Kaposi sarcoma in three pediatric liver transplantation recipients.

BACKGROUND: Kaposi sarcoma (KS) is an endothelial cell tumor, rare in children. It is 200 times more frequent after solid organ transplantation than in the general population. METHODS: We report three cases of pediatric patients who developed KS after liver transplantation (LT). RESULTS: Case 1, a 4-year-old boy undergoing LT due to familial intrahepatic cholestasis. Five months after LT, he presented with fever, dyspnea, and cough with enlarged lymph nodes and splenomegaly, anemia, thrombocytopenia, elevated liver enzymes, and positive EBV viral load. Lymph node biopsy diagnosed KS with an elevated HHV8 viral load. Case 2, a 4-year-old boy who underwent LT due to secondary biliary cirrhosis resulting from extrahepatic biliary atresia. Two years later, graft dysfunction was noticed with positive EBV viral load, thrombocytopenia, massive cervical lymph node enlargement, and splenomegaly. Lymph node biopsy diagnosed KS, Castleman's disease, and plasmablastic lymphoma related to HHV8 infection. Case 3, a 15-month-old girl, who received two LT due to biliary cirrhosis. Six months later, she presented with diarrhea, abdominal distension, anemia, thrombocytopenia, enlarged lymph nodes, splenomegaly, and positive CMV viral load. Axillary lymph node biopsy diagnosed KS and HHV8 infection was confirmed. In all three cases, tacrolimus was discontinued and, after diagnosis, sirolimus was started. All recovered without relapse and have a good graft function. CONCLUSIONS: Kaposi sarcoma is a rare disease post-LT in children. Recognizing keywords and early diagnosis is crucial for timely treatment and survival.

Clinical and Pathological Features of Double-Hit and Triple-Hit High-Grade B-Cell Lymphomas: A Retrospective Study from Three Portuguese Tertiary Centers.

Background: High-grade B-cell lymphoma (HGBL) with rearrangements of MYC and BCL2 and/or BCL6, called double and triple-hit lymphomas (DTH-HGBL), are lymphoid malignancies with inferior outcomes when treated with standard chemotherapy. The identification of DTH-HGBL cases is challenging, considering their variable clinical, morphologic, and immunohistochemical features. Materials and Methods: Retrospective revision of medical data of patients diagnosed with DTH-HGBL confirmed by FISH, between January 2010 and January 2020, in three Tertiary Portuguese Hospitals (Coimbra Hospital and University Center, Portuguese Oncology Institute - Coimbra and Portuguese Oncology Institute - Porto). Pathological features, morphology, and immunohistochemical profile were evaluated by at least two experienced pathologists in hematopoietic and lymphoid neoplasms. Results: The cohort included 24 patients: 33.3% triple-hit, 58.3%, MYC/BCL2 double-hit and 8.3% MYC/BCL6 double-hit. There was no gender predominance, with a median age of 62.5±14.3y, 33.3% were diagnosed as nodal disease, and 66.7% as extranodal. Morphologic features of DLBCL were present in 50% of cases, morphological features of both DLBCL and Burkitt lymphoma (DLBCL/BL) in 45.8% and 4.2% of blastoid morphology. Immunohistochemical evaluation, regarding the Hans algorithm, revealed a Germinal center (GC)/GC-like subtype in 83.3% of cases and a non-GC/non-GC-like subtype in 16.7%.  MYC was positive in 42.9% and the median proliferative index was 80±12.4%. Conclusion: DTH-HGBL has a very broad range of features. We consider that a cost-effective approach would be to perform cytogenetic analysis in DLBCL and DLBCL/BL cases with GC/GC-like subtype. MYC and BCL2 immunohistochemistry can be useful to identify patients who may benefit from more aggressive therapies, but not as tools for case selection for FISH.

Lymphocyte-Depleted Hodgkin's Lymphoma in Coeliac Disease: A Diagnostic Challenge During the COVID-19 Pandemic.

A 51-year-old woman presented with constitutional symptoms, polydipsia, early satiety, nausea, vomiting, and a pruritic vesicular rash. On physical examination, she was febrile, had low peripheral oxygen saturation in room air (91%), hepatomegaly, lower limb edema, and palpable cervical adenopathies. She was hospitalized for diagnostic investigations and treatment. An autoimmune panel was requested which was positive for anti-parietal gastric cell, anti-endomysial, and anti-tissue transglutaminase antibodies, raising the suspicion for coeliac disease (CD). Gastric and duodenal biopsies were not diagnostic for CD, which was compatible with necrolytic migratory erythema similar to the vesicular rash biopsy. Thoracic-abdomino-pelvic computed tomography scan and fludeoxyglucose F18-positron emission tomography identified supra- and infra-diaphragmatic hypermetabolic adenopathies, with hypermetabolic activity in the lungs, suggestive of pulmonary lymphomatous involvement. Fine-needle aspiration of one supraclavicular adenopathy was performed but was not enough for histological diagnosis. The patient's respiratory insufficiency worsened and she died on day 63 of hospitalization. The final diagnosis was achieved on an anatomopathological autopsy that showed lymphocyte-depleted Hodgkin's lymphoma. The association of CD with other lymphomas besides enteropathy-type T-cell lymphoma is not clear. There is no clear relationship between CD and lymphocyte-depleted Hodgkin's lymphoma, which is the rarest subtype of classic Hodgkin's lymphoma and, by itself, has a very poor prognosis. This case highlights the challenge in diagnosis and significant delay due to isolation associated with coronavirus disease 2019 infection.

Methotrexate-Associated Lymphoproliferative Disorder in a Patient with Psoriasis: A Case Report and Review of the Literature.

Iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPDs) are heterogeneous clinicopathological entities developing in patients receiving immunosuppression. Outside the posttransplant setting, methotrexate (MTX), a drug commonly used for the treatment of autoimmune diseases, is an immunosuppressive agent frequently reported to be associated with LPD. MTX-associated LPD (MTX-LPD) includes a spectrum of lymphocytic proliferations, ranging from polyclonal hyperplasia to malignant lymphoma. MTX-LPD diagnosis can be challenging, as signs and symptoms are often nonspecific and may overlap with those of several other conditions, including exacerbation of the underlying autoimmune disease. Spontaneous regression of LPD after MTX discontinuation is characteristic of MTX-LPD, therefore avoiding chemotherapeutic intervention in a significant proportion of patients. Other cases, however, should receive chemotherapy.

Erdheim-Chester disease: a rare non-Langerhans histiocytosis.

A 3-year-old girl was admitted to our hospital with diabetes insipidus and a left eye proptosis. During investigation of diabetes insipidus, an extensive osteolytic mass, involving skull base and maxillo-facial bones, was revealed. Biopsy exhibited dense infiltrate of foamy histiocytes, which were positive for CD68 and CD163 and negative for CD1a and S100 confirming histopathological diagnosis of Erdheim-Chester disease. Treatment with dabrafenib was initiated, with good response and no side effects.

An unusual case of parotid gland B-cell lymphoma complicating Sjögren Syndrome / Un caso inusual de linfoma de células B de la glándula parótida a complicar el Síndrome de Sjögren

Sjögren Syndrome is a multisystemic autoimmune disease that is heterogeneous in its presentation, course and outcome. There is no single clinical, laboratorial or radiological feature that serves as gold standard for the diagnosis and/or classification of this syndrome. The occurrence of lymphoma is known to be one of the most severe complications. We report a case of a 66-year-old female diagnosed with Sjögren Syndrome secondary to systemic lupus erythematous that presented with an enlargement of the left parotid gland consistent with the diagnosis of lymphoma confirmed with biopsy. She received chemotherapy with favorable response and today is asymptomatic with hydroxychloroquine 400mg id. This case report highlights the importance of optimal interventions and active surveillance of Sjogren Syndrome, in order to achieve an early identification of its complications and to prevent worse outcomes of this disease

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CitrusKB: a comprehensive knowledge base for transcriptome and interactome of Citrus spp. infected by Xanthomonas citri subsp. citri at different infection stages.

Citrus canker type A is a serious disease caused by Xanthomonas citri subsp. citri (X. citri), which is responsible for severe losses to growers and to the citrus industry worldwide. To date, no canker-resistant citrus genotypes are available, and there is limited information regarding the molecular and genetic mechanisms involved in the early stages of the citrus canker development. Here, we present the CitrusKB knowledge base. This is the first in vivo interactome database for different citrus cultivars, and it was produced to provide a valuable resource of information on citrus and their interaction with the citrus canker bacterium X. citri. CitrusKB provides tools for a user-friendly web interface to let users search and analyse a large amount of information regarding eight citrus cultivars with distinct levels of susceptibility to the disease, with controls and infected plants at different stages of infection by the citrus canker bacterium X. citri. Currently, CitrusKB comprises a reference citrus genome and its transcriptome, expressed transcripts, pseudogenes and predicted genomic variations (SNPs and SSRs). The updating process will continue over time by the incorporation of novel annotations and analysis tools. We expect that CitrusKB may substantially contribute to the field of citrus genomics. CitrusKB is accessible at http://bioinfo.deinfo.uepg.br/citrus. Users can download all the generated raw sequences and generated datasets by this study from the CitrusKB website.

A Genomic and Transcriptomic Overview of MATE, ABC, and MFS Transporters in Citrus sinensis Interaction with Xanthomonas citri subsp. citri.

The multi-antimicrobial extrusion (MATE), ATP-binding cassette (ABC), and major facilitator superfamily (MFS) are the main plant transporters families, playing an essential role in the membrane-trafficking network and plant-defense mechanism. The citrus canker type A (CC), is a devastating disease caused by Xanthomonas citri subsp. citri (Xac), affecting all citrus species. In this work, we performed an in silico analysis of genes and transcripts from MATE, ABC, and MFS families to infer the role of membrane transporters in Citrus-Xac interaction. Using as reference, the available Citrus sinensis genome and the citrus reference transcriptome from CitrusKB database, 67 MATE, 91 MFS, and 143 ABC genes and 82 MATE, 139 MFS, and 226 ABC transcripts were identified and classified into subfamilies. Duplications, alternative-splicing, and potentially non-transcribed transporters' genes were revealed. Interestingly, MATE I and ABC G subfamilies appear differently regulated during Xac infection. Furthermore, Citrus spp. showing distinct levels of CC susceptibility exhibited different sets of transporters transcripts, supporting dissimilar molecular patterns of membrane transporters in Citrus-Xac interaction. According to our findings, 4 MATE, 10 ABC, and 3 MFS are potentially related to plant-defense mechanisms. Overall, this work provides an extensive analysis of MATE, ABC, and MFS transporters' in Citrus-Xac interaction, bringing new insights on membrane transporters in plant-pathogen interactions.

The Terrestrial Carnivorous Plant Utricularia reniformis Sheds Light on Environmental and Life-Form Genome Plasticity.

Utricularia belongs to Lentibulariaceae, a widespread family of carnivorous plants that possess ultra-small and highly dynamic nuclear genomes. It has been shown that the Lentibulariaceae genomes have been shaped by transposable elements expansion and loss, and multiple rounds of whole-genome duplications (WGD), making the family a platform for evolutionary and comparative genomics studies. To explore the evolution of Utricularia, we estimated the chromosome number and genome size, as well as sequenced the terrestrial bladderwort Utricularia reniformis (2n = 40, 1C = 317.1-Mpb). Here, we report a high quality 304 Mb draft genome, with a scaffold NG50 of 466-Kb, a BUSCO completeness of 87.8%, and 42,582 predicted genes. Compared to the smaller and aquatic U. gibba genome (101 Mb) that has a 32% repetitive sequence, the U. reniformis genome is highly repetitive (56%). The structural differences between the two genomes are the result of distinct fractionation and rearrangements after WGD, and massive proliferation of LTR-retrotransposons. Moreover, GO enrichment analyses suggest an ongoing gene birth-death-innovation process occurring among the tandem duplicated genes, shaping the evolution of carnivory-associated functions. We also identified unique patterns of developmentally related genes that support the terrestrial life-form and body plan of U. reniformis. Collectively, our results provided additional insights into the evolution of the plastic and specialized Lentibulariaceae genomes.

(Cyto)genomic and epigenetic characterization of BICR 10 cell line and three new established primary human head and neck squamous cell carcinoma cultures.

BACKGROUND: Head and neck squamous cell carcinoma cell lines are useful preclinical models to understand the molecular processes underlying the development of such tumors, and to establish targeted therapies. OBJECTIVE: We performed a comprehensive (cyto)genomic and epigenetic characterization of three new established primary human head and neck squamous cell carcinoma cultures and an established, yet undercharacterized cell line: BICR 10. METHODS: Karyotyping, multiplex fluorescence in situ hybridization, array comparative genomic hybridization and methylation-specific multiplex ligation-dependent probe amplification were applied. RESULTS: The three primary cultures turned out to be a near-triploid and BICR 10 near-diploid. Banding and molecular cytogenetic analysis revealed non-random numerical and structural aberrations. The most common rearrangements identified in BICR 10 cell line were non-complex derivatives of reciprocal translocations, in which the breakpoints often appeared in centromeric/near-centromeric regions. In the 3 primary cell cultures the most common rearrangements observed were iso- and derivatives chromosomes derived from translocations. Overall, gains of 7p, 8q and losses at 3p, 8p, 9p, 18q and Xp were present in all four studied samples. Among the analyzed genes, BICR 10 cell line exhibited enhanced methylation of gene promoter; however, in all studied samples PAX5, WT1 and GATA5 were methylated. CONCLUSION: The here reported comprehensive characterization of BICR 10 cell line and the new established cultures enriches the resources available for head and neck cancer research, especially for testing therapeutic agents.

Genomic and epigenetic characterization for the comparison of synchronous bilateral tongue squamous cell carcinomas-A case report.

The tongue is the most common and aggressive site for tumors in the oral cavity. These tumors are usually located in the lateral border of the tongue and are often related to the use of tobacco and alcohol. Clinical management of these tumors is predominantly based on anatomic location and TNM classification. The identification of molecular signatures with ability to explain the different outcomes observed in these patients is of paramount importance to guide and help their management. CASE PRESENTATION: we herein describe an 88-year-old woman diagnosed with synchronous bilateral tongue carcinoma. This woman did not present the traditional risk factors related to oral cancer-alcohol, tobacco, or presence of human papiloma virus (HPV). Both tumors were classified by a pathologist as pT2. This patient was submitted to surgery, 6 months later was diagnosed with cervical metastasis and in the following 2 months died. Copy number alterations and methylation status of these 2 simultaneous tumors were analyzed using array comparative genomic hybridization, multiplex ligation-dependent probe amplification, and methylation specific multiplex ligation-dependent probe amplification. In conclusion, in both tumors we identified several molecular traits usually found among oral cavity tumors and some of those have been associated with clinical outcome, reinforcing their importance to accurately establish biomarkers with clinical applicability. Specific genomic and epigenetic signatures for each of these 2 tumors were also observed allowing their molecular discrimination. The tumor of the right side of the tongue exhibited more copy number gains than the tumor of the left side. In the left side tumor less and smaller copy number alterations and more methylated genes were observed, which could be indicative of an early phase of tumor development. This case shows the molecular heterogeneity of oral cavity tumors even in the same patient and anatomic site, which could be the key to explain the different outcomes of oral tumor patients.

Genetic and epigenetic characterization of the tumors in a patient with a tongue primary tumor, a recurrence and a pharyngoesophageal second primary tumor.

BACKGROUND: The choice of therapeutic modality for oral carcinoma in recurrent or second primary tumors remains controversial, as the treatment modalities available might be reduced by the treatment of the first tumor, and the overall survival is lower when compared with patients with a single or first tumor. Identifying biomarkers that predict the risk of relapse and the response to treatment is an emerging clinical issue. CASE PRESENTATION: A Caucasian 49-years-old man was treated with chemotherapy followed by chemoradiotherapy for a primary left side tongue tumor, achieving a complete response. After 49-months of follow-up, a local recurrence was diagnosed. After 3 months, a second primary tumor at the pharyngoesophageal region was detected. Genomic and epigenetic characterization of these three tumors was performed using array Comparative Genomic Hybridization, Multiplex Ligation-dependent Probe Amplification (MLPA) and Methylation Specific MLPA. RESULTS: The three tumors of this patient shared several imbalances in all chromosomes excluding chromosomes 9, 20 and 22, where genes related to important functional mechanisms of tumorigenesis are mapped. The shared genomic imbalances, such as losses at 1p, 2p, 3p, 4q, 5q, 6q, 7q, 8p, 10p, 11q, 12p, 12q, 13q, 15q, 16p, 16q, 17p, 17q, 18q, 19p, 19q, 21q and Xp and gains at 3q, 7q, 14q and 15q showed a common clonal origin for the diagnosed relapses. We identified some chromosomal imbalances and genes mapped in the chromosomes 2, 3, 4, 6, 7, 11, 14, 17, 18 and 22 as putative linked to chemoradioresistance and chemoradiosensitivity. We also observed that gains in short arm of chromosomes 6, 7, 8 and 18 were acquired after treatment of the primary tumor. We identified losses of VHL gene and promoter methylation of WT1 and GATA5 genes, as predictors of relapses. CONCLUSIONS: A common clonal origin for the diagnosed relapses was observed and we identified some putative candidate biomarkers of prognosis, relapse risk and treatment response that could guide the development of management strategies for these patients.

Primary gastric plasmacytoma: a rare entity.

Extramedullary plasmacytomas (EP) are tumours composed by a monoclonal population of plasma cells that arise in extraosseus tissues, comprising <5% of all plasma cell neoplasms. Usually, EP arise in the head and neck region, and the stomach is the second most common location-gastric plasmacytoma (GP). Clinical and radiological manifestations are unspecific and may mimic other tumours like gastric adenocarcinomas, gastric stromal tumours and lymphomas, mainly marginal cell lymphoma (MALT lymphoma) and usually definitive diagnosis is provided by pathological evaluation. We present a case of primary GP, discovered incidentally as a polypoid lesion. Tumour was composed by sheets of mature and immature plasmocytes positive for CD138 on immunohistochemistry, without Helicobacter pylori identification. The patient is alive 6 years later and without tumour relapse.

WT1, MSH6, GATA5 and PAX5 as epigenetic oral squamous cell carcinoma biomarkers - a short report.

PURPOSE: Oral squamous cell carcinoma (OSCC) is a frequently occurring aggressive malignancy with a heterogeneous clinical behavior. Based on the paucity of specific early diagnostic and prognostic biomarkers, which hampers the appropriate treatment and, ultimately the development of novel targeted therapies, we aimed at identifying such biomarkers through a genetic and epigenetic analysis of these tumors. METHODS: 93 primary OSCCs were subjected to DNA copy number alteration (CNA) and methylation status analyses using methylation-specific multiplex ligation-dependent probe amplification (MS-MPLA). The genetic and epigenetic OSCC profiles obtained were associated with the patients' clinic-pathological features. RESULTS: We found that WT1 gene promoter methylation is a predictor of a better prognosis and that MSH6 and GATA5 gene promoter methylation serve as predictors of a worse prognosis. GATA5 gene promoter methylation was found to be significantly associated with a shorter survival rate. In addition, we found that PAX5 gene promoter methylation was significantly associated with tongue tumors. To the best of our knowledge, this is the first study that highlights this specific set of genes as epigenetic diagnostic and prognostic biomarkers in OSCC. CONCLUSIONS: Our data highlight the importance of epigenetically assessing OSCCs to identify key genes that may serve as diagnostic and prognostic biomarkers and, potentially, as candidate therapeutic targets.

Genetic imbalances detected by multiplex ligation-dependent probe amplification in a cohort of patients with oral squamous cell carcinoma-the first step towards clinical personalized medicine.

Oral tumors are a growing health problem worldwide; thus, it is mandatory to establish genetic markers in order to improve diagnosis and early detection of tumors, control relapses and, ultimately, delineate individualized therapies. This study was the first to evaluate and discuss the clinical applicability of a multiplex ligation-dependent probe amplification (MLPA) probe panel directed to head and neck cancer. Thirty primary oral squamous cell tumors were analyzed using the P428 MLPA probe panel. We detected genetic imbalances in 26 patients and observed a consistent pattern of distribution of genetic alterations in terms of losses and gains for some chromosomes, particularly for chromosomes 3, 8, and 11. Regarding the latter, some specific genes were highlighted due to frequent losses of genetic material--RARB, FHIT, CSMD1, GATA4, and MTUS1--and others due to gains--MCCC1, MYC, WISP1, PTK2, CCND1, FGF4, FADD, and CTTN. We also verified that the gains of MYC and WISP1 genes seem to suggest higher propensity of tumors localized in the floor of the mouth. This study proved the value of this MLPA probe panel for a first-tier analysis of oral tumors. The probemix was developed to include target regions that have been already shown to be of diagnostic/prognostic relevance for oral tumors. Furthermore, this study emphasized several of those specific genetic targets, suggesting its importance to oral tumor development, to predict patients' outcomes, and also to guide the development of novel molecular therapies.

Genetic gains and losses in oral squamous cell carcinoma: impact on clinical management.

PURPOSE: The identification of genetic markers associated with oral cancer is considered essential to improve the diagnosis, prognosis, early tumor and relapse detection and, ultimately, to delineate individualized therapeutic approaches. Here, we aimed at identifying such markers. METHODS: Multiplex Ligation-dependent Probe Amplification (MLPA) analyses encompassing 133 cancer-related genes were performed on a panel of primary oral tumor samples and its corresponding resection margins (macroscopically tumor-free tissue) allowing, in both types of tissue, the detection of a wide arrange of copy number imbalances on various human chromosomes. RESULTS: We found that in tumor tissue, from the 133 cancer-related genes included in this study, those that most frequently exhibited copy number gains were located on chromosomal arms 3q, 6p, 8q, 11q, 16p, 16q, 17p, 17q and 19q, whereas those most frequently exhibiting copy number losses were located on chromosomal arms 2q, 3p, 4q, 5q, 8p, 9p, 11q and 18q. Several imbalances were highlighted, i.e., losses of ERBB4, CTNNB1, NFKB1, IL2, IL12B, TUSC3, CDKN2A, CASP1, and gains of MME, BCL6, VEGF, PTK2, PTP4A3, RNF139, CCND1, FGF3, CTTN, MVP, CDH1, BRCA1, CDKN2D, BAX, as well as exon 4 of TP53. Comparisons between tumor and matched macroscopically tumor-free tissues allowed us to build a logistic regression model to predict the tissue type (benign versus malignant). In this model, the TUSC3 gene showed statistical significance, indicating that loss of this gene may serve as a good indicator of malignancy. CONCLUSIONS: Our results point towards relevance of the above mentioned cancer-related genes as putative genetic markers for oral cancer. For practical clinical purposes, these genetic markers should be validated in additional studies.

Rupture of splenic angiosarcoma: a rare cause of spontaneous haemoperitoneum.

Primary splenic angiosarcoma, a very rare mesenchymal tumour of endothelial cell origin, comprises 2.6% of all cases of angiosarcoma and 10% of all primitive splenic tumours. Clinical presentation is usually unspecific, with abdominal pain and anaemia. Rupture is a rare complication and should prompt emergency splenectomy. Prognosis is usually poor because of liver, lung or bone metastases. We describe the case of an 80-year-old woman admitted to the emergency room with syncope, hypotension and vomiting. She stabilised after fluid resuscitation. Investigations showed anaemia, a large, heterogeneous spleen and free fluid in the abdominal cavity. She underwent emergency splenectomy. Pathology revealed primary splenic angiosarcoma. The postoperative period was complicated by respiratory failure but the patient made an otherwise uneventful course and was discharged 2 weeks after surgery. Six months after the operation she remains free of disease with no adjuvant treatment.