First-line single-agent regorafenib in frail patients with metastatic colorectal cancer: a pilot phase II study of the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD).

BACKGROUND: Treatment of frail patients with advanced colorectal cancer (CRC) is controversial. This pilot phase II trial aimed to assess the efficacy and safety of regorafenib when administered in first-line to frail patients with advanced CRC. METHODS: Frail patients without prior advanced colorectal cancer treatment were included in the study. Definition of frailty was defined per protocol based on dependency criteria, presence of chronic comorbid pathologies and/or geriatric features. MAIN OBJECTIVE: to assess progression-free survival (PFS) rate at 6 months. Treatment consisted of 28-day cycles of orally administered regorafenib 160 mg/day (3 weeks followed by 1 week rest). RESULTS: Forty-seven patients were included in the study. Median age was 81 years (range 63-89). Frailty criteria: dependency was observed in 26 patients (55%), comorbidities in 27 (57%) and geriatric features in 18 (38%). PFS rate at 6 months was 45% (95% confidence interval [CI] 30-60]. Median PFS was 5.6 months (95%CI 2.7-8.4). Median overall survival (OS) was 16 months (95%CI 7.8-24). Complete response, partial response and stable disease were observed in one, two and 21 patients respectively (objective response rate 6.4%; disease control rate 51%). Thirty-nine patients (83%) experienced grade 3-4 adverse events (AEs). The most common grade 3-4 AEs were hypertension (15 patients; 32%), asthenia (14; 30%), hypophosphatemia (6; 13%); diarrhea (4; 8%), hand-foot-skin reaction (4; 8%). There were two toxic deaths (4.2%) (grade 5 rectal bleeding and death not further specified). Dose reduction was required in 26 patients (55%) and dose-delays in 13 patients (28%). CONCLUSIONS: The study did not meet the pre-specified boundary of 55% PFS rate at 6 months. Toxicity observed (83% patients experienced grade 3 and 4 AEs) preclude its current use in clinical practice on this setting. Disease control rate and overall survival results are interesting and might warrant further investigation to identify those who benefit from this approach. TRIAL REGISTRATION: This trial was prospectively registered at EudraCT ( 2013-000236-94 ). Date of trial registration: April 9th, 2013.

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.

Management of atypical uremic hemolytic syndrome in pregnant patient.

Atypical uremic haemolytic syndrome is a variant of thrombotic micro-andiopathy characterized by non-autoimmune hemolytic anemia, thrombocytopenia and acute renal failure as a result of excessive activation of the complement. Up to 60% of patients have mutations in the genes that encode the complement system. A disensing factor is required for its manifestation, including gestation. It is an entity with a high morbidity, which can decrease drastically if an early diagnosis is made and appropriate treatment is initiated. Administration of ecuilizumab has demonstrated rapid process disruption, reducing the need for extrarenal purification therapies and improving renal function and patient prognosis.

Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation.

Median survival of patients with brain metastases from nonsmall cell lung cancer (NSCLC) is poor and more effective treatments are urgently needed. We have evaluated the efficacy of erlotinib in this setting and its association with activating mutations in the epidermal growth factor receptor (EGFR) gene. We retrospectively identified patients with NSCLC and brain metastases treated with erlotinib. EGFR mutations in exons 19 and 21 were analysed by direct sequencing. Efficacy and tolerability were compared according to EGFR mutational status. 69 NSCLC patients with brain metastases were identified, 17 of whom harboured EGFR mutations. Objective response rate in patients with EGFR mutations was 82.4%; no responses were observed in unselected patients (p<0.001). Median (95% CI) time to progression within the brain for patients harbouring EGFR mutations was 11.7 (7.9-15.5) months, compared to 5.8 (5.2-6.4) months for control patients whose EGFR mutational status had not been assessed (p<0.05). Overall survival was 12.9 (6.2-19.7) months and 3.1 (2.5-3.9) months (p<0.001), respectively. The toxicity of erlotinib was as expected and no differences between cohorts were observed. Erlotinib is active in brain metastases from NSCLC; this clinical benefit is related to the presence of activating mutations in exons 19 or 21 of the EGFR gene.

Management of atypical uremic hemolytic syndrome in pregnant patient. / Manejo de síndrome hemolítico urémico atípico en la paciente gestante.

Atypical uremic haemolytic syndrome is a variant of thrombotic micro-andiopathy characterized by non-autoimmune hemolytic anemia, thrombocytopenia and acute renal failure as a result of excessive activation of the complement. Up to 60% of patients have mutations in the genes that encode the complement system. A disensing factor is required for its manifestation, including gestation. It is an entity with a high morbidity, which can decrease drastically if an early diagnosis is made and appropriate treatment is initiated. Administration of ecuilizumab has demonstrated rapid process disruption, reducing the need for extrarenal purification therapies and improving renal function and patient prognosis.

Influence of BRAF and PIK3CA mutations on the efficacy of FOLFIRI plus bevacizumab or cetuximab as first-line therapy in patients with RAS wild-type metastatic colorectal carcinoma and <3 baseline circulating tumour cells: the randomised phase II VISNÚ-2 study.

BACKGROUND: We explored the influence of BRAF and PIK3CA mutational status on the efficacy of bevacizumab or cetuximab plus 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) as first-line therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: VISNÚ-2 was a multicentre, randomised, phase II study. Patients with RAS wild-type mCRC and <3 circulating tumour cells/7.5 ml blood were stratified by BRAF/PIK3CA status (wild-type versus mutated) and number of affected organs (1 versus >1), and allocated to bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m2 then 250 mg/m2 weekly) plus FOLFIRI [irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 (bolus) then 2400 mg/m2 (46-h continuous infusion) every 2 weeks]. The primary endpoint was progression-free survival (PFS). All analyses were exploratory. RESULTS: Two hundred and forty patients with BRAF/PIK3CA wild-type (n = 196) or BRAF- and/or PIK3CA-mutated tumours (n = 44) were enrolled. Median PFS was 12.7 and 8.8 months in patients with BRAF/PIK3CA wild-type and BRAF/PIK3CA-mutated tumours, respectively [hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.80-1.85; P = 0.3602]. In the BRAF- and/or PIK3CA-mutated cohort, median PFS was 2.8, 8.8 and 15.0 months in patients with BRAF/PI3KCA-mutated (n = 8), BRAF-mutated/PI3KCA wild-type (n = 16) and BRAF wild-type/PI3KCA-mutated (n = 20) tumours, respectively (P = 0.0002). PFS was similar with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in BRAF/PIK3CA wild-type (HR = 0.99; 95% CI 0.67-1.45; P = 0.9486) and BRAF/PIK3CA-mutated tumours (HR = 1.11; 95% CI 0.53-2.35; P = 0.7820). The most common grade 3/4 treatment-related adverse events were neutropenia, diarrhoea and asthenia in both treatment groups. CONCLUSIONS: BRAF/PIK3CA status influences outcomes in patients with RAS wild-type mCRC but does not appear to assist with the selection of first-line targeted therapy.

Treatment patterns for metastatic colorectal cancer in Spain.

PURPOSE: The primary aim of this retrospective study was to describe the treatment patterns according to the type of treatment received by patients with metastatic colorectal cancer (mCRC) in Spain. METHODS: This was a retrospective, observational, multicenter study performed by 33 sites throughout Spain that included consecutive patients aged 18 years or older who had received or were receiving treatment for mCRC. RESULTS: At the time of inclusion, of the 873 evaluable patients, 507 (58%) had received two lines, 235 (27%) had received three lines, 106 (12%) had received four lines, and the remaining patients had received up to ten lines. The most frequent chemotherapy schemes were the FOLFOX or CAPOX regimens (66%) for first-line treatment, FOLFOX, CAPOX or FOLFIRI (70%) for second-line treatment, and FOLFOX, FOLFIRI or other fluoropyrimidine-based regimens for third- and fourth-line (over 60%) treatment. Sixty percent of patients received targeted therapy as part of their first-line treatment, and this proportion increased up to approximately 70% of patients as part of the second-line of treatment. A relevant proportion of patients were treated with unknown KRAS, and especially the BRAF, mutation statuses. CONCLUSIONS: This study reveals inconsistencies regarding adherence to the recommendations of the ESMO guidelines for the management of mCRC in Spain. Improved adherence to the standard practice described in such guidelines for the determination of RAS and BRAF mutation statuses and the use of targeted therapies in first-line treatment should be considered to guarantee that patients can benefit from the best therapeutic approaches available.

Massive lower gastrointestinal haemorrhage, successfully treated with corticosteroids, as main symptom of Schönlein-Henoch purpura.

Schönlein-Henoch purpura is a small vessel disease that affects mainly skin and kidney, although several gastrointestinal symptoms may occur including abdominal pain, intussusception, perforation or bleeding. Massive lower gastrointestinal haemorrhage is rare and even more as the main symptom of the disease. We present a case of a 2-year-old boy with Schönlein-Henoch purpura who developed a massive lower gastrointestinal bleeding requiring blood transfusion. In this patient both Schönlein-Henoch purpura and gastrointestinal haemorrhage were successfully treated with intravenous methylprednisolone, avoiding surgical intervention. Physicians need to have a high index of suspicion when evaluating these patients, even more when dermatologic signs are scarce. Glucocorticosteroid therapy may be effective when treating severe gastrointestinal symptoms.

[The megacystis-microcolon-intestinal hypoperistalsis syndrome: apropos of a case with prolonged survival]. / Síndrome de megavejiga-microcolon-hipoperistalsis intestinal: a propósito de un caso de supervivencia prolongada.

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a severe congenital disease with autosomal recessive inheritance, characterized by vesical distension and intestinal hypoperistalsis what causes intestinal obstruction in newborn, with other abnormalities associated. It presents a low incidence, about a hundred cases are reported in the bibliography. Life expectancy doesn't reach a year because of the sepsis failure generally. In our study the survival is higher than the majority of the cases reported, with good cuality of life and acceptable ponderal development. Home parenteral nutrition with the following and multidisciplinary collaboration in a strict way, establish the success' key in this pathology.

Label-free in-flow detection of receptor recognition motifs on the biomolecular corona of nanoparticles.

Nanomedicine, nanotargeting and nanotherapeutics have in the last few years faced several difficulties in translating the promising results obtained in vitro to an in vivo scenario. The origin of this discrepancy might be found in the lack of a detailed and realistic characterization of the biological surface of nanoparticles. Despite the capability to engineer nanomaterials with a great variety and a precise control of the surface functionalization, the targeting capability is lost when the nanoparticles are embedded in complex biological media, due to the formation of a biological layer (biomolecular corona). This biological layer represents the ultimate nanoparticle surface, likely to interact with the cell machinery. Therefore, in addition to traditional nanoparticle characterization techniques, a more insightful investigation of the biomolecular corona is needed, including the capability to assess the orientation and functionality of specific key molecular features. Here we present a method for the rapid screening of exposed protein recognition motifs on the surface of nanoparticles exploiting quartz crystal microbalance (QCM). We quantify accessible functional epitopes of transferrin-coated nanoparticles and correlate them to differences in nanoparticle size and functionalization. The target recognition occurs label free in flow, thereby pushing our investigation into a more in vivo-like scenario. Our method is applicable to a wide array of nanoparticles and therefore holds the potential to become an advanced technique for the classification of all kinds of nanobioconstructs based on their biological external functionality.

Trends in hepatitis B and hepatitis C seroprevalence among blood donors - Haiti, 2005-2014.

Background and Objectives: Data on the seroprevalence of viral hepatitis are limited in Haiti; consequently, the epidemiology is poorly described. This study aims to provide a descriptive analysis of hepatitis B virus (HBV) and hepatitis C virus (HCV) seroprevalence of blood donations in Haiti. Materials and Methods: Using Haiti's National Blood Safety Program and Haitian Red Cross reports from 2005 to 2014, we analysed the results of screening tests of donor serum samples to assess HBV and HCV seroprevalence among adults aged 17 to 65 years. Results: A total of 198 758 donor samples were screened from 2005 to 2014, of which 0·56% were positive for antibody to hepatitis C virus (anti-HCV) and 3·80% were positive for hepatitis B surface antigen. Over the 10-year study period, anti-HCV seroprevalence among blood donors increased by 31% from 0.66% to 0.86% (95% CI: 1·01-1·70); however, this trend was not uniform over time, with a significant decrease from 0·66% in 2005 to 0·39% in 2009 (95% CI: 0·43- 0·82) and 0·43% in 2012 (95% CI: 0·50-0·90). Conversely, HBV decreased significantly by 13% from 3·95% in 2005 to 3·42% in 2014 (95% CI: 0·77-0·97), a trend that was also observed in 2012 and 2013. Conclusion: The significant, uniform decrease in HBV seroprevalence in more recent years may represent the positive impact of public health interventions in preventing the transmission of blood-borne infections. More research is needed to understand why the trends in HCV transmission are non-uniform and to investigate the significant increase in more recent years.

Biological recognition of graphene nanoflakes.

The systematic study of nanoparticle-biological interactions requires particles to be reproducibly dispersed in relevant fluids along with further development in the identification of biologically relevant structural details at the materials-biology interface. Here, we develop a biocompatible long-term colloidally stable water dispersion of few-layered graphene nanoflakes in the biological exposure medium in which it will be studied. We also report the study of the orientation and functionality of key proteins of interest in the biolayer (corona) that are believed to mediate most of the early biological interactions. The evidence accumulated shows that graphene nanoflakes are rich in effective apolipoprotein A-I presentation, and we are able to map specific functional epitopes located in the C-terminal portion that are known to mediate the binding of high-density lipoprotein to binding sites in receptors that are abundant in the liver. This could suggest a way of connecting the materials' properties to the biological outcomes.

Geographic distribution of blood collections in Haiti before and after the 2010 earthquake.

BACKGROUND: The January 2010 Haiti earthquake destroyed the National Blood Transfusion Center and reduced monthly national blood collections by > 46%. Efforts to rapidly scale-up blood collections outside of the earthquake-affected region were investigated. STUDY DESIGN AND METHODS: Blood collection data for 2004-2014 from Haiti's 10 administrative departments were grouped into four regions: Northern, Central, Port-au-Prince and Southern. Analyses compared regional collection totals during the study period. RESULTS: Collections in Port-au-Prince accounted for 52% of Haiti's blood supply in 2009, but fell 96% in February 2010. Haiti subsequently increased blood collections in the North, Central and Southern regions to compensate. By May 2010, national blood collections were only 10·9% lower than in May 2009, with 70% of collections coming from outside of Port-au-Prince. By 2013 national collections (27 478 units) had surpassed 2009 levels by 30%, and Port-au-Prince collections had recovered (from 11 074 units in 2009 to 11 670 units in 2013). CONCLUSION: Haiti's National Blood Safety Program managed a rapid expansion of collections outside of Port-au-Prince following the earthquake. Annual collections exceeded pre-earthquake levels by 2012 and continued rising annually. Increased regional collections provided a greater share of the national blood supply, reducing dependence on Port-au-Prince for collections.

Towards a classification strategy for complex nanostructures.

The range of possible nanostructures is so large and continuously growing, that collating and unifying the knowledge connected to them, including their biological activity, is a major challenge. Here we discuss a concept that is based on the connection of microscopic features of the nanomaterials to their biological impacts. We also consider what would be necessary to identify the features that control their biological interactions, and make them resemble each other in a biological context.

SEOM Clinical Guideline of localized rectal cancer (2016).

Localized rectal adenocarcinoma is a heterogeneous disease and current treatment recommendations are based on a preoperative multidisciplinary evaluation. High-resolution magnetic resonance imaging and endoscopic ultrasound are complementary to do a locoregional accurate staging. Surgery remains the mainstay of treatment and preoperative therapies with chemoradiation (CRT) or short-course radiation (SCRT) must be considered in more locally advanced cases. Novel strategies with induction chemotherapy alone or preceding or after CRT (SCRT) and surgery are in development.

[Treatment of bone metastatic pain with Sm153-EDTMP. Evaluation of the analgesic response and the existence of differences according to the primary tumor and the metastatic pattern]. / Tratamiento del dolor óseo metastásico con Sm153-EDTMP. Valoración de la respuesta analgésica y de la existencia de diferencias según el tipo de tumor y el patrón metastásico.

AIMS: To evaluate the response to Sm153-EDTMP treatment in patients with metastatic bone pain and the existence of differences in the response according to the scintigraphic pattern (99mTc-MDP) and the primary tumor. MATERIAL AND METHODS: We have evaluated the response to Sm153-EDTMP treatment in 32 patients (17 male and 15 female) who received 38 doses (1 mCi/kg). The primary tumor was prostate cancer in 15 patients, breast in 13, lung in 2, intestinal carcinoid in one and unknown in one. Two types of response were considered: a) effective and b) non-effective. Patients were classified into 3 groups according to the metastatic pattern: 1) Superscan (SS), 2) Generalized metastases (GM) and 3) Regional metastases (RM). RESULTS: There was effective response in 24 doses (63.15%) and non-effective in 14 (36.84%). The mean duration of the response was 12.08 weeks. Patients with GM pattern showed 16 effective responses (76.19%) and 5 non-effective (23.8%). In SS pattern there were 6 effective responses (60%) and 4 non-effective (40%) and 2 effective (28.57%) and 5 non-effective (71.53%) in RM pattern. These differences did not reach statistical significance (p > 0.05). We did not find differences in the response between prostate cancer (12 effective and 6 non-effective) and breast cancer (10 effective and 6 non-effective) (p = 0.79968). CONCLUSIONS: Sm153-EDTMP treatment is efficacious in patients with metastatic bone pain with effective response in 63.15% of the treatments. The response percentage was lower in patients with RM pattern but the differences did not reach statistical significance. There were no differences in the response between prostate and breast cancer patients.

Ampollas Hemorrágicas en Purpura de Henoch - Schönlein en paciente pediátrico a propósito de un caso y revisión de la literatura / Hemorrhagic Bullous in Henoch - Schönlein Purpura in childrenabout a case and review of the literature

RESUMEN La Púrpura de Henoch - Schönlein (PHS) es una vasculitis leucocitoclástica, autolimitada que en la mayoría de los casos presenta manifestaciones cutáneas de purpura palpable acompañada de dolor articular, abdominal y alteración de la función renal. Reportamos un caso pediátrico de púrpura con ampollas de contenido hemorrágico variedad rara de presentación y difícil diagnóstico.

SUMARY Henoch-Schönlein purpura (HSP) is a self-limited a leukocytoclastic vasculitis, the most case have palpable purpura skin manifestations with arthralgia strong abdominal pain, and renal function compromise. We report a pediatric case of purpura with hemorrhagic blisters rare variety of presentation and difficult diagnosis.

Conjunctival intraepithelial and invasive squamous cell carcinomas treated with strontium-90.

Twenty-seven patients with malignant epithelial tumors of the conjunctiva were treated between 1967 and 1987. Histological diagnosis was intraepithelial epithelioma in 15 cases (56%) and squamous cell carcinoma in 12 (44%). All patients were treated with a strontium-90 source on cup-shaped applicators of different sizes according to the extension of the tumor. Surface dose ranged from 60 Gy in a single treatment to 140 Gy in 7 fractions, depending on the thickness of the lesion. Fifteen patients were previously untreated, 7 were irradiated after some type of surgical treatment and 5 were treated for recurrence after multiple surgical excisions. Follow-up period ranged from 2 to 15 years. No patient died of his tumor. There were four local recurrences, three of them in patients with intraepithelial carcinoma. Two of the recurrences were salvaged with a new beta-ray treatment and the other two with enucleation. Since 1981, standard policy was to irradiate the entire conjunctiva in patients with diagnosis of intraepithelial epithelioma. Five patients developed cataracts. Considering the high primary control rate and minimal morbidity, strontium irradiation should be considered as a first-choice treatment for conjunctival tumors.

Vitamin C status, cervico-vaginal infection and premature rupture of amniotic membranes.

A prospective study to evaluate the role of vitamin C and cervico-vaginal infection in the premature rupture of amniotic membranes (PROM) was designed. The leukocyte vitamin C levels of 44 pregnant women that did not consume vitamin supplements was evaluated at weeks 20, 28 and 32 of pregnancy. On each evaluation the presence of cervico-vaginal infection was diagnosed and treated. The leukocyte vitamin C level throughout gestation showed a decrease towards week 28 and then it recovered at the end of pregnancy. Six of every ten women had normal flora in their vaginal secretion cultures. Eleven cases had PROM (0.24), no association was found between cervico-vaginal infection and PROM. The leukocyte vitamin C levels on week 20 of gestation showed an association with PROM. (chi 2 = 6.34, p < 0.05, odds ratio 6.75 [CI 1.26-26.03]).

Effects of S-9977-2 on histamine levels in rats.

S-9977-2 is a new molecule with promnesic and antiamnesic properties. In this study, we investigated the effects of i.p. administration of S-9977-2 on histamine (HA) levels in several regions of the rat brain, and also in peripheral areas, using high performance liquid chromatography (HPLC) with fluorometric detection. S-9977-2 (0.025 mg/kg) induced an increase in the content of HA in the anterior hypothalamic region, with a significant effect 30 min after injection (1.77 +/- 0.36 nmol/g vs. 2.43 +/- 0.40 nmol/g; p < 0.01). It did not significantly modify HA levels in the posterior hypothalamic region, hippocampus, fronto-parietal cortex, blood, spleen, or adrenal glands. A clear tendency to increase HA content was observed in the hippocampus (0.16 +/- 0.03 nmol/g vs. 0.39 +/- 0.31 nmol/g, ns) and fronto-parietal cortex (0.55 +/- 0.45 nmol/g vs. 0.70 +/- 0.28 nmol/g; ns). S-9977-2 at doses of 0.005 and 0.125 mg/kg i.p. did not produce any significant change in HA levels in any of the samples tested 30 min after administration. The present results demonstrate that S-9977-2 increases HA levels in the anterior hypothalamus, which is the brain region with the highest content in histaminergic fibers. This fact suggests that the neuronal HA system might be involved directly or indirectly in the pharmacological actions of S-9977-2.