A signature of circulating microRNAs predicts the response to treatment with FOLFIRI plus aflibercept in metastatic colorectal cancer patients.

The benefit of adding the antiangiogenic drug aflibercept to FOLFIRI regime in metastatic colorectal cancer (CRC) patients resistant to or progressive on an oxaliplatin-based therapy has been previously demonstrated. However, the absence of validated biomarkers to predict greater outcomes is a major challenge encountered when using antiangiogenic therapies. In this study we investigated profiles of circulating microRNAs (miRNAs) to build predictive models of response to treatment and survival. Plasma was obtained from 98 metastatic CRC patients enrolled in a clinical phase II trial before receiving FOLFIRI plus aflibercept treatment, and the circulating levels of 754 individual miRNAs were quantified using real-time PCR. A distinct signature of circulating miRNAs differentiated responder from non-responder patients. Remarkably, most of these miRNAs were found to target genes that are involved in angiogenic processes. Accordingly, some of these miRNAs had predictive value and entered in predictive models of response to therapy, progression of disease, and survival of patients treated with FOLFIRI plus aflibercept. Among these miRNAs, circulating levels of hsa-miR-33b-5p efficiently discriminated between responder and non-responder patients and predicted the risk of disease progression. Moreover, the combination of circulating VEGF-A and miR-33b-5p levels improved clinical stratification of metastatic CRC patients who were to receive FOLFIRI plus aflibercept treatment. In conclusion, our study supports circulating miRNAs as valuable biomarkers for predicting better outcomes in metastatic CRC patients treated with FOLFIRI plus aflibercept.

Respiratory distress syndrome caused by influenza H1N1 in a patient with a simultaneous pancreas-kidney transplantation.

Adult respiratory distress syndrome is a severe respiratory failure due to noncardiogenic pulmonary edema with high mortality rates (50-70%). The most common etiology of respiratory distress is sepsis, but it may also be caused by several of the immunosuppressants prescribed in transplantation. In the last year, influenza H1N1 virus infection has become more relevant. It has shown a greater incidence among immunosuppressed patients as well as those with chronic kidney disease or diabetes mellitus. We present the case of a patient with simultaneous pancreas-kidney transplantation who presented respiratory distress after the second dose of thymoglobulin. Initially, we interpreted that the thymoglobulin was the cause, so it was replaced with basiliximab. Empirical treatment was started with 3 doses of 6-methylprednisolone (250 mg), with a favorable response. After 7 days, we received the results of the reverse-transcriptase polymerase chain reaction of a nasal smear and blood culture, which were positive for H1N1 virus. In our knowledge, this is the first reported case of a patient with simultaneous pancreas-kidney transplantation and respiratory distress secondary to H1N1 virus infection who showed a favorable response to corticosteroid therapy.

First-in-man phase I trial of two schedules of the novel synthetic tetrahydroisoquinoline alkaloid PM00104 (Zalypsis) in patients with advanced solid tumours.

BACKGROUND: PM00104 binds guanines at DNA minor grooves, impacting DNA replication and transcription. A phase I study was undertaken to investigate safety, dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), pharmacokinetics (PKs) and preliminary antitumour activity of PM00104 as a 1- or 3-h infusion three-weekly. METHODS: Patients with advanced solid tumours received PM00104 in a dose escalation trial, as guided by toxicity and PK data. RESULTS: A total of 47 patients were treated; 27 patients on the 1-h schedule (0.23-3.6 mg m(-2)) and 20 patients on the 3-h schedule (1.8-3.5 mg m(-2)). Dose-limiting toxicities comprised reversible nausea, vomiting, fatigue, elevated transaminases and thrombocytopenia, establishing the 1-h schedule RP2D at 3.0 mg m(-2). With the 3-h schedule, DLTs of reversible hypotension and neutropenia established the RP2D at 2.8 mg m(-2). Common PM00104-related adverse events at the RP2D comprised grade 1-2 nausea, fatigue and myelosuppression. In both schedules, PKs increased linearly, but doses over the 1-h schedule RP2D resulted in higher than proportional increases in exposure. A patient with advanced urothelial carcinoma had RECIST shrinkage by 49%, and three patients had RECIST stable disease ≥6 months. CONCLUSION: PM00104 is well tolerated, with preliminary evidence of antitumour activity observed. The 1-h 3-weekly schedule is being assessed in phase II clinical trials.

Treatment recommendations for metastatic colorectal cancer

Metastatic colorectal cancer (CRC) represents an important health problem in which several biological predictive and prognostic factors have been identified, including clinical features and molecular markers that might influence the response to treatment. Actually, certain prognostic factors are considered key elements, along with disease extent, for deciding the therapeutic approach. However, a distinction between resectable/potentially resectable and unresectable patients must be made in order to establish an adequate therapeutic strategy. Different drugs and chemotherapy regimens are currently available, and their administration depends on patient characteristics, disease-related factors and the treatment objective. Moreover, special situations such as peritoneal carcinomatosis and local treatment of CRC in the setting of metastatic disease should be considered when deciding the most appropriate treatment strategy. This article reviews all the previously mentioned issues involved in the management of metastatic CRC and suggests some general recommendations for its treatment (AU)

Non-skin solid tumors as a cause of morbidity and mortality after liver transplantation.

The use of immunosuppressive agents in renal transplant recipients increases the risk of tumor development. The global incidence of tumors in renal transplant recipients is 4% to 18% and is especially high for skin lesions, non-Hodgkin lymphoma, and genital malignancy but not for lung, breast, prostate gland, or colorectal lesions. Between May 1983 and May 2008, we performed 663 renal transplantation procedures; 85.5% were first transplantation procedures. Mean patient age was 46.93 years. Patients received treatment with combinations of immunosuppressive agents including corticosteroids, cyclosporine, OKT3, mycophenolate mofetil, tacrolimus, azathioprine, and basiliximab or daclizumab. The incidence of nonskin tumors was 4.07%. Mean age at diagnosis was 61.41 years, mean interval between transplantation and diagnosis of tumor was 6.04 years, and mean duration of graft function was 7.59 years. Mortality was due to tumor in 20.14% of patients, and of those with cancer, 74.07% died; all patients who died had a functioning graft. The most common malignant lesions were lung cancer in men and breast cancer in women. The incidence of nonskin tumors was lower than that in published series, probably because of routine screening of patients while on the waiting list and in transplant recipients with functioning grafts.

Interferon-alpha and its deleterious effects on kidney transplant: regarding one case

No disponible

No disponible

[Multicenter study of darbepoetin alfa in the treatment of anemia secondary to chronic renal insufficiency on dialysis]. / Estudio multicéntrico de darbepoetin alfa en el tratamiento de la anemia secundaria a insuficiencia renal crónica en diálisis.

This Spanish single-arm, multicenter, prospective clinical trial assessed the maintenance of hemoglobin concentrations (Hb) between 10-13 g/dL with unit doses of darbepoetin alfa and the safety of the treatment in dialysis patients. Eight-hundred twenty-six patients with chronic renal failure (CRF) (94% receiving haemodialysis and 6% receiving peritoneal dialysis) previously maintained on stable recombinant human erythropoietin (r-HuEPO) therapy with stable hemoglobin (Hb) concentrations (mean Hb concentration = 11.7 g/dL) were switched to darbepoetin alfa at a reduced dosing frequency for 24 weeks (a 20-week titration phase plus a 4-week treatment evaluation phase). Subjects receiving r-HuEPO two or three times weekly were switched to darbepoetin alfa once weekly, and those. who were receiving r-HuEPO once weekly were switched to darbepoetin alfa once every two weeks. The initial dose of darbepoetin alfa was determined from the r-HuEPO dose at inclusion into the study using a formula equating the peptide mass of the two molecules and rounding to the nearest available prefilled syringe dose. Overall, 86.8% of patients completed the 24-weeks of study. Changing the treatment from r-HuEPO to darbepoetin alfa and increasing the dose interval did not result in any clinically significant change in the Hb concentration. From base-line to the evaluation phase, the mean Hb fell 0.09 (95% CI, -0.2; -0.0) g/dl, with an increase of 0.19 (95% CI, 0.0;0.3) g/dL i.v. and a decrease of 0.22 (95% CI, -0.3; -0.1) g/dL s.c.). This maintenance of the mean Hb concentration was accompanied by a mean 9.8% reduction of the darbepoetin alfa dose (19.7% (95% CI, -24.9; -14.2) i.v. and 4.7% (95% CI, -8.5; -0.7) s.c. Treatment with darbepoetin alfa was well tolerated and no unexpected adverse events were reported. In conclusion, the replacement of previous r-HuEPO treatment by darbepoetin alfa in the therapy of anemia secondary to chronic renal failure in diaiyzed patients was effective, well tolerated, and decreased the frequency of dose administration compared with the previous r-HuEPO treatment. Darbepoetin alfa administered once weekly or once every two weeks maintained the baseline Hb levels whilst allowing dose reduction, which was higher in patients receiving i.v. darbepoetin alfa.

Estudio multicéntrico de darbepoetin alfa en el tratamiento de la anemia secundaria a insuficiencia renal crónica en diálisis / Darbepoietin treatment of anemia secondary to chronic renal failure in dialysis

Este ensayo clínico prospectivo, multicéntrico, de un solo brazo, evaluó el mantenimiento de las concentraciones de hemoglobina (Hb) entre 10-13 g/dL con darbepoetin alfa y la seguridad de este tratamiento, en pacientes con insuficiencia renal crónica (IRC) en diálisis (94% hemodiálisis, 6% diálisis peritoneal, concentración de Hb basal = 11,7 g/dL) tratados hasta el inicio de este estudio con eritropoyetina recombinante humana (r-HuEPO). Se incluyeron 826 pacientes con concentraciones de Hb y dosis de r-HuEPO estables (824 recibieron al menos una dosis de darbepoetin alfa y fueron evaluables para el análisis de seguridad). Los pacientes recibieron darbepoetin alfa durante 24 semanas (20 de titulación más 4 de evaluación). La dosis inicial de darbepoetin alfa se determinó a partir de la dosis previa de r-HuEPO, utilizando la equivalencia en masa peptídica entre ambas moléculas y ajustando a la jeringa precargada más próxima. Se administró darbepoetin alfa 1 × semana (en pacientes en tratamiento previo con r-HuEPO 2-3 × semana) o cada dos semanas (en los pacientes con r-HuEPO 1 × semana). El 86,8% de los pacientes completaron las 24 semanas de estudio. El cambio del tratamiento a menor frecuencia de dosificación no produjo modificaciones clínicamente significativas en la concentración de Hb [los cambios desde la visita basal al período de evaluación consistieron en un descenso de 0,09 (IC 95%, –0,2; –0,0) g/dL, con aumento de 0,19 (IC 95% 0,0; 0,3) g/dL en la vía iv y descenso de 0,22 (IC 95%, –0,3; –0,1) g/dL en la vía sc]. Este mantenimiento de Hb se acompañó de una reducción media de la dosis de darbepoetin alfa de un 9,8% (IC 95%, –12,9; –6,6) [19,7% (IC 95%, -24,9;-14,2) (vía iv) y 4,7% (IC 95%, –8,5; –0,7) (vía sc)]. El tratamiento con darbepoetin alfa fue bien tolerado, no observándose acontecimientos adversos inesperados. En conclusión, la sustitución de cér-HuEPO por darbepoetin alfa en la terapia de la anemia secundaria a IRC en pacientes en diálisis fue eficaz, bien tolerada y disminuyó la frecuencia de administración de dosis en comparación con el tratamiento previo con r-HuEPO. Darbepoetin alfa 1 vez por semana o 1 vez cada 2 semanas mantuvo los niveles de Hb basales a la vez que permitió una reducción de la dosis por ambas vías de administración, siendo mayor en los pacientes tratados por vía iv

This Spanish single-arm, multicenter, prospective clinical trial assessed the maintenance of hemoglobin concentrations (Hb) between 10-13 g/dL with unit doses of darbepoetin alfa and the safety of the treatment in dialysis patients. Eight-hundred twenty-six patients with chronic renal failure (CRF) (94% receiving haemodialysis and 6% receiving peritoneal dialysis) previously maintained on stable recombinant human erythropoietin (r-HuEPO) therapy with stable hemoglobin (Hb) concentrations (mean Hb concentration = 11.7 g/dL) were switched to darbepoetin alfa at a reduced dosing frequency for 24 weeks (a 20-week titration phase plus a 4-week treatment evaluation phase). Subjects receiving r-HuEPO two or three times weekly were switched to darbepoetin alfa once weekly, and those. who were receiving r-HuEPO once weekly were switched to darbepoetin alfa once every two weeks. The initial dose of darbepoetin alfa was determined from the r-HuEPO dose at inclusion into the study using a formula equating the peptide mass of the two molecules and rounding to the nearest available prefilled syringe dose. Overall, 86.8% of patients completed the 24-weeks of study. Changing the treatment from r-HuEPO to darbepoetin alfa and increasing the dose interval did not result in any clinically significant change in the Hb concentration. From baseline to the evaluation phase, the mean Hb fell 0.09 (95% CI, –0.2; –0.0) g/dl, with an increase of 0.19 (95% CI, 0.0;0.3) g/dL iv and a decrease of 0.22 (95% CI, –0.3; –0.1) g/dL sc). This maintenance of the mean Hb concentration was accompanied by a mean 9.8% reduction of the darbepoetin alfa dose (19.7% (95% CI, –24.9;-14.2) iv and 4.7% (95% CI, –8.5; –0.7) sc. Treatment with darbepoetin alfa was well tolerated and no unexpected adverse events were reported. In conclusion, the replacement of previous r-HuEPO treatment by darbepoetin alfa in the therapy of anemia secondary to chronic renal failure in diaiyzed patients was effective, well tolerated, and decreased the frequency of dose administration compared with the previous r-HuEPO treatment. Darbepoetin alfa administered once weekly or once every two weeks maintained the baseline Hb levels whilst allowing dose reduction, which was higher in patients receiving iv darbepoetin alfa

Weekly docetaxel in breast cancer: applying clinical data to patient therapy.

The use of weekly 35-40 mg/m2 docetaxel, typically on a schedule of 6 weeks of therapy followed by a 2-week break, has produced response rates ranging from 33%-50% in patients with advanced breast cancer, the majority of whom have already received chemotherapy. These encouraging levels of response are seen across disease sites and in patients with prior anthracycline exposure. Importantly, the weekly administration of docetaxel allows prolonged treatment to a high cumulative dose: the weekly regimen is minimally myelotoxic, and neuropathy and other adverse events are infrequent. Weekly single-agent docetaxel may be a useful therapy in particular groups of patients such as those with reduced bone marrow reserve. It may also be a helpful means of delivering a highly active cytotoxic drug in combination with radiation therapy, other proven chemotherapy agents such as doxorubicin, and new, highly promising biological agents such as HERCEPTIN:

Gemcitabine/paclitaxel-based three-drug regimens in advanced urothelial cancer.

Transitional cell carcinoma (TCC) of the urothelium is a highly chemosensitive tumour. Combination chemotherapy can provide both palliation and a modest survival advantage in patients with advanced disease. At present, the combination of cisplatin, methotrexate, doxorubicin and vinblastine (M-VAC) is the most widely used for advanced TCC with an overall response rate of 40-72% in phase II, and 35-45% in phase III studies, and a median survival of approximately 12 months. These modest results and the unsuccessful attempts to increase efficacy with dose intensive M-VAC schedules have prompted the identification of new active agents in TCC, such as the taxanes and gemcitabine. The overall response rates for two-drug regimens of cisplatin-paclitaxel, carboplatin-paclitaxel and cisplatin-gemcitabine range from 63 to 72%, 14 to 65% and 42 to 66%, respectively. The overall response rates for platinum-paclitaxel-gemcitabine three-drug regimens range from 58 to 80%. The potential clinical benefit of these new three-drug combinations in the treatment of TCC needs to be tested in future phase III studies.

Tumor markers at the time of recurrence in patients with germ cell tumors.

BACKGROUND: alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG), and lactate dehydrogenase (LDH) closely follow the course of germ cell tumors (GCTs) and are widely used for diagnosis, prognosis, and follow-up purposes. The objective of this study was to assess the concordance of tumor markers at the time of diagnosis and recurrence. METHODS: The authors reviewed the records of 794 patients with GCTs treated in three Spanish hospitals from 1977-1996 and analyzed the concordance between AFP, HCG, and LDH levels at diagnosis and first and second recurrence. A positive marker was defined as a level of AFP > 10 ng/mL, HCG > 5 IU/L, or LDH > the upper limit of normal. One hundred twenty-five patients were identified who developed a first recurrence (123 had marker levels recorded). The median age was 27 years (range, 14-78 years). Histology was seminoma in 36 patients (29%) and nonseminomatous GCT (NSGCT) in 87 patients (71%). RESULTS: Seventy-nine patients (64%) had elevated tumor markers at diagnosis and 76 (62%) at first recurrence. An elevated marker was present at first recurrence in 58 of 79 patients (73%) with initially positive markers and in 18 of 44 patients (41%) with initially negative markers. In 84 of 123 patients (68%), the same marker pattern (positive or negative) was present at the time of diagnosis and at first recurrence, 78% in seminomas and 64% in NSGCTs. The earliest indicator of recurrence was an elevated marker in patients with NSGCTs and a radiologic finding in patients with seminomas. Thirty patients developed a second recurrence, 27 of whom (90%) had the same marker pattern as at first recurrence. CONCLUSIONS: Tumor marker pattern at diagnosis is not a good predictor of the pattern at recurrence, particularly in patients with NSGCTs. Marker assessment should be included in the follow-up schedule regardless of levels at the time of diagnosis. Early detection of recurrence should not rely only on marker levels, even in patients with elevated levels at presentation.

BOMP/EPI intensive alternating chemotherapy for IGCCC poor-prognosis germ-cell tumors: the Spanish Germ-Cell Cancer Group experience (GG)

BACKGROUND: Patients with poor-prognosis germ-cell tumors according to the IGCCC have a poor long-term survival. This study evaluates the efficacy and toxicity of the intensive alternating chemotherapy regimen BOMP/EPI in these patients. PATIENTS AND METHODS: Patients with IGCCC poor-prognosis germ-cell tumors treated at 13 centres were studied. Treatment consisted of bleomycin 30 mg, vincristine 2 mg, methotrexate 300 mg/m2 and cisplatin 100 mg/m2 (BOMP), alternating after a 14-day interval with etoposide 120 mg/m2 day 1-4, ifosfamide 1.3 g/m2 day 1-4 and cisplatin 25 mg/m2 day 1-4 (EPI). BOMP was administered 21 days after the EPI. Bleomycin was administered weekly per 12 weeks. RESULTS: Thirty-eight patients were treated. The median number of cycles administered was 7 (1-10 cycles). Eighteen patients achieved complete responses with chemotherapy alone (12 had necrosis and 2 mature teratoma at postchemotherapy resection), and four achieved complete responses with chemotherapy and surgical resection of viable cancer. Thus, an overall favorable response was achieved in 22 patients (60%). Four additional patients had marker-negative non-resected residual masses. Eleven patients were considered treatment failures, including one who died early and another who succumbed to granulocytopenic sepsis and renal failure. Hematologic toxicity was the most common, with 26 patients (70%) having grade 4 granulocytopenia. After a median follow-up of 41 months, the actuarial two-year overall survival and progression-free survival were 64% and 58%, respectively. CONCLUSION: BOMP/EPI is active in poor-prognosis germ-cell tumors according to the IGCCC criteria. The results obtained compare favorably with those expected with conventional chemotherapy, and justify further studies.

Infectious complications in 126 patients treated with high-dose chemotherapy and autologous peripheral blood stem cell transplantation.

The effect of an extensive prophylactic antimicrobial regimen was prospectively assessed in 126 patients after high-dose chemotherapy and autologous PBSC. They received ciprofloxacin (500 mg/12 h), acyclovir (200 mg/6 h), and itraconazole (200 mg/12 h) orally until neutrophil recovery. Febrile patients received i.v. imipenem (500 mg/6 h) to which vancomycin and amikacin were added if fever persisted for 2-3 and 5 days, respectively. Amphotericin B lipid complex was further given on day 7 or 8 of fever. Median times for a neutrophil count of >0.5 x 10(9)/l and a platelet count of >20 x 10(9)/l were 9 and 11 days. Severe neutropenia (<0.1 x 10(9)/l) lasted for a median of 5 days in which 72% of febrile episodes and 50% of cases of bacteremia occurred. Gram-positive bacteria were isolated in 30 of 40 episodes of bacteremia, 25 of which were caused by Staphylococcus epidermidis. Clinical foci were the intravascular catheter in 35 cases, respiratory infection in 11, cellulitis in two, anal abscess in one, and neutropenic enterocolitis in one. The high incidence of febrile episodes (94%) and bacteremias (31%) may be due to the lack of efficacy of antimicrobial prophylaxis and the persistence of a 5-day period of severe neutropenia.