The inhibitory and transcriptional effects of the epigenetic repurposed drugs hydralazine and valproate in lymphoma cells.

Lymphoma is a disease that affects countless lives each year. In order to combat this disease, researchers have been exploring the potential of DNMTi and HDACi drugs. These drugs target the cellular processes that contribute to lymphomagenesis and treatment resistance. Our research evaluated the effectiveness of a combination of two such drugs, hydralazine (DNMTi) and valproate (HDACi), in B-cell and T-cell lymphoma cell lines. Here we show that the combination of hydralazine and valproate decreased the viability of cells over time, leading to the arrest of cell-cycle and apoptosis in both B and T-cells. This combination of drugs proved to be synergistic, with each drug showing significant growth inhibition individually. Microarray analyses of HuT 78 and Raji cells showed that the combination of hydralazine and valproate resulted in the up-regulation of 562 and 850 genes, respectively, while down-regulating 152 and 650 genes. Several proapoptotic and cell cycle-related genes were found to be up-regulated. Notably, three and five of the ten most up-regulated genes in HuT 78 and Raji cells, respectively, were related to immune function. In summary, our study suggests that the combination of hydralazine and valproate is an effective treatment option for both B- and T-lymphomas. These findings are highly encouraging, and we urge further clinical evaluation to validate our research and potentially improve lymphoma treatment.

Central nervous system international prognostic index impacts overall survival in diffuse large b-cell lymphoma treated with r-chop in a third level cancer center from Mexico: a survey of 642 patients

Background: Central nervous system international prognosis index (CNS-IPI) is validated in European and the USA cancer databases. However, no validation has been done in Mexican population. Objective: The objective of the study was to assess the impact of the CNS-IPI on central nervous system (CNS) relapse and survival in Mexican patients with diffuse large B-cell lymphoma (DLBCL). Methods: In this retrospective analysis, clinical, biochemical, and histological variables and the CNS-IPI were analyzed. Results: Six hundred and forty-two patients with DBLCL were included in the study. The mean ± SD age was 56.8 ± 14.9 years. Most had an ECOG of 0-1: 75% (n = 484) had absence of B-symptoms and advanced disease (clinical stage: III-IV, n = 433, 67.4%). According to the CNS-IPI, almost one-half were in the low-risk category. According to the CNS-IPI, CNS relapse rate was 1.36% (95% CI: 83.2-92.8), 3.1% (95% CI: 132.4-162.8), and 7.4% (95% CI 61-91) for patients in the low-, intermediate-, and high-risk categories, respectively. The median overall survival in the high-risk group (CNS-IPI) was 22 months, and it has not been achieved after 80 months of follow-up for the other groups. Conclusions: CNS-IPI was associated with survival; therefore, we propose its use as a prognostic tool for prospective validation.

A Cohort Study of the Prognostic Impact of Exon-16 EZH2 Mutations in a Mexican-Mestizo Population of Patients with Diffuse Large B-Cell Lymphoma.

BACKGROUND: Novel prognostic factors in patients with diffuse large B-cell lymphoma (DLBCL) are required in the era of Rituximab. OBJECTIVE: The objective of the study was to study the prognostic impact of exon-16 enhancer-of-zeste homolog-2 (EZH2) mutations in patients with DLBCL. METHODS: In a cohort of patients with DLBCL treated between 2015 and 2017, we analyzed the presence of EZH2 mutations and their association with clinical response (CR), relapse, progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 198 patients were included; of them, 30 (15.2%) had mutations at codon 641, in exon 16 of EZH2. Response was achieved in 151 patients (76.3%), and 43 (21.7%) relapsed or progressed during follow-up. EZH2 mutations were associated with relapse/progression (risk ratio [RR] 1.18; 95% confidence interval [CI] 0.98-1.42; p = 0.031), while a trend for not achieving a complete response was observed (RR: 0.876; 95%CI 0.74-1.038; p = 0.071). Of note, Tyr641His and Tyr641Ser EZH2 mutations were associated with shorter PFS (hazard ratio 3.234; 95% CI 1.149-9.1; p = 0.026). CONCLUSION: The presence of EZH2 mutations was negatively associated with relapse/progression and showed a trend for lack of complete response. Further studies are needed to define better the prognostic significance of these mutations in Mexican-Mestizo DLBCL patients.

Central Nervous System International Prognostic Index Impacts Overall Survival in Diffuse Large B-cell Lymphoma Treated with R-Chop in a third Level Cancer Center from Mexico: A Survey of 642 Patients.

BACKGROUND: Central nervous system international prognosis index (CNS-IPI) is validated in European and the USA cancer databases. However, no validation has been done in Mexican population. OBJECTIVE: The objective of the study was to assess the impact of the CNS-IPI on central nervous system (CNS) relapse and survival in Mexican patients with diffuse large B-cell lymphoma (DLBCL). METHODS: In this retrospective analysis, clinical, biochemical, and histological variables and the CNS-IPI were analyzed. RESULTS: Six hundred and forty-two patients with DBLCL were included in the study. The mean ± SD age was 56.8 ± 14.9 years. Most had an ECOG of 0-1: 75% (n = 484) had absence of B-symptoms and advanced disease (clinical stage: III-IV, n = 433, 67.4%). According to the CNS-IPI, almost one-half were in the low-risk category. According to the CNS-IPI, CNS relapse rate was 1.36% (95% CI: 83.2-92.8), 3.1% (95% CI: 132.4-162.8), and 7.4% (95% CI 61-91) for patients in the low-, intermediate-, and high-risk categories, respectively. The median overall survival in the high-risk group (CNS-IPI) was 22 months, and it has not been achieved after 80 months of follow-up for the other groups. CONCLUSIONS: CNS-IPI was associated with survival; therefore, we propose its use as a prognostic tool for prospective validation.

Late-Onset Hematological Toxicity (LOHT) in Patients with B-Cell Lymphomas: A Survey in 758 Cases

ABSTRACT Background: The increasing survival of patients with non-Hodgkin lymphoma has allowed the diagnosis of long-term complications, including late-onset hematological toxicity (LOHT), transitory cytopenias, or therapy-related myeloid neoplasm (t-MDS/t-AML). Objective: The objective of the study was to determine the frequency and clinical evolution of LOHT in patients with lymphoproliferative malignancies. Materials and Methods: Two cohorts of patients B-cell lymphomas were reviewed. Patients who achieved full hematologic recovery at the end of treatment, and thereafter developed any degree of cytopenia were included in the study. Clinical and biochemical parameters were compared between patients with and without cytopenias with X2 test. Bi- and multivariate analyses were performed to evaluate factors associated with the development of late-onset cytopenias. Results: Of 758 patients enrolled, 19 developed cytopenias (2.5%). Transitory cytopenia was documented in 6 cases, 3 developed ICUS, 8 t-MDS, and 2 t-AML. In patients with FL, only hemoglobin < 12 g/dL (p = 0.032) and >6 nodal areas (p = 0.037) at diagnosis were factors statistically significant for the development of cytopenia. During cytopenias, 55% of patients died. Conclusions: LOHT constitutes a cause of morbidity and mortality in 2.5% of lymphoma patients treated with different therapy regimens.

18f-Fluorodeoxyglucose Positron Emission Tomography Versus Bone Marrow Biopsy for the Evaluation of Bone Marrow Infiltration in Newly Diagnosed Lymphoma Patients

ABSTRACT Background: Bone marrow evaluation (BME) is crucial for establishing an accurate staging and prognosis in lymphoma patients. Objective: The objective of the study was to study the diagnostic performance of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) against bone marrow biopsy (BMB) for BME. Methods: Five hundred patient files of newly diagnosed lymphoma patients treated at an academic medical center were reviewed for BME at diagnosis by BMB and FDG PET-CT. Diagnostic performance of FDG PET-CT for detecting bone marrow infiltration (BMI) was assessed, as well as clinical predictors for positive BMB and positive FDG PET-CT. Results: BMB was positive in 16.3% of all patients, and 28.7% had a positive FDG PET-CT for BMI. Overall, the sensitivity of FDG PET-CT was 74.1% and specificity 80.1%. As for predictors for BMB and FDG PET-CT positivity, B symptoms and thrombocytopenia were independent factors for BMI. Seventy-four patients had discordant results between BMB and FDG PET-CT, non-Hodgkin lymphoma (NHL) having the most significant discordance. This discrepancy did not affect treatment. Conclusions: FDG PET-CT shows excellent performance for the detection of BMI in Hodgkin lymphoma. For diffuse large B-cell lymphoma, we recommend performing BMB and FDG PET-CT as complementary tests. In all other NHL, a unilateral BMB is mandatory at diagnosis.

Late-Onset Hematological Toxicity (LOHT) in Patients with B-Cell Lymphomas: A Survey in 758 Cases.

BACKGROUND: The increasing survival of patients with non-Hodgkin lymphoma has allowed the diagnosis of long-term com- plications, including late-onset hematological toxicity (LOHT), transitory cytopenias, or therapy-related myeloid neoplasm (t-MDS/t-AML). OBJECTIVE: The objective of the study was to determine the frequency and clinical evolution of LOHT in patients with lymphoproliferative malignancies. MATERIALS AND METHODS: Two cohorts of patients B-cell lymphomas were reviewed. Patients who achieved full hematologic recovery at the end of treatment, and thereafter developed any degree of cytopenia were included in the study. Clinical and biochemical parameters were compared between patients with and without cytopenias with X2 test. Bi-and multivariate analyses were performed to evaluate factors associated with the development of late-onset cytopenias. RESULTS: Of 758 patients enrolled, 19 developed cytopenias (2.5%). Transitory cytopenia was documented in 6 cases, 3 developed ICUS, 8 t-MDS, and 2 t-AML. In patients with FL, only hemoglobin < 12 g/dL (p = 0.032) and >6 nodal areas (p = 0.037) at diagnosis were factors statistically significant for the development of cytopenia. During cytopenias, 55% of patients died. CONCLUSIONS: LOHT constitutes a cause of morbidity and mortality in 2.5% of lymphoma patients treated with different therapy regimens.

18f-Fluorodeoxyglucose Positron Emission Tomography Versus Bone Marrow Biopsy for the Evaluation of Bone Marrow Infiltration in Newly Diagnosed Lymphoma Patients.

BACKGROUND: Bone marrow evaluation (BME) is crucial for establishing an accurate staging and prognosis in lymphoma patients. OBJECTIVE: The objective of the study was to study the diagnostic performance of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) against bone marrow biopsy (BMB) for BME. METHODS: Five hundred patient files of newly diagnosed lymphoma patients treated at an academic medical center were reviewed for BME at diagnosis by BMB and FDG PET-CT. Diagnostic performance of FDG PET-CT for detecting bone marrow infiltration (BMI)was assessed, as well as clinical predictors for positive BMB and positive FDG PET-CT. RESULTS: BMB was positive in 16.3% of all patients, and 28.7% had a positive FDG PET-CT for BMI. Overall, the sensitivity of FDG PET-CT was 74.1% and specificity 80.1%. As for predictors for BMB and FDG PET-CT positivity, B symptoms and thrombocytopenia were independent factors for BMI. Seventy-four patients had discordant results between BMB and FDG PET-CT, non-Hodgkin lymphoma (NHL) having the most significant discordance. This discrepancy did not affect treatment. CONCLUSIONS: FDG PET-CT shows excellent performance for the detection of BMI in Hodgkin lymphoma. For diffuse large B-cell lymphoma, we recommend performing BMB and FDG PET-CT as complementary tests. In all other NHL, a unilateral BMB is mandatory at diagnosis.

Imatinib Intolerance Is Associated With Blastic Phase Development in Philadelphia Chromosome-Positive Chronic Myeloid Leukemia.

BACKGROUND: Over the past years, the survival of patients with Philadelphia-positive chronic myeloid leukemia (CML Ph(+)) has increased as a result of therapy with tyrosin kinase inhibitors (TKIs). Intolerance to TKIs has been described in approximately 20% of patients receiving treatment. We studied the incidence of imatinib intolerance in patients with CML Ph(+) and their outcome in our CML reference site, as there is no information about the evolution of patients intolerant to TKIs. PATIENTS AND METHODS: A group of 86 patients with CML Ph(+) receiving imatinib monotherapy who abandoned treatment were the basis for this study. We present the trends of their disease evolution. RESULTS: The median of age at diagnosis was 42 years. Within a year, 19 (22%) of 86 patients developed imatinib intolerance, all of them with grade III or IV disease that required imatinib dose reduction or discontinuation. Of these patients, 16 (84%) of 19 developed transformation to blastic phase. The cumulative incidences of blastic phase development were 47% in the nonintolerant group and 84% in the intolerant group. There was a relative risk for those with imatinib intolerance to develop blastic phase of 1.78 (95% confidence interval, 1.28 to 2.42) (P < .05). CONCLUSION: Most imatinib-intolerant patients develop blastic phase transformation, with a poor survival of 3 to 6 months; no effective rescue treatment is available. Future research should to determine whether the origin of this evolution is really due to the intolerance itself or whether it is due to a more aggressive form of the disease, perhaps related to genetic transformation.

[Initial surgical management of squamous carcinoma of the vulva]. / Manejo quirúrgico inicial del carcinoma epidermoide vulvar.

Vulvar cancer accounts for approximately 4% of gynecological malignancies. At the Instituto Nacional de Cancerologia in Mexico it occupies the fourth place. The purpose of this study is to assess the management of squamous carcinoma of the vulva with initial surgical treatment. It is a descriptive retrospective, observational study, from January 1, 2002 to December 31, 2012. Twenty-seven patients, clinical stages I, II, or III, initial surgical management, with at least one year of follow-up were included. In 51.85% a partial vulvectomy was performed and in 40.74% a wide excision; 66.66% underwent inguinofemoral dissection. Recurrence occurred in 25.91% of cases and the overall survival at 10 years was 63%. It is concluded that with invasion of up to 1 mm of lymph node, affection is 0%; with invasion of 1 mm and up to 5 mm this increases to 25%; an invasion of more than 5 mm implies up to 45%. Recurrence in our study was primarily distant, necessitating long-term monitoring with emphasis on symptoms to request imaging studies when suspected. Adjuvant therapy should be offered to patients with positive nodes, close or positive margins, and tumors larger than 4 cm.

[Spindle and epithelioid hemangio-endothelioma of the lymph node. Report of one case]. / Hemangioendotelioma epitelioide y fusiforme de ganglio linfático. Caso clínico.

Primary vascular tumors of lymph nodes are extremely rare with the exception of AlDS-related Kaposi's sarcoma. The diagnosis of epithelioid hemangio-endothelioma (EH) is difficult to make without ancillary studies, since it is devoid of morphological features indicating its vascular nature and it may be overlooked when it appears as a primary tumor of lymph nodes. Spindle and epithelioid hemangio-endothelioma (SEH) is considered to be a variant of EH, which has been reported to occur exclusively in lymph nodes and the spleen. We report a 70-year-old male with chronic lymphocytic leukemia (CLL) and left cervical lymphadenopathy. An excisional biopsy was performed, and microscopically the lymph node showed effacement of nodal architecture by a tumor composed of spindle cells disposed in intersecting fascicles, and characterized by abundant eosinophilic cytoplasm, elongated nuclei and conspicuous nucleoli. A second population of cells had an epithelioid appearance with intracyto-plasmic vacuoles containing red blood cells. lmmunohistochemically, the tumor cells were positive for CD31 and CD34. The final diagnosis was SEH of the lymph node.

Hemangioendotelioma epitelioide y fusiforme de ganglio linfático: Caso clínico / Spindle and epithelioid hemangio-endothelioma of the lymph node: Report of one case

Background: Primary vascular tumors of lymph nodes are extremely rare with the exception of AlDS-related Kaposi's sarcoma. The diagnosis of epithelioid hemangio-endothelioma (EH) is difficult to make without ancillary studies, since it is devoid of morphological features indicating its vascular nature and it may be overlooked when it appears as a primary tumor of lymph nodes. Spindle and epithelioid hemangio-endothelioma (SEH) is considered to be a variant of EH, which has been reported to occur exclusively in lymph nodes and the spleen. We report a 70-year-old male with chronic lymphocytic leukemia (CLL) and left cervical lymphadenopathy. An excisional biopsy was performed, and microscopically the lymph node showed effacement of nodal architecture by a tumor composed of spindle cells disposed in intersecting fascicles, and characterized by abundant eosinophilic cytoplasm, elongated nuclei and conspicuous nucleoli. A second population of cells had an epithelioid appearance with intracyto-plasmic vacuoles containing red blood cells. lmmunohistochemically, the tumor cells were positive for CD31 and CD34. The final diagnosis was SEH of the lymph node.

[Cutaneous hyalohyphomycosis in a patient with acute lymphoblastic leukemia]. / Hialohifomicosis cutánea en un paciente con leucemia linfoblástica.

Invasive fungal infections most frequently caused by Aspergillus sp. and Candida sp. are significant causes of morbidity and mortality in severely immunocompromised patients, especially those who are neutropenic or who have undergone bone marrow or solid-organ transplant. We report a case of cutaneous hyalohyphomycosis in a 24-year-old female with acute lymphoblastic leukemia.

Hialohifomicosis cutánea en un paciente con leucemia linfoblástica / Cutaneous hyalohyphomycosis in a patient with acute lymphoblastic leukemia

Las infecciones fúngicas causadas por Aspergillus sp. y Candida sp. son causa importante de morbilidad y mortalidad en pacientes gravemente inmunodeficientes, especialmente en aquellos con neutropenia o receptores de trasplante de médula ósea o de órganos sólidos. Informamos sobre una hialohifomicosis cutánea en una mujer de 24 años de edad con leucemia linfoblástica.

Invasive fungal infections most frequently caused by Aspergillus sp. and Candida sp. are significant causes of morbidity and mortality in severely immunocompromised patients, especially those who are neutropenic or who have undergone bone marrow or solid-organ transplant. We report a case of cutaneous hyalohyphomycosis in a 24-year-old female with acute lymphoblastic leukemia.

[Plasmoblastic lymphoma initially recognized as ovarian tumor]. / Presentación inicial de un linfoma plasmablástico como tumor ovárico.

Plasmablastic lymphoma is an uncommon B-cell lymphoma representing <3% of all non-Hodgkin lymphoma associated with human immunodeficiency virus infection. It displays a distinctive affinity for extranodal presentation in the oral cavity. The case of a plasmablastic lymphoma present in the ovary, cervix and soft thigh tissues of a 27-year-old woman with human immunodeficiency infection is reported.

[Plasmablastic lymphoma of the gastrointestinal tract in AIDS patients]. / Linfomas plasmoblásticos del tracto gastrointestinal en pacientes con sida.

The risk of developing non-Hodgkin lymphoma (NHL) is 200 times higher in HIV-positive patients than otherwise healthy persons. Plasmablastic lymphoma (PL) represents < 3% of all NHL associated with HIV infection. The aim of this study was to review the clinical-pathologic features of PL of the gastrointestinal tract in 5 patients with HIV/aids disease. We performed a retrospective study of PL of the gastrointestinal tract diagnosed at the National Institute of Cancer at Mexico City, from 2000 to 2009. Clinical and pathological information was obtained and immunohistochemical studies were performed in paraffin-embedded tissue sections. The presence of Epstein-Barr Virus (EBV) was examined by in situ polymerase chain reaction (PCR). Four male and 1 female were included with a median of age of 29 years. Three tumors involved the ano-rectal area, one tumor the ascendant colon and one tumor the stomach. All tumors were histologically characterized by a monotonous proliferation of large lymphoid cell with plasmablastic features. Tumor cells were CD 138 / MUM-1 positive and CD 20 / PAX-5 negative in all cases. EVB genome was detected by in situ PCR in 4 cases. The median of follow-up was 18 months, and revealed that three patients are alive with neoplasm disease and two patients are still alive with no evidence of the neoplasm. Recognition of this entity by pathologists and clinicians is important in order to establish the correct diagnosis and the early treatment of these patients.

Linfomas plasmoblásticos del tracto gastrointestinal en pacientes con sida / Plasmablastic lymphoma of the gastrointestinal tract in AIDS patients

Los pacientes con infección por el virus de inmunodeficiencia humana (HIV) tienen 200 veces más riesgo de desarrollar un linfoma no Hodgkin (LNH) con respecto a la población general. El linfoma plasmoblástico (LP) representa menos del 3% de todos los LNH asociados con el HIV. El objetivo de este estudio es informar las características clínico-patológicas de 5 pacientes con enfermedad HIV/sida y LP del tracto gastrointestinal. Se revisaron de forma retrospectiva los casos de LP del tracto gastrointestinal diagnosticados en el Instituto Nacional de Cancerología de la Ciudad de México en el periodo comprendido entre los años 2000 al 2009. Se analizaron las características clínico-patológicas y se realizaron cortes de bloques de tejidos embebidos en parafina para reacciones de inmunohistoquímica. La presencia del virus de Epstein Barr (VEB) se examinó por reacción en cadena de la polimerasa (PCR) in situ. De los cinco pacientes, cuatro fueron hombres y una mujer, con una mediana de edad de 29 años. Tres tumores se localizaron en la región anorrectal, uno en colon ascendente y el restante en el estómago. Histológicamente, todos los tumores se caracterizaron por una proliferación difusa de células grandes de aspecto plasmoblástico. Las células neoplásicas fueron CD 138/MUM-1 positivas y CD 20 / PAX-5 negativas. En cuatro pacientes se detectó el genoma del VEB en las células neoplásicas mediante PCR in situ. La mediana de seguimiento fue 18 meses; tres pacientes estaban vivos con enfermedad y dos sobreviven sin evidencias de la neoplasia. El diagnóstico precoz de LP como una entidad clínico-patológica es importante para establecer el tratamiento correcto y mejorar el pronóstico de estos pacientes.

The risk of developing non-Hodgkin lymphoma (NHL) is 200 times higher in HIV-positive patients than otherwise healthy persons. Plasmablastic lymphoma (PL) represents < 3% of all NHL associated with HIV infection. The aim of this study was to review the clinical-pathologic features of PL of the gastrointestinal tract in 5 patients with HIV/aids disease. We performed a retrospective study of PL of the gastrointestinal tract diagnosed at the National Institute of Cancer at Mexico City, from 2000 to 2009. Clinical and pathological information was obtained and immunohistochemical studies were performed in paraffin-embedded tissue sections. The presence of Epstein-Barr Virus (EBV) was examined by in situ polymerase chain reaction (PCR). Four male and 1 female were included with a median of age of 29 years. Three tumors involved the ano-rectal area, one tumor the ascendant colon and one tumor the stomach. All tumors were histologically characterized by a monotonous proliferation of large lymphoid cell with plasmablastic features. Tumor cells were CD 138 / MUM-1positive and CD 20 / PAX-5 negative in all cases. EVB genome was detected by in situ PCR in 4 cases. The median of follow-up was 18 months, and revealed that three patients are alive with neoplasm disease and two patients are still alive with no evidence of the neoplasm. Recognition of this entity by pathologists and clinicians is important in order to establish the correct diagnosis and the early treatment of these patients.

Ocular metastases from breast carcinoma.

Intraocular metastases are the most common malignancy of the eye, and the primary cause is breast cancer. This is a retrospective analysis, which reports the clinical experience of eye metastases in 16 patients during the period of January, 1991, to December, 2002, who attended a tertiary referral center in Mexico City. Mean age at diagnosis was 40 yr (range 24-58). Most of patients were initially in clinical stage IIB-IV. Median time from breast cancer diagnosis to development of ocular metastases was 22.5 mo and from metastatic disease to ocular metastases was 10 mo. Ocular symptoms were decrease of visual acuity, ocular pain, nonspecific symptoms, proptosis, and palpebral edema. Three patients had bilateral ocular metastases. Fourteen patients were treated with radiation, and clinical response was documented in 4/15 eyes; ocular pain responded in three patients with this symptom. No ocular enucleations were performed. One patient developed glaucoma. No other major toxicities were documented. Median survival time was 26 mo and 25% of our patients were alive at a maximum follow-up of 90 mo. This entity requires early recognition in order to preserve the visual function and quality of life of patients with breast cancer, since their prognosis has improved in recent years.