FLT3-ITD and CD135 Over-Expression are Frequent Findings of Poor Survival in Adult Patients with Acute Leukemias.

BACKGROUND: Fms-like tyrosine kinase 3 (FLT3) expression and mutation have been considered a poor prognostic factor in acute myeloid leukemia (AML). FLT3-ITD mutation is present in 30% of adult patients with AML and 2-5% in childhood acute lymphoblastic leukemia (ALL). The impact of these mutations on the prognosis of ALL patients, has not yet been established. Moreover, a limited number of publications regarding the level of expression of the FLT3 receptor (CD135) in both leukemias exist. This study aimed to analyze the clinical outcomes associated to the presence of FLT3-ITD mutation and the expression of CD135. METHODS: 82 adult patients with newly diagnosed acute leukemia (39 with AML and 43 with ALL) were included. Flow cytometry and RT-PCR were done to analyze the expression of CD135 and the presence of FLT3 ITD mutation, respectively. RESULTS: FLT3-ITD was present in 14 (36%) of AML and 15 (35%) of ALL patients. Disease free survival (DFS) and overall survival (OS) were lower in ALL patients having a CD135 expression >3000 cells/µL. There was a trend for poor OS in AML patients expressing FLT3 ITD. OS was worse in AML patients with high expression of CD135. CONCLUSION: A higher (35%) frequency of FLT3-ITD was found in adult ALL patients. The presence of FLT3-ITD was associated with a trend of poor OS in AML cases, and overexpression of CD135 was correlated with poor DFS in ALL cases and poor OS in both acute leukemias.

Clinical relevance of NKT cells and soluble MIC-A in Hodgkin lymphoma.

Previous studies demonstrated that the majority of Hodgkin lymphoma (HL) patients achieve response after treatment, while 5% become refractory. Studies analyzing the role of lymphocyte subsets in peripheral blood are limited. This investigation sought to evaluate peripheral blood lymphocyte subsets and soluble MHC class I chain-related proteins A and B (sMIC-A/B) and their correlation with survival in patients with newly diagnosed HL. The study recruited 36 patients and 72 healthy donors. HL patients showed a decrease in CD4, B, monocytes, NK, and NKT cells; and an increase in γ-δ T cells and soluble MIC-A serum levels. Higher values of s-MIC-A  >100 ng/mL and NKT cells >40 µL correlated with poor overall survival (OS). In conclusion, in HL peripheral blood CD4 T and B cells, monocytes, NK, and NKT cells were decreased, while s-MIC-A and γ-δ T cells increased. Higher values of s-MIC-A and NKT cells correlated with poor survival.

Important decrease in invariant natural killer T, CD4+ regulatory T cells, CD8+ regulatory T cells, gamma-delta T cells, and CD4+ T lymphocytes in HIV-negative patients with hemophilia.

Hereditary hemophilias are X-linked inherited bleeding disorders defined as deficiencies of the coagulation factors VIII or IX. They are characterized by easy to provoke or spontaneous bleeding. HIV infection in hemophilic patients is a risk factor for the reduction of CD4+ T cells. There is no information regarding the cellular immune function in HIV-negative patients with hemophilia. To evaluate the number of lymphocyte subsets in adult patients with hemophilia A or B as compared with healthy donors. 39 Adult hemophilics and 27 healthy donors were included. Lymphocyte subsets [CD4 and CD8 T cells, natural killer cells, natural killer T (NKT) cells, invariant NKT (iNKT) cells, gamma-delta T (γδT) cells, type 1 and 2 dendritic cells, CD14 monocytes, CD4 and CD8 regulatory T cells (Tregs), and B cells], were analyzed by flow cytometry. A significant decrease of CD4+ T lymphocytes, γδT cells, iNKT cells, CD4+ and CD8+ Tregs was observed in patients with hemophilia. Those patients having factor VIII inhibitor had the lowest CD4+ Treg and CD8+ Treg counts. CD14 monocytes were increased, as well as iNKT and type 2 dendritic cells in obese-overweight hemophilics. CD4+ lymphocytes, iNKT, γδT cells, and Tregs (CD4+ and CD8+), are significantly decreased in patients with hemophilia. Depletion of Tregs is more important in patients with factor VIII inhibitor. Physicians caring for hemophilia patients should realize that, even when they are not suffering infections frequently, may have early evidence of cellular immunodeficiency.

Post-treatment improvement of NK cell numbers predicts better survival in myeloma patients treated with thalidomide-based regimens.

Multiple myeloma (MM) is a disease characterized by antitumoral immune dysfunction. The objective of the present study was to determine lymphocyte subsets (B, T, NK, NKT, iNKT, dendritic cells, and regulatory T cells) in 68 newly diagnosed patients and 113 healthy donors. Lymphocyte subsets were studied in the same patients 6 months after treatment. Pre-treatment values of CD4+ T cells, NK cells, type 2 dendritic cells, and B cells in MM patients were lower than in healthy donors. Forty patients (59%) received MPT treatment and 28 (41%) thal-dex. Patients with no response to treatment, exhibited a decrease in CD4+ T cells and NK cells, as well as an increase in Treg cell numbers. Median DFS and OS was lower in patients not achieving response, in patients having low numbers of NK cells, and higher values of LDH. The number of CD4 T cells, NK, DC2, and B cells at diagnosis is lower in patients with MM. Non-responder patients had lower CD4 and NK, but higher Treg cell values. Patients in which response is not achieved, and those holding lower values of NK cells and higher levels of LDH, have poor DFS and OS.

Prognostic Value of CD95, Active Caspase-3, and Bcl-2 Expression in Adult Patients with De Novo Acute Lymphoblastic Leukemia.

BACKGROUND: Acute lymphoblastic leukemia is an aggressive malignant disease with high mortality rates in adults. AIM OF THE STUDY: The expression levels of CD95, active caspase-3, and Bcl-2 were determined in 111 patients with de novo acute lymphoblastic leukemia (ALL) and correlated with overall survival (OS) and disease-free survival (DFS). METHODS: The immunophenotyped ok leukemia and the expression of CD95, active caspase-3, and Bcl-2, were determined by flow cytometry. Apoptotic variables were correlated by Spearman test, and survival by Kaplan-Meier method. Log-rank test was used to compare survival curves. RESULTS: From a total of 111 patients, 56 cases were B-ALL, 16 T-ALL, 16 B-ALL/CD33+, and 23 ambiguous lineage-AL (AmbLin-AL). The median expression of CD95 (61.5%) and active-caspase-3 (19.4%) was higher in T-ALL (p <0.05), whereas Bcl-2 was lower in T-ALL (p <0.038). There was a highly significant correlation in B-ALL, B-ALL/CD33+ and AmbLin-AL between CD95 and Bcl-2, CD95-Active caspase-3, and Bcl-2-Active caspase-3; while in T-ALL, there was only a correlation between CD95-Active caspase-3, and Bcl-2-Active caspase-3. OS and DFS were better for T-ALL than the other groups, especially in patients having higher values of CD95 and active caspase 3, and lower values of Bcl-2. The worse survival rates were observed in patients with B-ALL/CD33+, and AmbLin-AL. CONCLUSIONS: The prognosis of ALL in adults is influenced by the expression levels of Bcl-2, active-caspase-3, and CD95.

Should the Presence of Metastatic Para-Aortic Lymph Nodes in Locally Advanced Cervical Cancer Lead to More Aggressive Treatment Strategies?

STUDY OBJECTIVE: To evaluate risk factors in patients with locally advanced cervical cancer (LACC) undergoing pretherapeutic laparoscopic para-aortic lymphadenectomy (LPL) as well as the progression-free and overall survival rates specifically in the subgroup of patients with metastatic para-aortic lymph nodes (PLNs). DESIGN: Retrospective study conducted on demographic data, pathologic and surgical findings, complications, and disease status recorded for LACC patients undergoing LPL during the period 2009 to 2015. SETTING: Department of Gynecologic Oncology of the Complejo Hospitalario Universitario Insular-Materno Infantil, Canary Islands, Spain (Canadian Task Force Classification II-3). PATIENTS: Women with LACC undergoing pretherapeutic LPL. All patients were treated with definitive chemoradiotherapy after surgery, and those with metastatic PLN received extended lumboaortic radiation therapy. INTERVENTIONS: Survival analysis was performed with the Kaplan-Meier method. Statistical significance was considered for p <.05. MEASUREMENTS AND MAIN RESULTS: The study included 139 patients. The median age was 48 years (range, 28-73). The most frequent histologic type was squamous cell carcinoma (77%), and the most frequent 2009 FIGO stage was IIB (48.2%). LPL identified metastatic PLN in 18.7% of patients (n = 26). The mean overall survival for the whole population, after 23 months of follow-up, was 68.2 months (95% CI, 63-73.4). For patients without para-aortic metastases, the mean survival time was 76.9 months (95% CI, 70.3-80.4), whereas for patients with positive PLNs the median survival time was 21 months (95% CI, 6.1-35.9; p <.0001). A logistic regression analysis revealed that the presence of metastatic PLNs and tumor size (>5 cm) were both independent risk factors for poor survival (OR, 117.5; 95% CI, 11.6-990.2; p <.0001, and OR, 21.5; 95% CI, 2-230.3; p = .01, respectively). CONCLUSION: LACC patients with metastatic PLNs had a poor prognosis and low survival rate. We postulate that this finding could be accounted for by the presence of hidden systemic disease and high recurrence rate after therapy. Efforts should be made to improve available therapeutic strategies for this particular subgroup of patients.

Safety and Feasibility Analysis of Laparoscopic Lymphadenectomy in Pelvic Gynecologic Malignancies: A Prospective Study.

OBJECTIVE: The aims of this study were to evaluate prospectively the safety and feasibility of laparoscopic lymphadenectomy in gynecologic oncology and to analyze risk factors associated with surgical adverse events. MATERIALS AND METHODS: This study included 444 consecutive laparoscopic lymphadenectomy procedures conducted in 358 consecutive gynecologic oncology patients, between 2007 and 2014. Surgical adverse events were classified into intraoperative, early postoperative (≤6 weeks after surgery), and late postoperative (>6 weeks after surgery). Logistic regression analysis was used to assess the independent effects of different variables on the probability of complications. Differences were considered to be statistically significant for P values less than 0.05. RESULTS: Two hundred forty-four pelvic lymphadenectomy and 200 aortic lymphadenectomy procedures were carried out during the studied period. All pelvic lymphadenectomy procedures were conducted with a transperitoneal approach, whereas 94.5% of aortic lymphadenectomy procedures were conducted with an extraperitoneal approach. A total of 52.2% of tumors were found to originate in the cervix, 38% in the endometrium, 6.4% in the ovary, 2.8% were sarcoma, and 0.6% were in a different region. The laparotomy conversion rate was 2.8%. The rate of intraoperative adverse events was 1.9%, the most frequent ones being vascular injuries followed by ureteral, bowel, or neurologic injuries. The rate of early-postoperative adverse events was 3.3%, the most frequent one being incisional hernia followed by hemoperitoneum, pelvic abscess, intestinal injury, and paralytic ileus. One patient with endometrial cancer died after surgery due to sepsis of unknown origin. The rate of late-postoperative adverse events was 3.6% and consisted mainly of symptomatic lymphocele or lymphedema. A logistic regression analysis showed that factors associated with increased risk of lymphadenectomy surgical complications were surgical bleeding and operative time (odds ratio, 2.6; 95% confidence interval, 1.1-6; P = 0.02 and odds ratio, 2.6; 95% confidence interval, 1-6.7; P = 0.04). CONCLUSIONS: Laparoscopic lymphadenectomy is a safe and feasible procedure in gynecologic oncology but not free of complications. We postulate that gynecologic oncologists should be properly trained in the management of such complications and be aware of the importance of adequate hemostasis and operating time during surgery.

Bariatric Surgery: Does It Play a Role in Fertility-Preserving Treatment Among Obese Young Women With Endometrial Cancer?

We present the case of a 17-year-old nulliparous woman with a history of obesity (body mass index 36.2 kg/m(2)), type 2 diabetes, and polycystic ovary syndrome, who was diagnosed with grade 1 endometrioid adenocarcinoma without radiological evidence of myometrial invasion or metastatic disease. After failure of a fertility-preserving treatment with a levonorgestrel-releasing intrauterine device, bariatric surgery was proposed to treat the obesity and improve control of her type 2 diabetes in an attempt to increase the chances of obtaining response to local treatment. Nine months after laparoscopic sleeve gastrectomy and 18 months after insertion of the intrauterine device, the patient reached normal body weight (body mass index 20.3 kg/m(2)) and showed complete response to treatment. As far as we know, this is the first published case of an adolescent obese patient treated with bariatric surgery concomitantly with fertility-preserving management of endometrial cancer. We propose that bariatric surgery may play a role as an adjuvant therapy in fertility-preserving treatment of endometrial cancer with local progestin, in which it could enhance remission rates and reduce recurrence.

Renovascular hypertension as a rare complication of laparoscopic extraperitoneal paraaortic lymphadenectomy.

We describe the case of a 35-year-old woman who presented with renovascular hypertension caused by a compressive hematoma, which was caused by polar artery injury occurred during a laparoscopic extraperitoneal paraaortic lymphadenectomy procedure. To our knowledge, this is the first description of a renovascular disorder associated with this increasingly common procedure. We propose that the occurrence of vascular injury during laparoscopic extraperitoneal paraaortic lymphadenectomy requires an early image control study aimed at monitoring for compressive disorders, which could lead to abnormal renal function.

Role of CD4+CD25+highFoxp3+CD62L+ regulatory T cells and invariant NKT cells in human allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for some hematological diseases; however, graft-versus-host disease (GVHD) is still one of the most important and deleterious complications. Regulatory T cells and iNKT cells can decrease the incidence and severity of GVHD, while preserving the graft-versus-tumor response. In order to analyze the relationship between the transfused dose of these cells, the presence of GVHD and survival, 15 normal donors and 15 patients with hematological diseases who underwent allogeneic HSCT from HLA-identical siblings were studied. The mobilization and infused doses of valpha24-vbeta11(iNKT cells) lymphocytes and CD4+CD25+FoxP3+, CD4+CD25+FoxP3+CD62L+, regulatory T cells were analyzed. All patients were conditioned with busulfan and cyclophosphamide and received cyclosporine and methotrexate as GVHD prophylaxis. iNKT and FoxP3 cells were mobilized after G-CSF administration. Acute GVHD was present in 9 of 15 (60%) and cGVHD in 7 of 13 (54%) patients. Patients who received a dose <0.6 x 10(6)/kg of iNKT cells and >4 x 10(6)/kg of FoxP3 had better disease-free survival and overall survival. Individuals transfused with >1.1 x 10(6)/kg of FoxP3+ CD62L+ Treg cells had better overall survival. In conclusion, iNKT and Treg cells are mobilized with G-CSF in healthy donors and the dose of iNKT cells and FoxP3 and CD62L+ regulatory T cells is of clinical importance in human HSCT.

Rituximab therapy for chronic and refractory immune thrombocytopenic purpura: a long-term follow-up analysis.

The aim of this study was to evaluate the long-term response to rituximab in patients with chronic and refractory immune thrombocytopenic purpura (ITP). Adults with ITP fail to respond to conventional therapies in almost 30% of cases, developing a refractory disease. Rituximab has been successfully used in these patients. We used rituximab at 375 mg/m2, IV, weekly for a total of four doses in 18 adult patients. Complete remission (CR) was considered if the platelet count was >100 x 10(9)/l, partial remission (PR) if platelets were >50 x 10(9)/l, minimal response (MR) if the platelet count was >30 x 10(9)/l and <50 x 10(9)/l, and no response if platelet count remained unchanged. Response was classified as sustained (SR) when it was stable for a minimum of 6 months. Median age was 43.5 years (range, 17 to 70). Median platelet count at baseline was 12.5 x 10(9)/l (range, 3.0 to 26.3). CR was achieved in five patients (28%), PR in five (28%), MR in four (22%), and two patients were classified as therapeutic failures (11%). Two additional patients were lost to follow-up. The median time between rituximab therapy and response was 14 weeks (range, 4 to 32). SR was achieved in 12 patients (67%). There were no severe adverse events during rituximab therapy. During follow-up (median, 26 months; range, 12 to 59), no other immunosuppressive drugs were used. In conclusion, rituximab therapy is effective and safe in adult patients with chronic and refractory ITP. Overall response rate achieved is high, long term, and with no risk of adverse events.

Extramedullary leukemic relapses following hematopoietic stem cell transplantation with nonmyeloablative conditioning.

Of a group of 149 patients who underwent allogeneic stem cell transplantation using the "Mexican approach", a nonablative preparative regimen, 49 individuals developed bone marrow relapse, and 8 patients developed extramedullary relapse (EMR). All EMR cases presented in patients who received allografts for myeloid malignancies. In contrast, bone marrow relapses presented in patients with myeloid or lymphoid malignancies. EMR presented 60 to 1010 days after the allograft and appeared in 3 cases as subcutaneous nodules in different parts of the body, in the vertebrae in 3 cases, and in the kidney and the breast in 1 case each. One patient had both subcutaneous nodules and epididymis EMR. When EMR was noted, acute graft-versus-host disease (GVHD) had presented in 4 patients, and limited forms of chronic GVHD were present in 3 patients. All but 1 of the patients were full chimeras when the EMR ensued, and the EMR preceded an overt hematologic relapse in all but 1 of the patients. Patients who experienced an overt hematologic relapse died 20 to 180 days (median, 40 days) after the EMR. The only individual alive 240 days after relapse shows no evidence of a full-blown hematologic relapse. An EMR after allogeneic hematopoietic stem cell transplantation usually has a bad prognosis and presents mainly in individuals with high-risk malignancies.

Trasplante de células hematopoyéticas en mieloma múltiple / Hematopoietic stem cell transplantation in multiple myeloma

Multiple myeloma (MM) is the second most common hematologic malignancy, affecting approximately 14,000 new patients per year in the United States. For over four decades, the standard treatment for MM has been a regimen of melphalan combined with prednisone. Using this treatment modality, complete responses are rare, and 50% of patients have had disease that was resistant to chemotherapy. Attempts have been made to improve the outcome of MM by administering combinations of I. V. polichemotherapy, but these treatments are equivalent in terms of overall survival. High-dose therapy with peripheral blood stem cell support can be applied safely in these patients and achieves significantly higher complete remission rates as well as better event-free survival and overall survival. However, neither tumor-cell purging, positive selection, intensification of conditioning with additional chemotherapeutic agents, nor total body irradiation have been shown to improve outcome. The role of tandem transplantation with high-dose melphalan seems to be a good selection of treatment in hospitals having all resources. Future research will include the combination of the best remission-induction regimen with tandem transplants and maintenance treatments (thalidomide, idiotype or dendritic cell vaccination) that will sustain complete remission. Development of non-myeloablative allogeneic transplantation in order to exploit the graft-versus myeloma effect provides an alternative for patients who have a compatible donor. Combining all of these modalities with the new drugs developed few years ago (thalidomide, bortezomib, revlimid), we hope that MM will become a manageable chronic disease and perhaps a curable disease at least for 30% to 40% of the patients.

El mieloma múltiple (MM) es la segunda patología oncohematológica más frecuente. En Estados Unidos son diagnosticados anualmente 14,000 casos nuevos. En las últimas cuatro décadas el tratamiento estándar ha sido la combinación de melfalán y prednisona. Con este régimen raramente se logran remisiones completas y 50% de los pacientes no responden a esta terapia. Se han hecho intentos de mejorar los resultados combinando poliquimioterapia, pero la sobrevida global ha sido la misma. Al aplicar quimioterapia a dosis altas y rescate con trasplante de células hematopoyéticas se logra un mayor porcentaje de remisiones completas, asimismo, una mayor sobrevida libre de enfermedad y sobrevida global. La purga de células hematopoyéticas, selección positiva, intensificación del régimen de acondicionamiento con otras drogas o irradiación corporal total, no han demostrado utilidad en términos de sobrevida global. El doble trasplante autólogo de células hematopoyéticas parece ser una opción útil para hospitales que cuentan con la infraestructura y los recursos necesarios para realizarlo. En un futuro, la investigación deberá incluir el uso del mejor régimen de inducción a la remisión más doble trasplante autólogo y terapia de mantenimiento (talidomida o vacunas con células dendríticas), con la finalidad de al menos prolongar la remisión completa. El uso del trasplante alogénico no mieloablativo para provocar el efecto injerto contra mieloma parece una buena alternativa para los pacientes que tengan donador. Al combinar todas estas modalidades de tratamiento con las nuevas drogas desarrolladas en los últimos años (talidomida, bortezomid, revlimid), se espera que en un futuro el MM se convierta en una enfermedad crónica y curable en al menos 30 a 40% de los enfermos.

[Hematopoietic stem cell transplantation in multiple myeloma]. / Trasplante de células hematopoyéticas en mieloma múltiple.

Multiple myeloma (MM) is the second most common hematologic malignancy, affecting approximately 14,000 new patients per year in the United States. For over four decades, the standard treatment for MM has been a regimen of melphalan combined with prednisone. Using this treatment modality, complete responses are rare, and 50% of patients have had disease that was resistant to chemotherapy. Attempts have been made to improve the outcome of MM by administering combinations of i.v. poli-chemotherapy, but these treatments are equivalent in terms of overall survival. High-dose therapy with peripheral blood stem cell support can be applied safely in these patients and achieves significantly higher complete remission rates as well as better event-free survival and overall survival. However, neither tumor-cell purging, positive selection, intensification of conditioning with additional chemotherapeutic agents, nor total body irradiation have been shown to improve outcome. The role of tandem transplantation with high-dose melphalan seems to be a good selection of treatment in hospitals having all resources. Future research will include the combination of the best remission-induction regimen with tandem transplants and maintenance treatments (thalidomide, idiotype or dendritic cell vaccination) that will sustain complete remission. Development of non-myeloablative allogeneic transplantation in order to exploit the graft-versus myeloma effect provides an alternative for patients who have a compatible donor. Combining all of these modalities with the new drugs developed few years ago (thalidomide, bortezomib, revlimid), we hope that MM will become a manageable chronic disease and perhaps a curable disease at least for 30% to 40% of the patients.

[Prevalence of osteopenia and osteoporosis assessed by densitometry in postmenopausal women]. / Prevalencia de osteopenia y osteoporosis evaluada por densitometría en mujeres posmenopáusicas.

OBJECTIVE: Our goal was to know the osteopenia and osteoporosis prevalence, determined by densitometry using dual energy X-ray absorptiometry (DXA) to measure the bone mineral density (BMD) in postmenopausal women. SUBJECTS AND METHODS: A total the 202 postmenopausal women aged 37 at 74 years old was studied, at the Gynecologist and Obstetrics Hospital No. 3 Medical Center "La Raza" from the IMSS, initiated in December 2001 to June 2002. The measurement BMD using DXA with a LUNAR device and according the WHO criteria, we have calculated the prevalence of osteopenia and osteoporosis in normal postmenopausal women at the lumbar spine (LS) and/or femoral neck (FN). RESULTS: The osteopenia prevalence in LS was: 18.2% in the group aged 45-49 years old, 47.1% in the group aged 50-54, 43.7% in the group aged 55-59, 63.6 in the group aged 60-64, 53% in the group aged 65-69, and 30% in the group aged 70-74. The overall osteopenia prevalence in LS was 43.5%, confidence interval (CI) 95% from 43.08 to 44.03%. The osteoporosis of LS was 17.1% in the group aged 50-54 years old; 21.8 in the group aged 55-59; 22.7 in the group aged 60-64; 35.29% in the group aged 65-69; and 30% in the group aged 70-74. The overall osteoporosis prevalence in the LS was 19.8% (CI) 95% from 14.3 to 25.2%. The osteopenia prevalence in FN was. 19% in the group aged 45-49 years old; 40% in the group aged 50-54; 49% in the group aged 55-59; 54% in the group aged 60-64; 76% in the group aged 65-69 and 60% in the group aged 70-74. The overall osteopenia prevalence of FN was the 48% CI 95% from 40.65-54.59%. The osteoporosis prevalence in FN: 2.38% in the group aged 45-49 years old; 7.14 in the group aged 50-54; 5.45% in the group aged 55-59; 13.6% in the group aged 60-64; 5.8 in the group aged 65-69, and 20% in the group aged 70-74. The overall osteoporosis prevalence in FN was 7.4% IC 95% from 3.6-10.68%. CONCLUSIONS: The osteoporosis prevalence in this group is less than between American women (15%), and early detection is possible between women with BMD low, in the postmenopausal women with high risk factors and primary treatment need to be established and implemented.