients with PCEMZL treated with frontline RT exhibit excellent long-term survival, and the MALT-IPI score appropriately identifies patients at risk for treatment failure.

Impact of COVID-19 on Adolescent HIV Prevention and Treatment Research in the AHISA Network.

Members of the Adolescent HIV Prevention and Treatment Implementation Science Alliance (AHISA) network conduct research aiming to close gaps between what is known to be impactful across the HIV prevention and treatment cascade, and services delivered to optimize outcomes for adolescents/young adults (AYA) in high HIV-prevalence settings. The COVID-19 pandemic introduced new challenges which threaten to exacerbate care and access disparities. We report results of a survey among AHISA teams with active AYA HIV research programs in African countries to determine how the pandemic has impacted their efforts. Results highlighted the detrimental impact of the pandemic on research efforts and the expanded need for implementation research to help provide evidence-based, context-specific pandemic recovery support. Key lessons learned included the viability of remote service delivery strategies and other innovations, the need for adaptive systems that respond to evolving contextual needs, and the need for organized documentation plans, within empathic and flexible environments.

Impact of COVID-19 on Adolescent HIV Prevention and Treatment Services in the AHISA Network.

We investigated perceived impacts of COVID-19 on the delivery of adolescent HIV treatment and prevention services in sub-Saharan Africa (SSA) by administering a survey to members of the Adolescent HIV Prevention and Treatment Implementation Science Alliance (AHISA) from February to April 2021. We organized COVID-19 impacts, as perceived by AHISA teams, under three themes: service interruptions, service adjustments, and perceived individual-level health impacts. AHISA teams commonly reported interruptions to prevention programs, diagnostic testing, and access to antiretroviral therapy (ART). Common service adjustments included decentralization of ART refills, expanded multi-month ART distribution, and digital technology use. Perceived individual-level impacts included social isolation, loss to follow-up, food insecurity, poverty, and increases in adolescent pregnancies and sexually transmitted infections. The need for collaboration among stakeholders were commonly cited as lessons learned by AHISA teams. Survey findings highlight the need for implementation science research to evaluate the effects of pandemic-related HIV service adaptations in SSA.

LMO2 expression is frequent in T-lymphoblastic leukemia and correlates with survival, regardless of T-cell stage.

T- lymphoblastic leukemia/lymphoma (T-LL) is an aggressive malignancy of immature T-cells with poor overall survival (OS) and in need of new therapies. LIM-domain only 2 (LMO2) is a critical regulator of hematopoietic cell development that can be overexpressed in T-LL due to chromosomal abnormalities. Deregulated LMO2 expression contributes to T-LL development by inducing block of T-cell differentiation and continuous thymocyte self-renewal. However, LMO2 expression and its biologic significance in T-LL remain largely unknown. We analyzed LMO2 expression in 100 initial and follow-up biopsies of T-LL from 67 patients, including 31 (46%) early precursor T-cell (ETP)-ALL, 26 (39%) cortical and 10 (15%) medullary type. LMO2 expression was present in 50 (74.6%) initial biopsies with an average of 87% positive tumor cells (range 30-100%). LMO2 expression in ETP, medullary and cortical T-LLs was not statistically different. In patients with biopsies after initial therapy, LMO2 expression was stable. LMO2 expression was associated with longer OS (p = 0.048) regardless of T-lymphoblast stage or other clinicopathologic features. These findings indicate that LMO2 is a promising new prognostic marker that could predict patients' outcomes and potentially be targeted for novel chemotherapy, i.e. PARP1/2 inhibitors, which have been shown to enhance chemotherapy sensitivity in LMO2 expressing diffuse large B cell lymphoma (DLBCL) tumors by decreasing DNA repair efficiency.

Reasons for discordance between antiretroviral adherence measures in adolescents.

Adolescents with suboptimal medication taking may deceive caregivers about non-adherence. We conducted a 5-year longitudinal study of adolescents monitored simultaneously with both easily manipulated (e.g., self-report) and hard to manipulate (e.g., microelectronic data) strategies. Adolescents with repeatedly high adherence on the former and low adherence on the latter were invited along with their parental figures ("parents") to participate. We conducted focus groups and semi-structured interviews, separately for adolescents and parents, to elucidate drivers of discordant measures. Forty-seven adolescents and 26 parents participated in focus groups and 4 adolescents were interviewed. Adolescents described hiding pills, discarding pills, and lying. Their motivations included fear of disappointing those who care about them, desire to avoid admonishment by parents and clinic staff, and desire to avoid remedial adherence counseling. Both adolescents and parents considered negative feedback for prior poor adherence to be key motivation to hide current poor adherence from clinic staff. Providing positive feedback for truth-telling, rather than for "evidence" of excellent adherence, might help adolescent patients and their parents to develop stronger treatment alliances with each other and with clinic staff. Such alliances would allow adherence interventions to be better targeted and more fruitful in increasing adherence.

Use of motivational techniques to enhance unpaid caregiver engagement in a tailored skills training intervention.

OBJECTIVES: The Helping Invested Families Improve Veterans' Experiences Study (HI-FIVES) evaluated a skills training program to support family caregivers of cognitively or functionally impaired persons. HI-FIVES demonstrated sustained improvements in caregivers' and patients' experiences of VA care. The aim of this distinct, secondary qualitative study was to explore the potential processes related to the individual tailored skills-based telephone training underpinning HI-FIVES intervention effects. We explored topics caregivers selected, characteristics of action items created, patterns of action or inaction, and barriers to action item completion across topics. METHODS: Qualitative data was analysed from 118 dyads randomized into the HI-FIVES intervention which included three weekly facilitated training calls covering five education topics and action items developed by caregivers for each topic. Qualitative analysis of text responses to questions from the training calls was used. RESULTS: Three of the top four most selected topics were caregiver-oriented and caregivers created an action item most often for self-care topics. Caregiver-oriented topics also had the highest action item completion rates. The majority of action items created met SMART guidelines for goal setting and simple structure. With regard to barriers to action item completion, caregivers commonly reported still contemplating/pending. CONCLUSION: Our findings identify motivational interviewing as an effective technique to identify critical intervention content and address barriers to achieving caregiving goals. We suggest that caregivers felt more empowered to create and complete an action item when they had more control over completing the action item, such as in topics related to their own self-care.

EBV-positive HIV-associated diffuse large B cell lymphomas are characterized by JAK/STAT (STAT3) pathway mutations and unique clinicopathologic features.

Even in the era of highly active combination antiretroviral therapy (cART), patients with HIV have a disproportionate risk of developing aggressive lymphomas that are frequently Epstein-Barr virus (EBV)-related. Here, we investigate HIV-associated diffuse large B-cell lymphoma (HIV-DLBCL) and compare EBV-positive and EBV-negative cases. HIV-DLBCL were identified from two academic medical centres and characterised by immunohistochemistry, EBV status, fluorescence in situ hybridisation, cell of origin determination by gene expression profiling, and targeted deep sequencing using a custom mutation panel of 334 genes. We also applied the Lymphgen tool to determine the genetic subtype of each case. Thirty HIV-DLBCL were identified, with a median patient age of 46 years and male predominance (5:1). Thirteen cases (48%) were EBV-positive and 14 (52%) EBV-negative. Nine of the 16 tested cases (56%) had MYC rearrangement, three (19%) had BCL6 (two of which were double hit MYC/BCL6) and none had BCL2 rearrangements. Using the Lymphgen tool, half of the cases (15) were classified as other. All HIV-DLBCL showed mutational abnormalities, the most frequent being TP53 (37%), MYC (30%), STAT3 (27%), HIST1H1E (23%), EP300 (20%), TET2 (20%), SOCS1 (17%) and SGK1 (17%). EBV-negative cases were mostly of germinal centre B-cell (GCB) origin (62%), showed more frequent mutations per case (a median of 13·5/case) and significant enrichment of TP53 (57% vs. 15%; P = 0·046), SGK1 (36% vs. 0%; P = 0·04), EP300 (43% vs. 0%; P = 0·02) and histone-modifying gene (e.g. HIST1H1E, HIST1H1D, 79% vs. 31%; P = 0·02) mutations. EBV-positive cases were mostly of non-GCB origin (70%), with fewer mutations per case (median 8/case; P = 0·007), and these tumours were enriched for STAT3 mutations (P = 0·10). EBV-positive cases had a higher frequency of MYC mutations but the difference was not significant (36% vs. 15%; P = 0·38). EBV-association was more frequent in HIV-DLBCLs, arising in patients with lower CD4 counts at diagnosis (median 46·5 vs. 101, P = 0·018). In the era of cART, approximately half of HIV-DLBCL are EBV-related. HIV-DLBCL are enriched for MYC rearrangements, MYC mutations and generally lack BCL2 rearrangements, regardless of EBV status. Among HIV-DLBCL, tumours that are EBV-negative and EBV-positive appear to have important differences, the latter arising in context of lower CD4 count, showing frequent non-GCB origin, lower mutation burden and recurrent STAT3 mutations.

Epstein-Barr-virus-positive large B-cell lymphoma associated with breast implants: an analysis of eight patients suggesting a possible pathogenetic relationship.

Breast implant anaplastic large cell lymphoma (ALCL) is a T-cell neoplasm arising around textured breast implants that was recognized recently as a distinct entity by the World Health Organization. Rarely, other types of lymphoma have been reported in patients with breast implants, raising the possibility of a pathogenetic relationship between breast implants and other types of lymphoma. We report eight cases of Epstein-Barr virus (EBV)-positive large B-cell lymphoma associated with breast implants. One of these cases was invasive, and the other seven neoplasms were noninvasive and showed morphologic overlap with breast implant ALCL. All eight cases expressed B-cell markers, had a non-germinal center B-cell immunophenotype, and were EBV+ with a latency type III pattern of infection. We compared the noninvasive EBV+ large B-cell lymphoma cases with a cohort of breast implant ALCL cases matched for clinical and pathologic stage. The EBV+ large B-cell lymphoma cases more frequently showed a thicker capsule, and more often were associated with calcification and prominent lymphoid aggregates outside of the capsule. The EBV+ B-cell lymphoma cells were more often arranged within necrotic fibrinoid material in a layered pattern. We believe that this case series highlights many morphologic similarities between EBV+ large B-cell lymphoma and breast implant ALCL. The data presented suggest a pathogenetic role for breast implants (as well as EBV) in the pathogenesis of EBV+ large B-cell lymphoma. We also provide some histologic findings useful for distinguishing EBV+ large B-cell lymphoma from breast implant ALCL in this clinical setting.

Molecular profiling reveals a hypoxia signature in breast implant-associated anaplastic large cell lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently characterized T-cell malignancy that has raised significant patient safety concerns and led to worldwide impact on the implants used and clinical management of patients undergoing reconstructive or cosmetic breast surgery. Molecular signatures distinguishing BIA-ALCL from other ALCLs have not been fully elucidated and classification of BIA-ALCL as a WHO entity remains provisional. We performed RNA sequencing and gene set enrichment analysis comparing BIA-ALCLs to non-BIA-ALCLs and identified dramatic upregulation of hypoxia signaling genes including the hypoxia-associated biomarker CA9 (carbonic anyhydrase-9). Immunohistochemistry validated CA9 expression in all BIA-ALCLs, with only minimal expression in non-BIA-ALCLs. Growth induction in BIA-ALCL-derived cell lines cultured under hypoxic conditions was proportional to up-regulation of CA9 expression, and RNA sequencing demonstrated induction of the same gene signature observed in BIA-ALCL tissue samples compared to non-BIA-ALCLs. CA9 silencing blocked hypoxia-induced BIA-ALCL cell growth and cell cycle-associated gene expression, whereas CA9 overexpression in BIA-ALCL cells promoted growth in a xenograft mouse model. Furthermore, CA9 was secreted into BIA-ALCL cell line supernatants and was markedly elevated in human BIA-ALCL seroma samples. Finally, serum CA9 concentrations in mice bearing BIA-ALCL xenografts were significantly elevated compared to control serum. Together, these findings characterize BIA-ALCL as a hypoxia-associated neoplasm, likely attributable to the unique microenvironment in which it arises. These data support classification of BIA-ALCL as a distinct entity and uncover opportunities for investigating hypoxia-related proteins such as CA9 as novel biomarkers and therapeutic targets in this disease.

Psychological Reactance is a Novel Risk Factor for Adolescent Antiretroviral Treatment Failure.

Psychological reactance is an aversive response to perceived threats against personal agency. For adolescents receiving HIV treatment in Botswana, we utilized a two-question, medication-specific reactance tool to assess whether: (1) verbal reminders to take medicines made adolescents want to avoid taking them, and, (2) whether adolescents felt anger when reminded to take medicines. Reactant adolescents had 2.05-fold (95% CI 1.23, 3.41) greater odds of treatment failure than non-reactant adolescents (p = 0.03). Adjusted risk of treatment failure was 14% (95% CI 3%, 28%) greater for each point elevation in reactance score (p = 0.016). Autonomy over medication-taking did not modify the association between reactance and treatment failure. Psychological reactance may be a useful interventional target for improving adolescent adherence.

Implementing Teledermatology for Rural Veterans: An Evaluation Using the RE-AIM Framework.

Introduction: Few systematic evaluations of implementing teledermatology programs in large health care systems exist. We conducted a longitudinal evaluation of a U.S. Department of Veterans Affairs (VA) initiative to expand asynchronous consultative teledermatology services for rural veterans. Methods: The reach, effectiveness, adoption, implementation, and maintenance framework guided the evaluation, which included analysis of quantitative VA administrative data as well as an online survey completed by participating facilities. The first 2 years of the program were compared with the year before the start of funding. Results: Sixteen hub facilities expanded teledermatology's reach over the 2-year period, increasing the number of referral spoke sites, unique patients served, and teledermatology encounters. Effectiveness was reflected as teledermatology constituted an increasing fraction of dermatology activity and served more remotely located patients. Adoption through defined stages of implementation progressed as facilities engaged in a variety of strategies to enhance teledermatology implementation, and facilitators and barriers were identified. Program maintenance was assessed by Program Sustainability Index scores, which reflected the importance of executive support, and ongoing concerns about staffing and longitudinal funding. Discussion: Enabling hubs to create solutions that best fit their needs and culture likely increased reach and effectiveness. Important facilitators included organizational leadership and encouraging communication between stakeholders before and during the intervention. Conclusions: A systematic analysis of teledermatology implementation to serve rural sites in VA documented a high degree of implementation and sustainability as well as areas for improvement.

Implementation of Mobile Teledermatology: Challenges and Opportunities.

Background: While teledermatology is well-established in the Department of Veterans Affairs (VA), its implementation is far from complete. To facilitate consultative teledermatology and extend its reach, VA introduced a mobile teledermatology application (app) at three VA sites. Methods: We evaluated the initial implementation process using a mixed-methods, multiple case study approach to assess organizational readiness for change (ORC), which included examining facilitators, barriers, and contextual factors that affected implementation. We conducted: (1) group interviews and bimonthly reports to understand site processes; (2) semistructured interviews and surveys of individual participants representing a range of implementation roles; and (3) a review of internal organizational documents. We identified themes from interviews using an iterative process, and computed an ORC score based on surveys. Results: Forty-three individuals participated in the study. Qualitative data from all sites, corroborated by survey data available from one site, revealed a high readiness for change with an ORC score of 4.2, where 5 = maximal readiness for change. Facilitators included support from leadership and clinical champions, active telehealth programs, and an understanding and appreciation of the program and the resources needed. At all sites, however, technical issues negatively affected adoption; these included a suboptimal information technology infrastructure, which led to the inoperability of the app at two sites, and technical inefficiencies related to users' unfamiliarity with new devices and inconsistent internet access. Conclusions: Although a strong commitment to change and a confidence to effect change existed, these alone were insufficient to surmount barriers to implementation effectiveness. Clinical Trials Registration: NCT03241589.

Atypical Endovascular Cells in SARS-CoV-2 Pneumonia.

The autopsy findings for 3 cases of SARS-(CoV-2) pneumonia-related deaths are reported with pulmonary histology and immunohistochemistry findings. In 2 cases (cases 1 and 2), the time interval from presentation to death was approximately 1 week, whereas for case 3, the time interval from presentation to death was hours. Case 1 and case 2 presented with shortness of breath, cough, and flu-like symptoms. The decedent from case 3 died shortly after presenting to a local emergency room with high fever, chest and abdominal pain, and shortness of breath. All 3 cases had 1 or more comorbidities. The postmortem interval for cases 1 and 2 was 2 weeks as they died at sea and were stored on board within the respective cruise ships' refrigeration units, whereas case 3 was examined within 24 hours of death. The autopsies were conducted at the Miami-Dade County Medical Examiners Department under routine infectious precautions. Salient clinical history and autopsy findings are summarized. Microscopic examination revealed pneumonia with associated atypical endovascular cells.

Oculocardiac Reflex in a Pediatric Trauma Patient.

We describe the case of a 6-year-old boy who presented to a tertiary care emergency department after a motor vehicle accident with facial trauma and bradycardia. The patient was found to have an orbital floor fracture and inferior rectus muscle entrapment with resulting bradycardia secondary to the oculocardiac reflex. The oculocardiac reflex is an uncommon cause of bradycardia in the setting of trauma but should be considered because it can necessitate surgical intervention.

Long-term course of patients with primary ocular adnexal MALT lymphoma: a large single-institution cohort study.

While primary ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma (POAML) is the most common orbital tumor, there are large gaps in knowledge of its natural history. We conducted a retrospective analysis of the largest reported cohort, consisting of 182 patients with POAML, diagnosed or treated at our institution to analyze long-term outcome, response to treatment, and incidence and localization of relapse and transformation. The majority of patients (80%) presented with stage I disease. Overall, 84% of treated patients achieved a complete response after first-line therapy. In patients with stage I disease treated with radiation therapy (RT), doses ≥30.6 Gy were associated with a significantly better complete response rate (P = .04) and progression-free survival (PFS) at 5 and 10 years (P < .0001). Median overall survival and PFS for all patients were 250 months (95% confidence interval [CI], 222 [upper limit not reached]) and 134 months (95% CI, 87-198), respectively. Kaplan-Meier estimates for the PFS at 1, 5, and 10 years were 91.5% (95% CI, 86.1% to 94.9%), 68.5% (95% CI, 60.4% to 75.6%), and 50.9% (95% CI, 40.5% to 61.6%), respectively. In univariate analysis, age >60 years, radiation dose, bilateral ocular involvement at presentation, and advanced stage were significantly correlated with shorter PFS (P = .006, P = .0001, P = .002, and P = .0001, respectively). Multivariate analysis showed that age >60 years (hazard ratio [HR] 2.44) and RT<30.6Gy (HR=4.17) were the only factors correlated with shorter PFS (P = .01 and P = .0003, respectively). We demonstrate that POAMLs harbor a persistent and ongoing risk of relapse, including in the central nervous system, and transformation to aggressive lymphoma (4%), requiring long-term follow-up.