Distinctive genomic features of human T-lymphotropic virus type 1-related adult T-cell leukemia-lymphoma in Western populations.

Adult T-cell leukemia-lymphoma (ATLL) is an aggressive Human T-cell Leukemia Virus Type 1 (HTLV-1)-driven malignancy. Although Western hemisphere (Afro-Caribbean and South American) patients face worse prognoses, our understanding of ATLL molecular drivers derives mostly from Japanese studies. We performed multi-omic analyses to elucidate the genomic landscape of ATLL in Western cohorts. Recurrent deletion and/or damaging mutations involving FOXO3, ANKRD11, DGKZ, and PTPN6 implicate these genes as potential tumor suppressors. RNA-seq, published functional data and in vitro assays support the roles of ANKRD11 and FOXO3 as regulators of T-cell proliferation and apoptosis in ATLL, respectively. Survival data suggest ANKRD11 mutation may confer a worse prognosis. Japanese and Western cohorts, in addition to acute and lymphomatous subtypes, demonstrated distinct molecular patterns. GATA3 deletion was associated with unfavorable chronic cases. IRF4 and CARD11 mutations frequently emerged in relapses after interferon therapy. Our findings reveal novel putative ATLL driver genes and clinically relevant differences between Japanese and Western ATLL patients.

Evaluation of rapid antiretroviral initiation strategy in a cohort of newly diagnosed people living with HIV in Panama, 2018-2019.

Antiretroviral therapy (ART) has been adopted as a form of HIV treatment and prevention. This study assesses rapid ART initiation using clinical outcomes such as viral load (VL) and CD4+ T lymphocytes count. Over the course of one year, the progress of newly diagnosed people living with HIV who started ART early in a hospital in Panama City was followed. The evaluation of early initiation of ART in achieving viral suppression (VL <200 copies/ml) was analyzed using descriptive statistics. Additionally, the cost difference between early (first 7 days) and late initiation of ART was evaluated from the perspective of the service provider. In total, 209 people were followed up during the study; 85% were male, 70% started ART on same day from hospital arrival, 80% had suppressed viral load at 6 months, and the median count of CD4 increased from 285 (IQR: 166-429) to 509 (IQR: 373-696) over 12 months. Starting ART early led to a 42% increase for the provider in terms of staffing costs; however, the clients had the opportunity to decrease absenteeism in daily activities. The results reveal that early initiation of ART generates clinical and economic benefits for the person in treatment.

PLEKHA7 signaling is necessary for the growth of mutant KRAS driven colorectal cancer.

Plekha7 (Pleckstrin homology [PH] domain containing, family A member 7) regulates the assembly of proteins of the cytoplasmic apical zonula adherens junction (AJ), thus ensuring cell-cell adhesion and tight-junction barrier integrity. Little is known of Plekha7 function in cancer. In colorectal cancer (CRC) Plekha7 expression is elevated compared to adjacent normal tissue levels, increasing with clinical stage. Plekha7 was present at plasma membrane AJ with wild-type KRas (wt-KRas) but was dispersed in cells expressing mutant KRas (mut-KRas). Fluorescence lifetime imaging microscopy (FLIM) indicated a direct Plekha7 interaction with wt-KRas but scantily with mut-KRas. Inhibiting Plekha7 specifically decreased mut-KRas cell signaling, proliferation, attachment, migration, and retarded mut-KRAS CRC tumor growth. Binding of diC8-phosphoinositides (PI) to the PH domain of Plekha7 was relatively low affinity. This may be because a D175 amino acid residue plays a "sentry" role preventing PI(3,4)P2 and PI(3,4,5)P3 binding. Molecular or pharmacological inhibition of the Plekha7 PH domain prevented the growth of mut-KRas but not wt-KRas cells. Taken together the studies suggest that Plekha7, in addition to maintaining AJ structure plays a role in mut-KRas signaling and phenotype through interaction of its PH domain with membrane mut-KRas, but not wt-KRas, to increase the efficiency of mut-KRas downstream signaling.

Mutational profile and EBV strains of extranodal NK/T-cell lymphoma, nasal type in Latin America.

Extranodal NK/T-cell lymphoma (ENKTL) is an Epstein-Barr virus (EBV) associated lymphoma, prevalent in Asia and Latin America. Studies in Asian cohorts have identified some recurrent gene mutations in ENKTL; however, the mutational landscape of ENKTL in Latin America is unknown. In this study, we investigated the mutational profile and EBV strains of 71 ENKTL cases from Latin America (42 from Mexico, 17 from Peru, and 12 from Argentina) and compared it with Asian cohorts. The mutational analysis was performed by next generation sequencing (NGS) using an Ion AmpliSeq™ custom panel covering for the most frequently mutated genes identified in ENKTL. STAT3 was the most frequent mutated gene (16 cases: 23%), followed by MSN (10 cases; 14%), BCOR (9 cases; 13%), DDX3X (6 cases; 8%), TP53 (6 cases; 8%), MGA (3 cases; 4%), JAK3 (2 cases; 3%), and STAT5B (1 case; 1%). Mutations in STAT3, BCOR, and DDX3X were nearly mutually exclusive, suggesting different molecular pathways involved in the pathogenesis of ENKTL; whereas mutations in MGA, MSN, and TP53 were concomitant with other mutations. Most cases (75%) carried Type A EBV without the 30-bp LMP1 gene deletion. The overall survival was significantly associated with serum LDH level, Eastern Cooperative Oncology Group (ECOG) performance status, International Prognostic Index (IPI) score, and therapy (p < 0.05), but not associated with any mutation, EBV strain or deletion in EBV LMP1 gene. In conclusion, mutational analysis of ENKTL from Latin America reveals frequent gene mutations leading to activation of the JAK-STAT pathway (25%), mostly STAT3. Compared to Asian cohorts, BCOR, DDX3X and TP53 mutations were also identified but with different frequencies. None of these mutations were associated with prognosis.

[Undifferentiated (embryonal) liver sarcoma: reviaew of 6 cases in National Cancer Institute, Lima, Peru. Review of the literature]. / Sarcoma indiferenciado (embrionario) hepático: revisión de seis casos presentados en el Instituto Nacional de Enfermedades Neoplásicas. Revisión de la literatura.

Undifferentiated (embryonal) liver sarcoma is a rare tumor about 2% of all malignant liver tumors with a poor prognosis and usually occurs in children, this review aims to assess cases of primary embryonal sarcoma of the liver presented at our institution the past 8 years and improve recognition of its variants and evaluate immunohistochemical characteristics that help differentiated it from other tumors. Six cases of undifferentiated liver sarcoma were histologically evaluated and investigated by immunohistochemistry with a panel of antibodies using the equipment â€Å“Autostainer Link 48”. Usually masses were on average more than 20 cm, with solid, cystic, mucinous areas. The microscopic features include cells of spindle cell appearance, oval, starry, epithelioid and multinucleated cells densely arranged in a myxoid matrix. Trapped bile ducts and hepatic cords often present in the periphery of tumors. Intracellular and extracellular PAS positive hyaline globules. Immunohistochemistry showed very divergent differentiation.

Increased expression of CD70 in relapsed acute myeloid leukemia after hypomethylating agents.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While induction chemotherapy leads to remission in most patients, a significant number will experience relapse. Therefore, there is a need for novel therapies that can improve remission rates in patients with relapsed and refractory AML. CD70 is the natural ligand for CD27 (a member of the TNF superfamily) and appears to be a promising therapeutic target. Consequently, there is considerable interest in developing chimeric antigen receptor (CAR) T-cell therapy products that can specifically target CD70 in various neoplasms, including AML. In this study, we employed routine diagnostic techniques, such as immunohistochemistry and flow cytometry, to investigate the expression of CD70 in bone marrow samples from treatment-naïve and relapsed AML patients after hypomethylating agents (HMA). Also, we evaluated the impact of HMA on CD70 expression and examined CD70 expression in various leukemic cell subsets and normal hematopoietic progenitors.

Increased risk of hospitalization and death in Mexican children and adolescents with COVID-19 and comorbidities.

BACKGROUND: Although COVID-19 (coronavirus disease 2019) in children is usually mild, they need hospitalization and intensive care in exceptional cases. Adverse outcomes have been observed mainly among children with comorbidities, justifying their vaccination. This study aimed to assess the risk of hospitalization and death in Mexican children and adolescents with COVID-19 and comorbidities. METHODS: A cross-sectional study was performed on 366,542 confirmed COVID-19 cases under 18 years, reported by the Mexican Ministry of Health up to July 9, 2022. Logistic regression models were performed. RESULTS: The mean age was 10.98 years, 50.6% were male, and 7.3% reported at least one comorbidity. The percentage of hospitalization and death in COVID-19 patients with and without comorbidities was 3.52%, and 0.20%, respectively; children with comorbidities presented a higher percentage of hospitalization (14.0%) and death (1.9%). The probability of hospitalization was 5.6 times greater in pediatric patients with COVID-19 and comorbidities, and the comorbidities that showed the greatest risk were immunosuppression (odds ratio (OR) 22.06), chronic kidney disease (CKD) (11.36), and cardiovascular diseases (5.66). The probability of death in patients with comorbidities was 11.01 times higher than in those without diseases, and the highest risk was observed in those with CKD (OR 12.57), cardiovascular diseases (6.87), and diabetes (5.83). CONCLUSIONS: Pediatric patients with comorbidities presented a higher risk of severe COVID-19. It is suggested that vaccination should be promoted with greater emphasis on pediatric patients with comorbidities.

INTRODUCCIÓN: Aunque COVID-19 (enfermedad por coronavirus 2019) en niños es usualmente leve, en casos excepcionales requieren hospitalización y cuidados intensivos. Los resultados adversos han sido observados principalmente en los niños con comorbilidades, justificando su vacunación. El objetivo de este estudio fue evaluar el riesgo de hospitalización y muerte en niños y adolescentes mexicanos con COVID-19 y comorbilidades. MÉTODOS: Estudio transversal en 366,542 casos de COVID-19 confirmados, menores de 18 años y reportados por la Secretaría de Salud de México, hasta el 9 de julio del 2022. Se ejecutaron modelos multivariados de regresión logística. RESULTADOS: El promedio de edad fue de 10.98 años, 50.6% de sexo masculino, y 7.3% reportaron al menos una comorbilidad. El porcentaje de hospitalización y muerte en pacientes con COVID-19 sin comorbilidades fue 3.52% y 0.20%, respectivamente; mientras que los pacientes con comorbilidades presentaron más elevados porcentajes de hospitalización (14.0%) y muerte (1.9%). La probabilidad de hospitalización fue 5.6 veces más en los pacientes con COVID-19 y comorbilidades, comparando con aquellos sin comorbilidades. Las comorbilidades que mostraron más riesgo fueron inmunosupresión (razón de momios (RM) 22.06), enfermedad renal crónica (ERC) (RM 11.36) y enfermedades cardiovasculares (RM 5.66). La probabilidad de muerte en los pacientes con comorbilidades fue 11.01 veces más que en aquellos sin enfermedades, y fue más elevado en aquellos con ERC (RM 12.57), enfermedades cardiovasculares (RM 6.87) y diabetes (RM 5.83). CONCLUSIONES: Los pacientes pediátricos con comorbilidades presentaron mayor riesgo de COVID-19 severo, por lo que se sugiere promover con mayor énfasis la vacunación en ellos.

Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma.

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL. SIGNIFICANCE: Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival. This article is highlighted in the In This Issue feature, p. 85.

Effectiveness of a multidrug therapy consisting of Ivermectin, Azithromycin, Montelukast, and Acetylsalicylic acid to prevent hospitalization and death among ambulatory COVID-19 cases in Tlaxcala, Mexico.

OBJECTIVE: There is an urgent need for effective treatments to prevent or attenuate lung and systemic inflammation, endotheliitis, and thrombosis related to COVID-19. This study aimed to assess the effectiveness of a multidrug-therapy consisting of Ivermectin, Azithromycin, Montelukast, and Acetylsalicylic acid ("TNR4" therapy) to prevent hospitalization and death among ambulatory COVID-19 cases in Tlaxcala, Mexico. DESIGN AND METHODS: A comparative effectiveness study was performed among 768 confirmed SARS-CoV-2 cases aged 18-80 years, who received ambulatory care at the Ministry of Health of Tlaxcala. A total of 481 cases received the TNR4 therapy, while 287 received another treatment (comparison group). All participants received home visits and/or phone calls for clinical evaluation during the 14 days after enrollment. RESULTS: Nearly 85% of cases who received the TNR4 recovered within 14 days compared to 59% in the comparison group. The likelihood of recovery within 14 days was 3.4 times greater among the TNR4 group than in the comparison group. Patients treated with TNR4 had a 75% and 81% lower risk of being hospitalized or death, respectively, than the comparison group. CONCLUSIONS: TNR4 therapy improved recovery and prevented the risk of hospitalization and death among ambulatory COVID-19 cases.

Increased Risk of Hospitalization and Death in Patients with COVID-19 and Pre-existing Noncommunicable Diseases and Modifiable Risk Factors in Mexico.

BACKGROUND: The population in Mexico has high prevalence rates of noncommunicable diseases (NCDs). Hospitalization and death of COVID-19 patients in the countries most affected by the pandemic has been associated to chronic comorbidities. OBJECTIVE: To describe the prevalence of NCDs in patients with COVID-19 in Mexico and analyze the increased risk due to comorbidities and risk factors on hospitalization, utilization of intensive care units and death. METHODS: A cross-sectional study was performed from 212,802 confirmed COVID-19 cases reported by the Ministry of Health up to June 27, 2020. Odds ratios were performed using logistic regression model. RESULTS: Up to 47.40% of patients with COVID-19 diagnosis were also reported with a comorbidity, with hypertension being the most frequent (20.12%). The report of at least one NCD significantly increased the risk of death with respect to patients without such diagnoses. Chronic kidney disease increased the risk of death the most (OR 2.31), followed by diabetes (OR 1.69), immunosuppression (OR 1.62), obesity (OR 1.42), hypertension (OR 1.24), chronic obstructive pulmonary disease (OR 1.20). The comorbidities that most increased the risk of ICU and of intubation were diabetes, immunosuppression and obesity. CONCLUSION: NCD comorbidities increase the severity of COVID-19 infection. Given high NCD prevalence rates among the Mexican population, the pandemic poses a special threat to the health system and to society. Special prevention measures need to be strengthened for persons with NCD diagnoses in the short-term. In the mid-term, disease control strategies need to be improved to protect these patients against COVID-19 severity.

Increased risk of hospitalization and death in Mexican children and adolescents with COVID-19 and comorbidities / Riesgo incrementado de hospitalización y muerte en niños y adolescentes mexicanos con COVID-19 y comorbilidad

Abstract Background: Although COVID-19 (coronavirus disease 2019) in children is usually mild, they need hospitalization and intensive care in exceptional cases. Adverse outcomes have been observed mainly among children with comorbidities, justifying their vaccination. This study aimed to assess the risk of hospitalization and death in Mexican children and adolescents with COVID-19 and comorbidities. Methods: A cross-sectional study was performed on 366,542 confirmed COVID-19 cases under 18 years, reported by the Mexican Ministry of Health up to July 9, 2022. Logistic regression models were performed. Results: The mean age was 10.98 years, 50.6% were male, and 7.3% reported at least one comorbidity. The percentage of hospitalization and death in COVID-19 patients with and without comorbidities was 3.52%, and 0.20%, respectively; children with comorbidities presented a higher percentage of hospitalization (14.0%) and death (1.9%). The probability of hospitalization was 5.6 times greater in pediatric patients with COVID-19 and comorbidities, and the comorbidities that showed the greatest risk were immunosuppression (odds ratio (OR) 22.06), chronic kidney disease (CKD) (11.36), and cardiovascular diseases (5.66). The probability of death in patients with comorbidities was 11.01 times higher than in those without diseases, and the highest risk was observed in those with CKD (OR 12.57), cardiovascular diseases (6.87), and diabetes (5.83). Conclusions: Pediatric patients with comorbidities presented a higher risk of severe COVID-19. It is suggested that vaccination should be promoted with greater emphasis on pediatric patients with comorbidities.

Resumen Introducción: Aunque COVID-19 (enfermedad por coronavirus 2019) en niños es usualmente leve, en casos excepcionales requieren hospitalización y cuidados intensivos. Los resultados adversos han sido observados principalmente en los niños con comorbilidades, justificando su vacunación. El objetivo de este estudio fue evaluar el riesgo de hospitalización y muerte en niños y adolescentes mexicanos con COVID-19 y comorbilidades. Métodos: Estudio transversal en 366,542 casos de COVID-19 confirmados, menores de 18 años y reportados por la Secretaría de Salud de México, hasta el 9 de julio del 2022. Se ejecutaron modelos multivariados de regresión logística. Resultados: El promedio de edad fue de 10.98 años, 50.6% de sexo masculino, y 7.3% reportaron al menos una comorbilidad. El porcentaje de hospitalización y muerte en pacientes con COVID-19 sin comorbilidades fue 3.52% y 0.20%, respectivamente; mientras que los pacientes con comorbilidades presentaron más elevados porcentajes de hospitalización (14.0%) y muerte (1.9%). La probabilidad de hospitalización fue 5.6 veces más en los pacientes con COVID-19 y comorbilidades, comparando con aquellos sin comorbilidades. Las comorbilidades que mostraron más riesgo fueron inmunosupresión (razón de momios (RM) 22.06), enfermedad renal crónica (ERC) (RM 11.36) y enfermedades cardiovasculares (RM 5.66). La probabilidad de muerte en los pacientes con comorbilidades fue 11.01 veces más que en aquellos sin enfermedades, y fue más elevado en aquellos con ERC (RM 12.57), enfermedades cardiovasculares (RM 6.87) y diabetes (RM 5.83). Conclusiones: Los pacientes pediátricos con comorbilidades presentaron mayor riesgo de COVID-19 severo, por lo que se sugiere promover con mayor énfasis la vacunación en ellos.

Manejo de neoplasias oncohematológicas en el contexto de la pandemia de COVID-19: recomendación de expertos / Management of oncohematological neoplasms in the COVID-19 pandemic: experts recommendation

RESUMEN La pandemia por COVID-19 originado por el Coronavirus 2 causante de síndrome respiratorio agudo severo (SARS-CoV-2) es causante de una crisis de salud pública a nivel global. Muchos reportes indican resultados desalentadores en pacientes con cáncer respecto a la población general. Por ello, los expertos en el manejo de neoplasias oncohematológicas del Instituto Nacional de Enfermedades Neoplásicas, hospitales nacionales y una clínica privada de Lima Metropolitana han desarrollado recomendaciones obtenidas por consenso para continuar con el manejo de pacientes con neoplasias oncohematológicas en forma segura ante la coyuntura de pandemia.

ABSTRACT The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global public health crisis. Many reports indicate disappointing results in cancer patients compared to the general population. Therefore, experts in the management of oncohematological malignancies from the National Institute of Neoplastic Diseases, national hospitals and a private clinic in Metropolitan Lima have developed recommendations obtained by consensus to continue with the management of patients with oncohematological neoplasms safely in the face of the pandemic.

Sarcoma indiferenciado (embrionario) hepático: revisión de seis casos presentados en el Instituto Nacional de Enfermedades Neoplásicas. Revisión de la literatura / Undifferentiated (embryonal) liver sarcoma: review of 6 cases in National Cancer Institute, Lima, Peru. Review of the literature

El sarcoma indiferenciado (embrionario) hepático es un tumor poco frecuente, alrededor del 2% de todos los tumores malignos del hígado, con un pobre pronóstico y usualmente se presenta en niños, la presente revisión tiene como objetivo evaluarlos casos de sarcoma embrionario primario de hígado presentados en nuestra institución los 8 últimos años y mejorar el reconocimiento de sus variantes y evaluar sus características inmunohistoquímicas que ayuden a diferenciarlo de otros tumores. Seis casos de sarcoma indiferenciado hepático fueron evaluados histológicamente e investigados por inmunohistoquímica con un panel de anticuerpos utilizando el equipo ôAutostainer Link 48õ. Por lo general eran grandes masas en promedio mayor de 20 cm, con áreas sólidas, quísticas y gelatinosas. Las características microscópicas incluyen células de aspecto fusocelular, oval, estrellada, epitelioide o células multinucleadas densamente dispuestos en una matriz mixoide. Conductos biliares atrapados y cordones hepáticos a menudo presentes en la periferia de los tumores. Glóbulos hialinos intracelulares y extracelulares PAS positivos. La inmunohistoquímica mostró diferenciación muy divergente...

Undifferentiated (embryonal) liver sarcoma is a rare tumor about 2% of all malignant liver tumors with a poor prognosis and usually occurs in children, this review aims to assess cases of primary embryonal sarcoma of the liver presented at our institution the past 8 years and improve recognition of its variants and evaluate immunohistochemical characteristics that help differentiated it from other tumors. Six cases of undifferentiated liver sarcoma were histologically evaluated and investigated by immunohistochemistry with a panel of antibodies using the equipment ôAutostainer Link 48õ. Usually masses were on average more than 20 cm, with solid, cystic, mucinous areas. The microscopic features include cells of spindle cell appearance, oval, starry, epithelioid and multinucleated cells densely arranged in a myxoid matrix. Trapped bile ducts and hepatic cords often present in the periphery of tumors. Intracellular and extracellular PAS positive hyaline globules. Immunohistochemistry showed very divergent differentiation...