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.

Beyond diagnosis: exploring the significance of IgG4+ plasma cell count through immunostaining in IgG4-related disease.

OBJECTIVES: To evaluate whether the grade of IgG4+ plasma cell infiltration in biopsies is associated with clinical or serologic outcomes in IgG4-RD. METHODS: We included 57 patients with biopsy proven IgG4-RD according to the Comprehensive Diagnostic Criteria and/or the 2019 ACR/EULAR Classification Criteria. We collected histological, clinical (disease duration, phenotype, remission and relapses) and serological variables. RESULTS: 29 (50.9%) patients were men, mean age 49.9 years, with a median disease duration of 22 months. The distribution among clinical phenotypes were 14% pancreato-hepato-biliary, 12.3% retroperitoneal/aortic, 29.8% head and neck-limited, 29.8% Mikulicz/systemic and 14% undefined. Thirty-nine patients had a proliferative and 18 a fibrotic phenotype. Most biopsies were from lacrimal gland, lymph node, pancreas, orbit, kidney, retroperitoneum and thyroid gland. Thirty-nine (68.4%) patients had <100 IgG4+ plasma cells/HPF and 18 (31.6%) ≥100 IgG4+ plasma cells/HPF. Patients with ≥100 IgG4+ plasma cells/HPF were more likely to belong to the pancreato-hepato-biliary and the proliferative phenotypes, had fewer relapses and a higher remission rate. On multivariate analysis, the OR for remission at last follow-up was 6.7, 95% CI 1.1-4.42, p=0.03. The log-rank test showed a difference in relapse-free survival between the two groups (HR 2.6, 95% CI 1.2-5.6, p=0.01). According to the ROC analysis, patients with more than 61 IgG4+ plasma cells were less likely to relapse. CONCLUSIONS: A count of ≥100 IgG4+ plasma cells/HPF may identify patients with a proliferative phenotype, fewer relapses and a higher remission rate.

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.

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.

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.

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.

Rickettsia parkeri and Candidatus Rickettsia andeanae in Tick of the Amblyomma maculatum Group, Mexico.

We report Rickettsia parkeri and Candidatus Rickettsia andeanae in ticks of the Amblyomma maculatum group collected from dogs in Sonora, Mexico. Molecular characterization of these bacteria was accomplished by DNA amplification and sequence analysis of portions of the rickettsial genes gltA, htrA, ompA, and ompB.

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.

Rickettsia parkeri in Dermacentor parumapertus Ticks, Mexico.

During a study to identify zoonotic pathogens in northwestern Mexico, we detected the presence of a rickettsial agent in Dermacentor parumapertus ticks from black-tailed jackrabbits (Lepus californicus). Comparison of 4 gene sequences (gltA, htrA, ompA, and ompB) of this agent showed 99%-100% identity with sequences of Rickettsia parkeri.

[Rocky Mountain spotted fever in Mexican children: Clinical and mortality factors]. / Fiebre maculosa de las Montañas Rocosas en niños y adolescentes mexicanos: cuadro clínico y factores de mortalidad.

OBJECTIVE: Characterize clinical manifestations and predictors of mortality in children hospitalized for spotted fever. MATERIALS AND METHODS: Cross-sectional study in 210 subjects with a diagnosis of Rocky Mountain spotted fever (RMSF) in a pediatric hospital in Sonora, from January 1st, 2004 to June 30th, 2015. Data were analyzed using descriptive statistics and multivariate logistic regression. RESULTS: An upward trend was observed in RMSF morbidity and mortality. Fatality rate was 30%.Three predictors were associated with risk of death: delay ≥ 5 days at the start of doxycycline (ORa= 2.95, 95% CI 1.10-7.95), acute renal failure ((ORa= 8.79, 95% CI 3.46-22.33) and severe sepsis (ORa= 3.71, 95% CI 1.44-9.58). CONCLUSIONS: RMSF causes high mortality in children, which can be avoided with timely initiation of doxycycline. Acute renal failure and severe sepsis are two independent predictors of death in children with RMSF.

Utility of electrocorticography in the surgical treatment of cavernomas presenting with pharmacoresistant epilepsy.

AIM: To describe the general aspects of cavernomas and epilepsy and review the available literature on the utility of electrocorticography (ECoG) in cerebral cavernoma surgery. METHODS: We searched studies in PubMed, MedLine, Scopus, Web of Science, and Google Scholar (from January 1969 to December 2013) using the keywords "electrocorticography" or "ECoG" or "prognosis" or "outcome" and "cavernomas". Original articles that reported utility of ECoG in epilepsy surgery were included. Four review authors independently selected the studies, extracted data, and assessed the methodological quality of the studies using the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions, PRISMA guidelines, and Jadad Scale. A meta-analysis was not possible due to methodological, clinical, and statistical heterogeneity of included studies. We analysed six articles with a total of 219 patients. RESULTS: The most common surgical approach was lesionectomy using ECoG in the temporal lobe with Engel I outcome range from 72.7 to 100%. CONCLUSIONS: Small controlled studies suggest that ECoG-guided resection offers the best functional results in seizure control for subjects undergoing cavernoma surgery, especially in the temporal lobe.

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.

Indolent T-cell Lymphoproliferative Disorder of the Gastrointestinal Tract Mimicking Crohn's Disease.

Indolent clonal T-cell lymphoproliferative disorder (iCTLD-GI)/indolent T-cell lymphoma of the gastrointestinal tract (iTLP-GI) poses diagnostic challenges, and despite its rarity, accurate diagnosis is crucial for appropriate management. We report the case of 34-year-old female with a 19-year history of gastrointestinal symptoms suggestive of inflammatory bowel disease (IBD). Subsequent evaluation revealed iCTLD-GI/iTLP-GI with extensive Crohn's disease-like morphological alterations, previously unreported. These macroscopic and microscopic aspects underscore the need for a comprehensive evaluation to avoid misdiagnosis with IBD. Additionally, molecular studies have identified potential therapeutic targets, highlighting the evolving management strategies. This case underscores the diagnostic complexity of iCTLD-GI/iTLP-GI, especially when the condition mimicks IBD such as Crohn's disease.

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.

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.

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.