Estudio comparativo entre vías de acceso de implantación de Port-A-Cath* / Comparative study of access routes for Port-A-Cath(R) implantation

Introducción: Ha habido un aumento en la implantación de reservorios subcutáneos en los últimos años. El objetivo de este estudio es comparar las técnicas de punción venosa (PV) frente a la disección venosa (DV). Métodos: Estudio de cohortes retrospectivo. Incluyó a pacientes que requirieron un Port-A-Cath*. Se dividió a los pacientes en 2grupos: PV y DV. Los pacientes eran mayores de 18 años, requerían tratamiento intravenoso continuado, sin restricciones de patología. Se excluyó a quienes habían sido portadores de un reservorio previo y pacientes pediátricos. La elección de la técnica se basó en preferencias del cirujano. Se analizaron los parámetros clínicos de edad, sexo, ASA, IMC, motivo de colocación y lateralidad, y los datos referidos a las complicaciones y la tasa de retirada en cada uno de los grupos. El seguimiento medio fue de 2 años. Resultados: Fueron incluidos 386 pacientes durante 5 años: 228 en el grupo DV y 155 en el grupo PV. En 3 casos la técnica no quedó registrada. No hubo diferencias entre ambos grupos en edad, sexo, ASA, IMC y motivo de implantación (p > 0,05). La DV presentó menor cifra de complicaciones y se observó un mayor recambio y retirada de catéter en PV. A pesar de ello, no hubo diferencias estadísticamente significativas (p = 0,113). Conclusiones: Tanto la DV como la PV son técnicas seguras y eficaces. En nuestra experiencia, la DV presentó mejores resultados intraoperatorios y a largo plazo. Se recomienda realizar más estudios para discernir la técnica a utilizar con mayor seguridad

Introduction: There has been an increase in the implantation of subcutaneous reservoirs in recent years. The objective of this study was to compare puncture techniques against venous dissection. Methods: This retrospective cohort study included patients who required a Port-a-Cath and were divided into two groups: venous puncture (PV) and venous dissection (DV). Patients were over 18 years of age, requiring continued intravenous treatment, with no restriction of pathology. Patients with a previous reservoir and < 18 years old were excluded. The choice of the technique was based on the surgeon's preferences. We analyzed the clinical parameters of age, sex, ASA, BMI, reason for placement and laterality, and data related to the complications and withdrawal rate in each of the groups. Results: 386 patients were included for 5 years: 228 DV group and 155 PV group. In three cases, the technique was not documented. There were no differences between the two groups with respect to age, sex, ASA, BMI and reason for implantation (p > 0.05). The average follow-up was two years. The DV group was found to have a lower number of complications, while the PV group had an increased incidence of catheter replacement and removal. However, these differences were not statistically significant (p = 0.113). Conclusions: Both DV and PV are safe and effective techniques. In our experience, DV presented better intraoperative and long-term results. Further studies are recommended to discern which technique to use more safely

Comparative study of access routes for Port-A-Cath® implantation. / Estudio comparativo entre vías de acceso de implantación de Port-A-Cath.

INTRODUCTION: There has been an increase in the implantation of subcutaneous reservoirs in recent years. The objective of this study was to compare puncture techniques against venous dissection. METHODS: This retrospective cohort study included patients who required a Port-a-Cath and were divided into two groups: venous puncture (PV) and venous dissection (DV). Patients were over 18 years of age, requiring continued intravenous treatment, with no restriction of pathology. Patients with a previous reservoir and <18 years old were excluded. The choice of the technique was based on the surgeon's preferences. We analyzed the clinical parameters of age, sex, ASA, BMI, reason for placement and laterality, and data related to the complications and withdrawal rate in each of the groups. RESULTS: 386 patients were included for 5 years: 228 DV group and 155 PV group. In three cases, the technique was not documented. There were no differences between the two groups with respect to age, sex, ASA, BMI and reason for implantation (p>0.05). The average follow-up was two years. The DV group was found to have a lower number of complications, while the PV group had an increased incidence of catheter replacement and removal. However, these differences were not statistically significant (p=0.113). CONCLUSIONS: Both DV and PV are safe and effective techniques. In our experience, DV presented better intraoperative and long-term results. Further studies are recommended to discern which technique to use more safely.

Traumatic kidney injuries: A systematic review and meta-analysis.

BACKGROUND: Traumatic kidney injury is an infrequent event with a wide range of injury patterns. The aim of this paper is to review the incidence, mechanisms of injury, diagnostic methods, and therapeutic indications of renal injury according to the most recent evidence and to perform an analysis of mortality rates on these patients. OBJECTIVES: To perform a systematic review of the literature and a meta-analysis on traumatic kidney injuries. DATA SOURCES: A literature search was performed using PubMed, Embase, and Scopus databases. Articles published in English, French and Spanish were selected from 1963 to 2018. MeSH terms utilized were renal trauma, kidney trauma, blunt renal trauma, and penetrating renal trauma. STUDY PARTICIPANTS: The eligibility criteria included only original and human subject articles. Articles not involving human patients, cancer related, review articles, surveys, iatrogenic injuries, pediatric patients, and case reports were excluded from this search. RESULTS: Forty-six articles met the inclusion criteria of which 48,660 patients were identified and included in this review. Gender was reported in 32,918 cases, of which 75.3% of patients were male with a mean age of 33 years. Of the 44,865 patients where the mechanism of injury was described, we identified 36,086 (80.5%) patients that sustained blunt trauma, while 8,779 (19.5%) were due to penetrating mechanisms. Twenty one series with a total of 31,689 patients included the mortality rate. Overall mortality rate with exact binomial 95% confidence interval estimated via random effects model was 6.4% (4.8%-8.4%). CONCLUSIONS: Non-operative management has become the standard in renal trauma management with good results in morbidity and mortality. This has resulted in a decrease in the number of unnecessary iatrogenic nephrectomies and potential improvement in a patient's quality of life. When an invasive treatment is necessary, angioembolization for active bleeding or nephrorrhaphy is usually sufficient.

Tratamiento neoadyuvante con imatinib de un tumor gigante del estroma gastrointestinal rectal / Neoadjuvant treatment with imatinib for a giant tumor of the rectal gastrointestinal stroma

Alrededor de 5 % de los tumores del estroma gastrointestinal (GIST) se localizan en el recto. Cuando se encuentran localmente avanzados, el tratamiento neoadyuvante con imatinib ha demostrado buenos resultados para reducir el volumen de este tipo de tumores. Se presenta el caso de un paciente con diagnóstico de GIST rectal gigante, al que se le administró neoadyuvancia con imatinib y, posteriormente, se sometió a resección anterior baja con anastomosis coloanal. Es imprescindible que la evaluación y el tratamiento sean multidisciplinarios en los GIST rectales, para tratar de obtener los mejores resultados ante esta entidad tan poco frecuente, poder evitar la comorbilidad asociada y practicar cirugías menos agresivas tras una buena reacción terapéutica al imatinib

Less than 5% of gastrointestinal stromal tumors (GIST) are located at the rectum. When these tumors are locally advanced, neoadjuvant therapy with imatinib has shown good results, reducing its volume. We present the case of a patient with a giant rectal GIST tumor, who underwent neoadjuvant imatinib therapy, and posterior low anterior resection with coloanal anastomosis. In rectal GIST tumors it is essential the multidisciplinary evaluation and treatment, in order to obtain the best possible results in this rare entity. After a good response to the treatment with imatinib, aggressive surgeries can be avoided, along with the associated morbidity that comes with it

Phase 1-2 pilot clinical trial in patients with decompensated liver cirrhosis treated with bone marrow-derived endothelial progenitor cells.

The aim of this nonrandomized, open label, phase 1 clinical trial was to evaluate the safety and the feasibility of the treatment with autologous bone marrow-derived endothelial progenitor cells (EPC) in decompensated liver cirrhosis. In addition, the changes in liver function and hepatic venous pressure gradient (HVPG) and their relation with the characteristics of the cellular product were analyzed. Twelve patients with Child-Pugh ≥8 liver cirrhosis underwent bone marrow harvest for ex vivo differentiation of EPC. The final product was administered through the hepatic artery in a single administration. Patients underwent clinical and radiologic follow-up for 12 months. The phenotype and the ability to produce cytokines and growth factors of the final cellular suspension were analyzed. Eleven patients were treated (feasibility 91%). No treatment-related severe adverse events were observed as consequence of any study procedure or treatment. Model for end-stage liver disease score improved significantly (P 0.042) in the first 90 days after cells administration and 5 of the 9 patients alive at 90 days showed a decreased of HVPG. There was a direct correlation between the expression of acetylated-low density lipoprotein and von Willebrand factor in the cellular product and the improvement in liver function and HVPG. The treatment with EPCs in patients with decompensated liver cirrhosis is safe and feasible and might have therapeutic potential. Patients receiving a higher amount of functionally active EPC showed an improvement of liver function and portal hypertension suggesting that the potential usefulness of these cells for the treatment of liver cirrhosis deserves further evaluation.

First-line treatment with rituximab-hyperCVAD alternating with rituximab-methotrexate-cytarabine and followed by consolidation with 90Y-ibritumomab-tiuxetan in patients with mantle cell lymphoma. Results of a multicenter, phase 2 pilot trial from the GELTAMO group.

UNLABELLED: The prognosis for fit patients with mantle cell lymphoma has improved with intensive strategies. Currently, the role of maintenance/consolidation approaches is being tested as relapses continue to appear. In this trial we evaluated the feasibility, safety and efficacy of rituximab-hyperCVAD alternating with rituximab-methotrexate-cytarabine followed by consolidation with (90)Y-ibritumomab tiuxetan. Patients received six cycles followed by a single dose of (90)Y-ibritumomab tiuxetan. Thirty patients were enrolled; their median age was 59 years. Twenty-four patients finished the induction treatment, 23 achieved complete remission (77%, 95% confidence interval 60-93) and one patient had progressive disease (3%). Eighteen patients (60%), all in complete remission, received consolidation therapy. In the intent-to-treat population, failure-free, progression-free and overall survival rates at 4 years were 40% (95% confidence interval 20.4-59.6), 52% (95% confidence interval 32.4-71.6) and 81% (95% confidence interval 67.28-94.72), respectively. For patients who received consolidation, failure-free and overall survival rates were 55% (95% confidence interval 31.48-78.52) and 87% (95% confidence interval 70-100), respectively. Hematologic toxicity was significant during induction and responsible for one death (3.3%). After consolidation, grade 3-4 neutropenia and thrombocytopenia were observed in 72% and 83% of patients, with a median duration of 5 and 12 weeks, respectively. Six (20%) patients died, three due to secondary malignancies (myelodysplastic syndrome and bladder and rectum carcinomas). In conclusion, in our experience, rituximab-hyperCVAD alternated with rituximab-methotrexate-cytarabine and followed by consolidation with (90)Y-ibritumomab tiuxetan was efficacious although less feasible than expected. The unacceptable toxicity observed, especially secondary malignancies, advise against the use of this strategy. TRIAL REGISTRATION: clinical.gov identifier: NCT2005-004400-37.

Pilot clinical trial of type 1 dendritic cells loaded with autologous tumor lysates combined with GM-CSF, pegylated IFN, and cyclophosphamide for metastatic cancer patients.

Twenty-four patients with metastatic cancer received two cycles of four daily immunizations with monocyte-derived dendritic cells (DC). DC were incubated with preheated autologous tumor lysate and subsequently with IFN-α, TNF-α, and polyinosinic:polycytidylic acid to attain type 1 maturation. One DC dose was delivered intranodally, under ultrasound control, and the rest intradermally in the opposite thigh. Cyclophosphamide (day -7), GM-CSF (days 1-4), and pegIFN alpha-2a (days 1 and 8) completed each treatment cycle. Pretreatment with cyclophosphamide decreased regulatory T cells to levels observed in healthy subjects both in terms of percentage and in absolute counts in peripheral blood. Treatment induced sustained elevations of IL-12 in serum that correlated with the output of IL-12p70 from cultured DC from each individual. NK activity in peripheral blood was increased and also correlated with the serum concentration of IL-12p70 in each patient. Circulating endothelial cells decreased in 17 of 18 patients, and circulating tumor cells markedly dropped in 6 of 19 cases. IFN-γ-ELISPOT responses to DC plus tumor lysate were observed in 4 of 11 evaluated cases. Tracing DC migration with [(111)In] scintigraphy showed that intranodal injections reached deeper lymphatic chains in 61% of patients, whereas with intradermal injections a small fraction of injected DC was almost constantly shown to reach draining inguinal lymph nodes. Five patients experienced disease stabilization, but no objective responses were documented. This combinatorial immunotherapy strategy is safe and feasible, and its immunobiological effects suggest potential activity in patients with minimal residual disease. A randomized trial exploring this hypothesis is currently ongoing.

Phase I and pharmacokinetic study of gemcitabine administered at fixed-dose rate, combined with docetaxel/melphalan/carboplatin, with autologous hematopoietic progenitor-cell support, in patients with advanced refractory tumors.

The purpose of this trial was to define the maximum tolerated duration (MTD), dose-limiting toxicity (DLT), regimen-related toxicities (RRT), and pharmacokinetics of gemcitabine infused at a fixed dose rate (FDR) of 10 mg/m2/min, combined with docetaxel/melphalan/carboplatin, using autologous stem cell transplantation (ASCT). The duration of gemcitabine infusion was incrementally escalated as a single treatment on day -6 or as 4 daily infusions on days -5 to -2. Gemcitabine was followed by docetaxel (300 or 350 mg/m2) on day -5, and then melphalan (50 mg/m2/day) and carboplatin (333 mg/m2/day) on days -4 to -2. Fifty-two patients with refractory tumors were accrued with a median age of 40 (range: 6-66), a median of 3 (1-6) prior chemotherapy regimens, and 3 (1-7) organs involved. The gemcitabine MTD was defined at 20 hours (total dose 12,000 mg/m2) on both schedules. The DLT was enteritis. Three patients died from aspiration, catheter-related sepsis, and enteritis, respectively. The tumor response rate was 91%, with 50% complete responses. At current 2-year median follow-up, the event-free and overall survival (EFS, OS) rates are 54% (median 26 months) and 79% (median not reached), respectively. Gemcitabine area under the curve (AUC), but not clearance, increased linearly with infusion duration, and correlated with grade 3 RRT. Docetaxel showed a linear increase of its AUC and similar clearance compared with prior reports at lower doses. In conclusion, ASCT-supported infusions of gemcitabine at FDR could be prolonged up to 20 hours. The resulting gemcitabine/docetaxel/melphalan/carboplatin combination was highly active in refractory cancers and should be further tested in disease-specific trials.

Clinical benefit associated with idiotypic vaccination in patients with follicular lymphoma.

BACKGROUND: Follicular lymphoma is considered incurable, although cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy can induce sequential remissions. A patient's second complete response is typically shorter than that patient's first complete response. Idiotype vaccines can elicit specific immune responses and molecular remissions in patients with follicular lymphoma. However, a clinical benefit has never been formally proven. METHODS: Thirty-three consecutive follicular lymphoma patients in first relapse received six monthly cycles of CHOP-like chemotherapy. Patients who achieved a second complete response were vaccinated periodically for more than 2 years with autologous lymphoma-derived idiotype protein vaccine. Specific humoral and cellular responses were assessed, and patients were followed for disease recurrence. Statistical tests were two-sided. RESULTS: Idiotype vaccine could be produced for 25 patients who had a second complete response. In 20 patients (80%), a humoral (13/20) and/or a cellular (18/20) idiotype-specific response was detected. The median duration of the second complete response has not been reached, but it exceeds 33 months (range = 20+ to 51+ months). None of the 20 responders relapsed while undergoing active vaccination. All responders with enough follow-up for the comparison to be made experienced a second complete response that was statistically significantly (P<.0001) longer than both their first complete response (18 of 18 patients) and than the median duration of a CHOP-induced second complete response, i.e., 13 months (20 of 20 patients). The five nonresponders all had a second complete response that was shorter (median = 10 months; range = 8-13 months) than their first complete response (median = 17 months; range = 10-39 months). CONCLUSIONS: Idiotypic vaccination induced a specific immune response in the majority of patients with follicular lymphoma. Specific immune response was associated with a dramatic and highly statistically significant increase in disease-free survival. This is the first formal demonstration of clinical benefit associated with the use of a human cancer vaccine.

Effect of chemotherapy with alkylating agents on the yield of CD34+ cells in patients with multiple myeloma. Results of the Spanish Myeloma Group (GEM) Study.

BACKGROUND AND OBJECTIVES: Although alkylating agents are clearly beneficial in multiple myeloma (MM), their deleterious effect on bone marrow hematopoietic progenitor cells usually precludes their use as front-line therapy in patients scheduled to undergo autologous stem cell transplantation (ASCT). We analyzed the impact of first-line chemotherapy with alkylating agents on stem cell collection in MM patients. DESIGN AND METHODS: Seven hundred and eighty-nine patients included in the Spanish multicenter protocol GEM-2000 underwent mobilization therapy after four courses of alternating VBMCP/VBAD chemotherapy. RESULTS: The mobilization regimens consisted of standard or high-dose granulocyte colony-stimulating factor (G-CSF) in 551 (70%) patients, and chemotherapy and G-CSF in 206 (26%) patients. The CD34+ cell yield was lower than 4x10(6)/kg in 388 patients (49%), and equal or greater than 4x10(6)/kg in 401 patients (51%). Multivariate analysis indicated that advanced age (p<0.0001) and longer interval between diagnosis and mobilization (p=0.012) were the two variables associated with a lower CD34+ cell yield. Significant differences in CD34+ cell yield were not observed between the mobilization regimens. Of the 789 patients included in the protocol, 726 (92%) underwent the planned ASCT, whereas 25 (3%) patients did not because of the low number of CD34+ cells collected. Following ASCT, 0.5x10(9) neutrophils/L could be recovered after 11 days (median time; range, 5-71 days) and 20x10(9) platelets/L could be recovered after 12 days (median time; range, 6-69 days). INTERPRETATION AND CONCLUSIONS: A short-course of therapy with alkylating agents according to the GEM-2000 protocol was associated with an appropriate CD34+ cell collection, and allowed the planned ASCT to be performed in the majority of MM patients.

BCR-ABL induces the expression of Skp2 through the PI3K pathway to promote p27Kip1 degradation and proliferation of chronic myelogenous leukemia cells.

Chronic myelogenous leukemia (CML) is characterized by the expression of the BCR-ABL tyrosine kinase, which results in increased cell proliferation and inhibition of apoptosis. In this study, we show in both BCR-ABL cells (Mo7e-p210 and BaF/3-p210) and primary CML CD34+ cells that STI571 inhibition of BCR-ABL tyrosine kinase activity results in a G(1) cell cycle arrest mediated by the PI3K pathway. This arrest is associated with a nuclear accumulation of p27(Kip1) and down-regulation of cyclins D and E. As a result, there is a reduction of the cyclin E/Cdk2 kinase activity and of the retinoblastoma protein phosphorylation. By quantitative reverse transcription-PCR we show that BCR-ABL/PI3K regulates the expression of p27(Kip1) at the level of transcription. We further show that BCR-ABL also regulates p27(Kip1) protein levels by increasing its degradation by the proteasome. This degradation depends on the ubiquitinylation of p27(Kip1) by Skp2-containing SFC complexes: silencing the expression of Skp2 with a small interfering RNA results in the accumulation of p27(Kip1). We also demonstrate that BCR-ABL cells show transcriptional up-regulation of Skp2. Finally, expression of a p27(Kip1) mutant unable of being recognized by Skp2 results in inhibition of proliferation of BCR-ABL cells, indicating that the degradation of p27(Kip1) contributes to the pathogenesis of CML. In conclusion, these results suggest that BCR-ABL regulates cell cycle in CML cells at least in part by inducing proteasome-mediated degradation of the cell cycle inhibitor p27(Kip1) and provide a rationale for the use of inhibitors of the proteasome in patients with BCR-ABL leukemias.

Acquired potential N-glycosylation sites within the tumor-specific immunoglobulin heavy chains of B-cell malignancies.

BACKGROUND AND OBJECTIVES: Among B-cell malignancies, follicular lymphomas (FL) more frequently show acquired, potential N-glycosylation sites (AGS) within tumor-specific immunoglobulin. The aim of this study was to extend this observation and to evaluate the pattern of presentation of AGS within five different forms of B-cell lymphoma. DESIGN AND METHODS: We sequenced the tumor-specific immunoglobulin heavy chain variable region fragment, including complementarity-determining regions 2 and 3, of forty-seven consecutive patients with a B-cell malignancy enrolled in idiotype vaccine clinical trials. This sequencing approach is known to allow the identification of most AGS. We then statistically analyzed differences in presentation pattern, in terms of tumor histology, immunoglobulin isotype, AGS location and amino acid composition. RESULTS: All twenty-four FL cases presented with at least one AGS, whereas the vast majority of four B-cell lymphoma types other than FL did not. The non- FL group of tumors included four cases of Burkitt's lymphoma, six of diffuse large cell lymphoma, seven mantle cell lymphomas and six small lymphocytic lymphomas. Most IgM-bearing follicular lymphoma cases featured their AGS within complementarity-determining region 2, as opposed to those bearing an IgG, which mostly displayed the AGS within complementarity-determining region 3. The vast majority of AGS located within either complementarity-determining region ended with a serine residue, whereas those located within framework regions mostly featured threonine as the last amino acid residue. INTERPRETATION AND CONCLUSIONS: In our series, all cases of FL had AGS within their tumor-specific immunoglobulin heavy chain variable regions. In contrast, most B-cell malignancies other than FL did not. Further studies are warranted in order to establish the possible meaning of these findings in terms of disease pathogenesis, their diagnostic value in doubtful cases and their potential implications for immunotherapy.