Sclerosing Angiomatoid Nodular Transformation of the Spleen in a Patient With Granulomatosis With Polyangiitis.

We present an intriguing case involving a rare occurrence of sclerosing angiomatoid nodular transformation (SANT) in a 57-year-old woman with a history of granulomatosis with polyangiitis (GPA). Despite the extensive literature on SANT, its pathogenesis remains elusive. The patient, diagnosed with serum anti-proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA)-positive GPA seven years earlier, exhibited a splenic lesion during imaging, leading to laparoscopic splenectomy due to severe abdominal pain. Microscopic analysis unveiled nodular structures with vascular elements surrounded by fibrosclerotic stroma and chronic inflammatory cells. This case raises questions about the interplay between SANT, GPA activity, and vascular damage. Hypotheses regarding SANT's origin, including its potential association with organized hematoma or alterations in splenic blood flow, are discussed. The uniqueness of this case lies in the coexistence of PR3-ANCA-positive GPA and SANT, suggesting a potential link between GPA activity, vascular damage, and SANT development. While causality remains uncertain, this report marks the first documented case of a patient with PR3-ANCA-positive GPA developing SANT. The findings prompt reflection on a potential common pathophysiological mechanism and underscore the importance of considering SANT in cases of splenic lesions associated with conditions causing alterations in splenic blood flow. This contribution serves as a valuable addition to the existing knowledge, urging further research and consideration of SANT in diagnostic scenarios involving splenic abnormalities.

Is iron overload associated with worse outcomes in patients with chronic liver disease undergoing liver transplantation?

Background: Iron overload is frequent in patients with chronic liver disease, associated with shorter survival after liver transplantation in patients with hereditary hemochromatosis. Its effect on patients without hereditary hemochromatosis is unclear. The aim of the study was to study the clinical impact of iron overload in patients who underwent liver transplantation at an academic tertiary referral center. Methods: We performed a retrospective cohort study including all patients without hereditary hemochromatosis who underwent liver transplantation from 2015 to 2017 at an academic tertiary referral center in Mexico City. Explant liver biopsies were reprocessed to obtain the histochemical hepatic iron index, considering a score ≥ 0.15 as iron overload. Baseline characteristics were compared between patients with and without iron overload. Survival was estimated using the Kaplan-Meier method, compared with the log-rank test and the Cox proportional hazards model. Results: Of 105 patients included, 45% had iron overload. Viral and metabolic etiologies, alcohol consumption, and obesity were more frequent in patients with iron overload than in those without iron overload (43% vs. 21%, 32% vs. 22%, p = 0.011; 34% vs. 9%, p = 0.001; and 32% vs. 12%, p = 0.013, respectively). Eight patients died within 90 days after liver transplantation (one with iron overload). Complication rate was higher in patients with iron overload versus those without iron overload (223 vs. 93 events/100 personmonths; median time to any complication of 2 vs. 3 days, p = 0.043), without differences in complication type. Fatality rate was lower in patients with iron overload versus those without iron overload (0.7 vs. 4.5 deaths/100 person-months, p = 0.055). Conclusion: Detecting iron overload might identify patients at risk of early complications after liver transplantation. Further studies are required to understand the role of iron overload in survival.

Wilms' tumor 1 (WT1) antigen is overexpressed in Kaposi Sarcoma and is regulated by KSHV vFLIP.

In people living with HIV, Kaposi Sarcoma (KS), a vascular neoplasm caused by KS herpesvirus (KSHV/HHV-8), remains one of the most common malignancies worldwide. Individuals living with HIV, receiving otherwise effective antiretroviral therapy, may present with extensive disease requiring chemotherapy. Hence, new therapeutic approaches are needed. The Wilms' tumor 1 (WT1) protein is overexpressed and associated with poor prognosis in several hematologic and solid malignancies and has shown promise as an immunotherapeutic target. We found that WT1 was overexpressed in >90% of a total 333 KS biopsies, as determined by immunohistochemistry and image analysis. Our largest cohort from ACTG, consisting of 294 cases was further analyzed demonstrating higher WT1 expression was associated with more advanced histopathologic subtypes. There was a positive correlation between the proportion of infected cells within KS tissues, assessed by expression of the KSHV-encoded latency-associated nuclear antigen (LANA), and WT1 positivity. Areas with high WT1 expression showed sparse T-cell infiltrates, consistent with an immune evasive tumor microenvironment. We show that major oncogenic isoforms of WT1 are overexpressed in primary KS tissue and observed WT1 upregulation upon de novo infection of endothelial cells with KSHV. KSHV latent viral FLICE-inhibitory protein (vFLIP) upregulated total and major isoforms of WT1, but upregulation was not seen after expression of mutant vFLIP that is unable to bind IKKÆ´ and induce NFκB. siRNA targeting of WT1 in latent KSHV infection resulted in decreased total cell number and pAKT, BCL2 and LANA protein expression. Finally, we show that ESK-1, a T cell receptor-like monoclonal antibody that recognizes WT1 peptides presented on MHC HLA-A0201, demonstrates increased binding to endothelial cells after KSHV infection or induction of vFLIP expression. We propose that oncogenic isoforms of WT1 are upregulated by KSHV to promote tumorigenesis and immunotherapy directed against WT1 may be an approach for KS treatment.

Performance of the 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease in a Latin American Cohort.

BACKGROUND/OBJECTIVE: The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria (2019 AECC) for IgG4-related disease (IgG4-RD) is considered a significant advancement in the study of this condition. Most studies evaluating their performance have focused on White and Asian patients, leaving a knowledge gap regarding Latin American populations. Therefore, this study aimed to assess the performance of the 2019 AECC for IgG4-RD in a cohort of Latin American patients. METHODS: A multicenter medical records review study was conducted, involving centers from Argentina, Chile, Mexico, Peru, and Uruguay. Data on IgG4-RD patients and mimicker conditions were collected through a standardized online form. The criterion standard for diagnosing IgG4-RD was based on the fulfillment of the Comprehensive Diagnostic Criteria for IgG4-RD and/or the Consensus Statement on Pathology. The 2019 AECC was retrospectively applied. RESULTS: We included 300 patients, with 180 (60%) having IgG4-RD and 120 (40%) having mimicker conditions. The 2019 AECC had a sensitivity of 66.7% and a specificity of 100%. Sensitivity increased to 73.3% when disease-specific autoantibody items were removed, without affecting specificity. The true-positive cases had more involved organs, a higher availability of biopsy results, and were more likely to belong to the Mikulicz/systemic and proliferative phenotypes. CONCLUSIONS: The use of the 2019 AECC for IgG4-RD in a Latin American population confirms its high specificity in excluding those without the disease. The presence of concomitant autoimmune diseases and clinically nonsignificant disease-specific autoantibodies excludes a significant number of patients from fulfilling the criteria.

NIPBL::NACC1 Fusion Hepatic Carcinoma.

Several reports describing a rare primary liver tumor with histologic features reminiscent of follicular thyroid neoplasms have been published under a variety of descriptive terms including thyroid-like, solid tubulocystic, and cholangioblastic cholangiocarcinoma. Although these tumors are considered to represent histologic variants, they lack classic features of cholangiocarcinoma and have unique characteristics, namely immunoreactivity for inhibin and NIPBL::NACC1 fusions. The purpose of this study is to present clinicopathologic and molecular data for a large series of these tumors to better understand their pathogenesis. We identified 11 hepatic tumors with these features. Immunohistochemical and NACC1 and NIPBL fluorescence in situ hybridization assays were performed on all cases. Four cases had available material for whole-genome sequencing (WGS) analysis. Most patients were adult women (mean age: 42 y) who presented with abdominal pain and large hepatic masses (mean size: 14 cm). Ten patients had no known liver disease. Of the patients with follow-up information, 3/9 (33%) pursued aggressive behavior. All tumors were composed of bland cuboidal cells with follicular and solid/trabecular growth patterns in various combinations, were immunoreactive for inhibin, showed albumin mRNA by in situ hybridization, and harbored the NIPBL::NACC1 fusion by fluorescence in situ hybridization. WGS corroborated the presence of the fusion in all 4 tested cases, high tumor mutational burden in 2 cases, and over 30 structural variants per case in 3 sequenced tumors. The cases lacked mutations typical of conventional intrahepatic cholangiocarcinoma. In this report, we describe the largest series of primary inhibin-positive hepatic neoplasms harboring a NIPBL::NACC1 fusion and the first WGS analysis of these tumors. We propose to name this neoplasm NIPBL:NACC1 fusion hepatic carcinoma.

The Role of Postmastectomy Radiotherapy in Locally Advanced Breast Cancer After Pathological Complete Response to Neoadjuvant Chemotherapy.

The Case A previously healthy woman, aged 32 years, presented to the oncology clinic with a 6-month history of left-breast tumor, mastalgia, and swollen axillary nodes. Physical examination was relevant for a 6-cm palpable mass in the upper outer quadrant of the left breast and an ipsilateral 2-cm, nonfixed axillary lymph node. Mammography showed a 1-cm mass in the upper outer quadrant, a 5.2-cm mass in the lower outer quadrant, and enlarged pathologic lymph nodes (BI-RADS category 5 disease). Breast ultrasound revealed 3 axillary lymph nodes with cortical thickening and loss of normal morphology (the largest with a 2.6-cm length in the long axis) (Figure 1A-B). The breast´s core biopsy revealed a grade 3 apocrine invasive carcinoma with lymphovascular invasion; immunohistochemistry testing showed HER2-negative, hormone receptor-negative disease (estrogen receptor, 0%; progesterone receptor, 0%; HER2-negative, Ki67, 50%) (Figure 2A-B). A fine-needle aspiration biopsy of the axillary lymph nodes showed invasive breast carcinoma as well. Bone scintigraphy and a chest/abdomen CT scan ruled out metastatic disease. Upon initial diagnosis, clinical stage was deemed as cT3N1M0 (American Joint Committee on Cancer 8th edition: anatomic stage IIIA, clinical prognostic stage IIIC). After a multidisciplinary tumor board discussion, the patient underwent neoadjuvant chemotherapy with weekly paclitaxel, followed by 4 cycles of dose-dense doxorubicin plus cyclophosphamide. After completing neoadjuvant treatment, clinical examination was relevant for a residual 1-cm palpable left breast mass and no palpable axillary nodes. Mammography and breast ultrasound showed a 77% partial response in the primary tumors, and axillary nodes with normal morphology and size (Figure 1C-D). Due to multicentric tumor disease, breast-conserving surgery would not confer satisfactory cosmetic results on her, and a modified radical mastectomy with intraoperative sentinel lymph node biopsy (and second-stage breast reconstruction) was planned. However, during surgery, the surgeons failed to identify the mapped lymph node, and level I-III axillary lymph node dissection was performed. The pathology report described complete pathological response: Miller and Payne criteria grade 5 response with the absence of malignant cells within the mastectomy specimen and in 24 lymph nodes (Figure 2C-E). Pathological staging after neoadjuvant treatment concluded ypT0N0M0 disease. Subsequent treatment for this patient was discussed in another tumor board.

Características clínicas de los pacientes con fiebre manchada de las Montañas Rocosas, infección por dengue y chikungunya / Clinical features of patients with Rocky Mountain spotted fever, dengue and chikungunya infection

Resumen Introducción: La distinción clínica entre infecciones arbovirales y las provocadas por rickettsias es crucial para iniciar el tratamiento médico apropiado. Objetivo: Comparar las diferencias entre fiebre manchada de las Montañas Rocosas (FMMR) y otras enfermedades transmitidas por vector (dengue y chikungunya) con presentación clínica similar e identificar los datos que pudieran ayudar al diagnóstico rápido de esas enfermedades. Métodos: Se evaluaron datos sociodemográficos, clínicos y de laboratorio de 399 pacientes de cinco hospitales y clínicas en Sonora, México, entre 2004 y 2016, con el diagnóstico confirmado por laboratorio de FMMR, dengue o chikungunya. Resultados: El grupo con FMMR presentó la mayor letalidad (49/63 muertes, 77.8 %), seguido por el de chikungunya (3/161, 1.9 %) y el de dengue (3/161, 1.9 %). Las diferencias clínicas consistieron en la presencia de exantema, edema y prurito; además, se documentaron diferencias en múltiples biomarcadores como plaquetas, hemoglobina, bilirrubina indirecta y niveles de sodio sérico. Conclusión: El exantema en palmas y plantas, edema y ausencia de prurito, aunados a niveles altos de bilirrubina directa y trombocitopenia severa pudieran ser indicadores útiles para diferenciar a pacientes con FMMR en etapas avanzadas de aquellos con dengue y chikungunya.

Abstract Introduction: Clinical distinction between arbovirus infections and those caused by rickettsia is crucial to initiate appropriate medical treatment. Objective: To compare the differences between Rocky Mountain spotted fever (RMSF) and other vector-borne diseases (dengue and chikungunya) with similar clinical presentation, and to identify data that could aid rapid diagnosis of these diseases. Methods: Sociodemographic, clinical and laboratory data of 399 patients from five hospitals and clinics of Sonora, Mexico, with laboratory-confirmed diagnosis of RMSF, dengue, or chikungunya between 2004 and 2016 were evaluated. Results: The RMSF group had the highest lethality (49/63 deaths, 77.8 %), followed by the chikungunya group (3/161, 1.9 %) and the dengue group (3/161, 1.9 %). Clinical differences included the presence of rash, edema, and pruritus; in addition, differences in multiple biomarkers such as platelets, hemoglobin, indirect bilirubin, and serum sodium levels were documented. Conclusion: Rash on the palms and soles, edema and absence of pruritus, together with high levels of direct bilirubin and severe thrombocytopenia could be useful indicators to differentiate patients at RMSF advanced stages from those with dengue and chikungunya.

The genus Rickettsia in Mexico: Current knowledge and perspectives.

The genus Rickettsia encompasses 35 valid species of intracellular, coccobacilli bacteria that can infect several eukaryotic taxa, causing multiple emerging and re-emerging diseases worldwide. This work aimed to gather and summarise the current knowledge about the genus Rickettsia in Mexico, updating the taxonomy of the bacteria and their hosts by including all the records available until 2020, to elucidate host-parasite relationships and determine the geographical distribution of each Rickettsia species present in the country. Until now, 14 species of Rickettsia belonging to four groups have been recorded in Mexico. These species have been associated with 26 arthropod species (14 hard ticks, three soft ticks, two sucking lice, and seven fleas) and 17 mammal species distributed over 30 states in Mexico. This work highlights the high biological inventory of rickettsias for Mexico and reinforces the need to approach the study of this group from a One Health perspective.

Access to Palliative Care Services and Clinical Outcomes of Patients With Solid Malignancy-Associated Myelophthisis in a Resource-Limited Setting.

BACKGROUND: Myelophthisis (MPT) has been associated with a dreadful prognosis. Patients' access to palliative care (PC) and factors influencing its clinical outcomes are poorly described. Our aim was to analyze the impact of patient- and disease-specific characteristics on survival of patients with MPT and describe their use of PC in a resource-limited setting. METHODS: Retrospective study including patients with solid tumor MPT, diagnosed between 1996 and 2018. RESULTS: Seventy patients (median 58 years) were included. 58% were synchronously diagnosed with MPT at time of primary tumor diagnosis. Most common oncologic diagnoses were prostate (25.7%), gastrointestinal (20%), and breast (18.6%) neoplasms. Median overall survival (OS) was 1.9 months. Primaries other than prostate, breast, and lung (HR 1.37, 95% CI 1.15 - 1.8; p = 0.02) and transfusion requirements (HR 2.8, 95% CI 1.01 - 7.9; p = 0.04) were independently associated with decreased OS. Administration of multiple systemic therapeutic interventions (HR 0.15, 95% CI 0.06 - 0.39; p = 0.01) was the sole factor improving OS. Assessment by PC was pursued in 51.4% of patients. The median number of consults per patient was two, with no difference in assessment rate or consult number across different primaries (P = 0.96). Four cases of palliative sedation were reported, all performed by the primary care team. CONCLUSION: MPT is highly heterogeneous and risk stratification to optimize the use of therapeutic interventions in unison with palliative interventions is needed to maximize efforts toward improving patient quality of life. There is an alarming need of PC services in the multidisciplinary management of patients within developing regions.

Reproductive incompatibility between Amblyomma maculatum (Acari: Ixodidae) group ticks from two disjunct geographical regions within the USA.

The Amblyomma maculatum Koch group of ixodid ticks consists of three species: A. maculatum, A. triste, and A. tigrinum. However, since Koch described this group in 1844, the systematics of its members has been the subject of ongoing debate. This is especially true of A. maculatum and A. triste; recent molecular analyses reveal insufficient genetic divergence to separate these as distinct species. Further confounding this issue is the discovery in 2014 of A. maculatum group ticks in southern Arizona (AZ), USA, that share morphological characteristics with both A. triste and A. maculatum. To biologically evaluate the identity of A. maculatum group ticks from southern Arizona, we analyzed the reproductive compatibility between specimens of A. maculatum group ticks collected from Georgia (GA), USA, and southern Arizona. Female ticks from both Arizona and Georgia were mated with males from both the Georgia and Arizona Amblyomma populations, creating two homologous and two heterologous F1 cohorts of ticks: GA ♀/GA ♂, AZ ♀/AZ ♂, GA ♀/AZ ♂, and AZ ♀/GA ♂. Each cohort was maintained separately into the F2 generation with F1 females mating only with F1 males from their same cohort. Survival and fecundity parameters were measured for all developmental stages. The observed survival parameters for heterologous cohorts were comparable to those of the homologous cohorts through the F1 generation. However, the F1 heterologous females produced F2 egg clutches that did not hatch, thus indicating that the Arizona and Georgia populations of A. maculatum group ticks tested here represent different biological species.

Distribution and Occurrence of Amblyomma maculatum sensu lato (Acari: Ixodidae) and Rickettsia parkeri (Rickettsiales: Rickettsiaceae), Arizona and New Mexico, 2017-2019.

Amblyomma maculatum Koch sensu lato (s.l.) ticks are the vector of Rickettsia parkeri in Arizona, where nine cases of R. parkeri rickettsiosis have been identified since the initial case in 2014. The current study sought to better define the geographic ranges of the vector and pathogen and to assess the potential public health risk posed by R. parkeri in this region of the southwestern United States. A total of 275 A. maculatum s.l. ticks were collected from 34 locations in four counties in Arizona and one county in New Mexico and screened for DNA of Rickettsia species. Rickettsia parkeri was detected in 20.4% of the ticks, including one specimen collected from New Mexico, the first report of R. parkeri in A. maculatum s.l. from this state. This work demonstrates a broader distribution of A. maculatum s.l. ticks and R. parkeri in the southwestern United States than appreciated previously to suggest that R. parkeri rickettsiosis is underrecognized in this region.

Molecular Confirmation of Rickettsia parkeri in Amblyomma ovale Ticks, Veracruz, Mexico.

We found Rickettsia parkeri in Amblyomma ovale ticks collected in Veracruz, Mexico, in 2018. We sequenced gene segments of gltA, htrA, sca0, and sca5; phylogenetic reconstruction revealed near-complete identity with R. parkeri strain Atlantic Rainforest. Enhanced surveillance is needed in Mexico to determine the public health relevance of this bacterium.

Secondary Diffuse Large B-cell Lymphoma Mimicking Meningioma.

Meningiomas are the most common benign intracranial tumors accounting for up to 30% of non-glial tumors of the central nervous system (CNS); on neuroimaging studies, they usually appear as a lobular, extra-axial mass with well-circumscribed margins mostly located in the parasagittal aspect of the cerebral convexity. On magnetic resonance imaging (MRI) of the brain, meningiomas are typically isointense to hypointense relative to grey matter in the T1-weighted sequence and isointense to slight hyperintense relative to grey matter on the T2-weighted sequence with avid homogeneous enhancement after contrast administration. A thin linear enhancement along the dura infiltrating away from the lesion, known as the dural tail sign, was once thought to be a pathognomonic feature of meningiomas, but this non-specific sign can also be seen in other meningioma-like lesions. Several benign and malignant pathologies may mimic some of the neuroimaging characteristics of meningiomas; among them dural metastases of lymphomas. When approaching a patient with suspected meningioma, close attention to the neuroimaging features may help distinguish them from meningioma-like lesions. Here we present the case of a woman with CNS involvement of non-Hodgkin lymphoma that presented with a dural mass resembling the neuroimaging characteristics of a meningioma.

Molecular evidence of Borrelia burgdorferi sensu stricto and Rickettsia massiliae in ticks collected from a domestic-wild carnivore interface in Chihuahua, Mexico.

Sixty-five wild carnivores and twenty free-roaming dogs from the Janos Biosphere Reserve (JBR), northwestern Chihuahua, Mexico, were inspected for ticks which were tested by molecular assays to identify Borrelia and Rickettsia infections. Overall, 45 ticks belonging to five taxa, including Dermacentor parumapertus, Ixodes hearlei, Ixodes kingi, Rhipicephalus sanguineus s.l., and Ornithodoros sp. were collected from 9.2% of the wild carnivores and 60% of the free-roaming dogs. Borrelia burgdorferi s.s. DNA was detected in an I. kingi tick collected from a kit fox (Vulpes macrotis), while Rickettsia massiliae was detected in two (6.5%) of the 31 Rh. sanguineus s.l. collected from free-roaming dogs. Our results revealed host associations between free-roaming dogs and wild carnivore hosts and their ticks in the JBR. The presence of the etiological agents of Lyme disease and spotted fever rickettsiosis in ticks raises the potential risk of tick-borne diseases at the human-domestic-wildlife interface in northwestern Mexico.

Enfermedad granulomatosa hepática / Hepatic granulomatous disease

Resumen Los granulomas son lesiones circunscritas compuestas principalmente por células mononucleares que surgen en respuesta a estímulos antigénicos pobremente degradables. Se encuentran en 2 a 15 % de las biopsias hepáticas; su hallazgo puede significar desde un fenómeno incidental, hasta la manifestación de una enfermedad sistémica de origen infeccioso, autoinmune o neoplásico. El cuadro clínico suele apuntar a la patología subyacente, sin embargo, la lista de condiciones asociadas es amplia y difiere con base en los antecedentes epidemiológicos y a las características basales del paciente. El elemento de mayor utilidad para su estudio es la historia clínica exhaustiva, con énfasis en viajes recientes, exposición de riesgo y consumo de fármacos o alimentos crudos o exóticos. El análisis histopatológico detallado puede auxiliar en la identificación de la etiología, por ejemplo, la presencia de granulomas epitelioides con necrosis caseosa indica tuberculosis y su ausencia, sarcoidosis; la abundancia de eosinófilos es señal de reacciones farmacológicas o infecciones parasitarias; la presencia de cuerpos extraños puede ser la causa de la enfermedad granulomatosa hepática. En este artículo describimos los aspectos clínico-patológicos básicos de esta enfermedad y proveemos un breve resumen de las etiologías más comunes, principalmente en la región de Latinoamérica.

Abstract Granulomas are circumscribed lesions mainly composed of mononuclear cells that arise in response to poorly degradable antigenic stimuli. They are found in 2-15 % of liver biopsies and the meaning of their finding can range from an incidental phenomenon to the manifestation of a systemic disease of infectious, autoimmune or neoplastic origin. Clinical presentation usually points at the underlying pathology; however, the list of associated conditions is extensive, and differs based on patient epidemiological history and baseline characteristics. The most useful element for their study is a thorough medical history, with an emphasis on recent trips, exposures and consumption of drugs or raw or exotic foods. Detailed histopathological analysis may help identify the etiology. For example, the presence of epithelioid granulomas with caseous necrosis indicates tuberculosis and, its absence, sarcoidosis; eosinophil abundance can be associated with drug reactions or parasitic infections; and the presence of foreign bodies can be the cause of granulomatous liver disease (GLD). In this article, we describe the basic clinical-pathological aspects of GLD, and provide a brief summary of the most common etiologies, with an emphasis on the Latin-American region.