Short-term neuropsychiatric outcomes and quality of life in COVID-19 survivors.

BACKGROUND: The general medical impacts of coronavirus (COVID-19) are increasingly appreciated. However, its impact on neurocognitive, psychiatric health and quality of life (QoL) in survivors after the acute phase is poorly understood. We aimed to evaluate neurocognitive function, psychiatric symptoms and QoL in COVID-19 survivors shortly after hospital discharge. METHODS: This was a cross-sectional analysis of a prospective study of hospitalized COVID-19 survivors followed up for 2 months after discharge. A battery of standardized instruments evaluating neurocognitive function, psychiatric morbidity and QoL (mental and physical components) was administered by telephone. RESULTS: Of the 229 screened patients, 179 were included in the final analysis. Amongst survivors, the prevalence of moderately impaired immediate verbal memory and learning was 38%, delayed verbal memory (11.8%), verbal fluency (34.6%) and working memory (executive function) (6.1%), respectively. Moreover, 58.7% of patients had neurocognitive impairment in at least one function. Rates of positive screening for anxiety, depression and post-traumatic stress disorder were 29.6%, 26.8% and 25.1%, respectively. In addition, 39.1% of the patients had psychiatric morbidity. Low QoL for physical and mental components was detected in 44.1% and 39.1% of patients respectively. Delirium and psychiatric morbidity were associated with neurocognitive impairment, and female gender was related with psychiatric morbidity. CONCLUSION: Hospitalized COVID-19 survivors showed a considerable prevalence of neurocognitive impairment, psychiatric morbidity and poor QoL in the short term. It is uncertain if these impacts persist over the long term.

Molecular diversity of Staphylococcus aureus and the role of milking equipment adherences or biofilm as a source for bulk tank milk contamination.

Staphylococcus aureus is one of the most frequent pathogens causing intramammary infections in dairy herds. Consequently, virulence factors, pathobiology, and epidemiology of Staphylococcus aureus strains have been widely assessed through the years. Nevertheless, not much has been described about the epidemiology of Staph. aureus strains from bulk tank milk (BTM) and adherences on milking equipment (AMES), even when these strains may play a role in the quality of milk that is intended for human consumption. The objective of this study was to assess the strain diversity of 166 Staph. aureus isolates collected from 3 consecutive BTM samples, and from AMES in contact with milk from 23 Chilean dairy farms. Isolates were analyzed and typed using pulsed-field gel electrophoresis. Diversity of strains, both within and among farms, was assessed using Simpson's index of diversity (SID). On farms where Staph. aureus was isolated from both AMES and BTM (n = 8), pulsotypes were further analyzed to evaluate the role of AMES as a potential source of Staph. aureus strains in BTM. Among all Staph. aureus analyzed by pulsed-field gel electrophoresis, a total of 42 pulsotypes (19 main pulsotypes and 23 subtypes) were identified. Among dairy farms, strain diversity was highly heterogeneous (SID = 0.99). Within dairy farms, Staph. aureus strain diversity was variable (SID = 0 to 1), and 18 dairy operations (81.8%) had one pulsotype that was shared between at least 2 successive BTM samples. In those farms where Staph. aureus was isolated in both AMES and BTM (n = 8), 7 (87.5%) showed a clonal distribution of Staph. aureus strains between these 2 types of samples. The overlapping of certain Staph. aureus strains among dairy farms may point out common sources of Staph. aureus among otherwise epidemiologically unrelated farms. Indistinguishable Staph. aureus strains between AMES and BTM across dairy farms suggest that Staph. aureus-containing AMES may represent a source for BTM contamination, thus affecting milk quality. Our study highlights the role of viable Staph. aureus in AMES as a source for BTM contamination on dairy farms, and also describes the overlapping and presence of specific BTM and AMES pulsotypes among farms.

KCNN2 mutation in autosomal-dominant tremulous myoclonus-dystonia.

BACKGROUND AND PURPOSE: Despite recent advances in neurogenetics that have facilitated the identification of a number of dystonia genes, many familial dystonia syndromes remain without known cause. The aim of the study was to identify the cause of autosomal dominant tremulous myoclonus-dystonia in a UK kindred with affected individuals in three generations. METHODS: Known genetic causes of myoclonus-dystonia were excluded. We combined clinical and electrophysiological phenotyping with whole-exome sequencing and Sanger sequencing to identify candidate causal variants in a family with tremulous myoclonus-dystonia. RESULTS: The core phenotype consisted of childhood-onset dystonia predominantly affecting hands and neck, with a fast tremor with superimposed myoclonus and, in some individuals, subtle cerebellar signs. We identified a novel missense variant in potassium calcium-activated channel subfamily N member 2 (KCNN2) [NM_021614:c.1112G>A:p.(Gly371Glu)], which was the only variant that we were able to identify as segregating with the phenotype over three generations. This variant, which is absent from the most recent version of gnomAD, was predicted to be deleterious by SIFT and PolyPhen-2 and had an overall CADD score of 29.7. CONCLUSIONS: KCNN2, a member of the KCNN family of potassium channel genes, is highly conserved across species and in humans is highly expressed in the brain, particularly the cerebellum. KCNN2 mutations have never been described as pathological in human disease, but are recognized abnormalities in two rodent models of fast, jerky tremor. Segregation, absence of the variant in the normal population and in-silico prediction of a deleterious effect together with animal models compatible with the clinical phenotype are all in line with KCNN2 mutations being a plausible cause underlying myoclonus-dystonia.

Short communication: Virulence profiles of Staphylococcus aureus isolated from bulk tank milk and adherences on milking equipment on Chilean dairy farms.

Staphylococcus aureus is an important intramammary pathogen for dairy cows that also is remarkably important for public health. Multiple virulence factors can be involved simultaneously during the pathogenesis of a staphylococcal disease, including adhesion proteins, extracellular enzymes, and toxins. The main objective of this study was to assess virulence factors that are associated with cow intramammary infection (IMI) and of human health concern among Staph. aureus isolates obtained from bulk tank milk (BTM) and adherences on milking equipment surfaces. A total of 166 Staph. aureus isolates from 23 dairy farms were characterized according to their virulence profiles. For virulence factors of importance in IMI, the presence of the virulence markers thermonuclease (nuc) and coagulase (coa) and virulence genes such as fibronectin (fnbA) and intercellular adhesion (icaA, icaD) were assessed. For virulence factors of public health concern, presence of antimicrobial resistance (mecA and mecC) and enterotoxin (sea and seb) genes were analyzed. Among all Staph. aureus isolates, 5 virulence profiles were found; the profile nuc(+)coa(+)fnbA(+)icaA(+)icaD(+)mecA(-)mecC(-)sea(-)seb(-) was the most frequently observed (21 out of 23 dairy farms). No differences were found between the virulence profile frequencies of Staph. aureus from BTM and adherences on milking equipment surfaces. The virulence profiles most frequently observed included genes involved in the adherence and biofilm-forming ability of Staph. aureus, which could represent a potential advantage for the bacterium during the early stages of IMI colonization and for persistence on surfaces. Our results indicate a greater frequency of virulence factors of importance for IMI pathogenesis than virulence factors of public health concern, consistent with the dairy origin of isolates. The mecA, mecC, and seb genes were not observed among Staph. aureus isolates analyzed in this study. However, the sea gene was detected in 3 Staph. aureus isolated from BTM, thus posing a potential public health threat. Our results emphasize the importance of understanding the epidemiology and dynamics of Staph. aureus on dairy farms as a tool for the improvement of udder health and milk safety.

Tremor in motor neuron disease may be central rather than peripheral in origin.

BACKGROUND AND PURPOSE: Motor neuron disease (MND) refers to a spectrum of degenerative diseases affecting motor neurons. Recent clinical and post-mortem observations have revealed considerable variability in the phenotype. Rhythmic involuntary oscillations of the hands during action, resembling tremor, can occur in MND, but their pathophysiology has not yet been investigated. METHODS: A total of 120 consecutive patients with MND were screened for tremor. Twelve patients with action tremor and no other movement disorders were found. Ten took part in the study. Tremor was recorded bilaterally using surface electromyography (EMG) and triaxial accelerometer, with and without a variable weight load. Power spectra of rectified EMG and accelerometric signal were calculated. To investigate a possible cerebellar involvement, eyeblink classic conditioning was performed in five patients. RESULTS: Action tremor was present in about 10% of our population. All patients showed distal postural tremor of low amplitude and constant frequency, bilateral with a small degree of asymmetry. Two also showed simple kinetic tremor. A peak at the EMG and accelerometric recordings ranging from 4 to 12 Hz was found in all patients. Loading did not change peak frequency in either the electromyographic or accelerometric power spectra. Compared with healthy volunteers, patients had a smaller number of conditioned responses during eyeblink classic conditioning. CONCLUSIONS: Our data suggest that patients with MND can present with action tremor of a central origin, possibly due to a cerebellar dysfunction. This evidence supports the novel idea of MND as a multisystem neurodegenerative disease and that action tremor can be part of this condition.

Semiconductor laser linewidth reduction by six orders of magnitude via delayed optical feedback.

We demonstrate a coherence increase by six orders of magnitude of a standard quantum well semiconductor laser. Using a simple, optical-fiber-based feedback scheme, we stabilize the laser in a high-gain mode of a long external cavity. In a modified self-heterodyne measurement, we mix the high-gain mode with a strongly suppressed side mode and obtain an interference linewidth of only 12.6 Hz, corresponding to a decoherence of (3.1±2.9) Hz. In an independent characterization using an etalon, we deduce an upper limit of 300 Hz for the laser linewidth. The laser stably resides in this mode for tens of seconds. Our results agree with theoretical predictions.

Impact of nutritional status on the pharmacokinetics of erlotinib in rats.

Malnourishment is a complex condition in which physiopathological changes take place in multiple systems as a result of energy, protein and nutrient deficiency. The purpose of this study was to evaluate, using an experimental animal model, the impact of nutritional status on the pharmacokinetic profile of erlotinib, a reversible, highly selective, human epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. Two groups of rats -WN (well-nourished) and UN (undernourished) - were fed with different diets for 23-26 days. Rats were assigned randomly to one of three erlotinib treatments (n = 42) consisting of a single dose administered intravenously (i.v.), via oral solution or via oral suspension. Blood samples were assayed for erlotinib concentration. A population pharmacokinetic model was developed and pharmacokinetic parameters obtained in UN rats were compared with those in WN rats. Erlotinib clearance suffered a 5% decrease in the mild-undernutrition status. Moreover, when the drug was administered orally as a suspension, the extent and rate of absorption underwent a 20% increase in UN rats. The results of this study might help to explain, at least in part, the variability of erlotinib treatment and could represent the first step towards establishing new dosage guidelines for the treatment of undernourished cancer patients. Copyright © 2015 John Wiley & Sons, Ltd.

Ceftobiprole medocaril.

Ceftobiprole medocaril is a broad-spectrum 5th-generation cephalosporin with activity against Gram-positives such as methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae, and against Gram-negatives such as Pseudomonas aeruginosa. The recommended dose is 500 mg every 8 h in 2-hour infusions. Various clinical trials have demonstrated its usefulness in the treatment of community-acquired pneumonia and nosocomial pneumonia, with the exception of ventilator-associated pneumonia. In summary, it is a very useful antibiotic for the treatment of pneumonia.

Immune treatment in COVID-19.

Current immune treatment directed to avoid viral replication relies mainly in convalescent plasma and monoclonal antibodies (mAbs). No clinical benefit for convalescent plasma has been reported in a meta-analysis and systematic review compared to standard of care. MAbs are recombinant proteins capable to bind with SARS-CoV-2 preventing its entrance into cells. Several mAbs have shown reduction in viral load and/or progression of the disease such as casirivimab-imdevimab, bamlanivimab-etesevimab and sotrovimab. After the apparition of Omicron variant, it has been reported that sotrovimab retained its activity whereas the other two combinations exhibited loss of neutralizing activity. Several aspects as the target population, timing and doses, serological patient status and evolution of variants still require attention, monitorization and further studies for knowledge gaps.

A multicenter phase II randomized trial of docetaxel/gemcitabine versus docetaxel/capecitabine as first-line treatment for advanced breast cancer: a Gruppo Oncologico Italia Meridionale study.

OBJECTIVE: To evaluate two docetaxel-based regimens as first-line treatment in advanced breast cancer patients. METHODS: Patients were randomly assigned to docetaxel/gemcitabine (arm A: docetaxel 75 mg/m(2) on day 1, gemcitabine 1,000 mg/m(2) on days 1 and 8) or docetaxel/capecitabine (arm B: docetaxel 75 mg/m(2) on day 1, capecitabine 1,250 mg/m(2) twice daily on days 1-14); both chemotherapy regimens were repeated every 21 days. The primary objective of the study was to evaluate the response rate. RESULTS: Seventy-two patients were enrolled (36 each in arms A and B). Responses according to intention-to-treat analysis were as follows: arm A, 41.7% [95% confidence interval (CI) 25.6-57.8]; arm B, 38.9% (95% CI 23-54.8). Median progression-free survival was 10.9 months (95% CI 8.1-13.7) in arm A and 10 months (95% CI 8.8-11.2) in arm B. Overall survival was 26 months (95% CI 22.0-30.0) in arm A and 28 months (95% CI 23.4-32.6) in arm B. Both treatments were well tolerated; myelosuppression was the dose-limiting toxicity, with grade 3-4 neutropenia in 13.8 and 19.4% of the patients in arms A and B, respectively. No relevant differences in other toxicities were observed in the two arms, except for diarrhea (13.9%) and hand-foot syndrome (11.1%), which occurred only in arm B. CONCLUSIONS: Both regimens were active and well tolerated in advanced breast cancer.

[Development of the Q-PEX standard for quality certification of pharmaceutical care for outpatients of Pharmacy services]. / Desarrollo de la norma Q-PEX de certificación de calidad de la atención farmacéutica a pacientes externos de los servicios de Farmacia.

OBJECTIVE: The objective of this study is to describe the process of creation and development of the quality certification standard for pharmaceutical care for outpatients of the Pharmacy services. METHOD: The methodology was carried out by a group of experts from the Spanish Society of Hospital Pharmacy (SEFH) and consisted of three phases: situation analysis, development of the standard and definition of the self-assessment tool and, finally, piloting in several hospitals, determining its feasibility, carrying out a new revision and readaptation. RESULTS: A standard was defined with 118 items distributed in ten areas. Of these, 19 were considered compulsory, 36 basic, 40 medium and 23 advanced. Three levels of certification were established, as well as the definition and percentages of compliance with the requirements. The certification process was divided into two stages, the one of previous preparation and the audit itself, where the initial certification would be covered, with four phases - first three led by the certification Company, and the last one by SEFH and the subsequent follow-up and re-certification audits. Two hospitals piloted the process carried out the piloting of the whole process, both obtaining a basic level after the adoption of measures and corrective actions, after which the final definition of the external evaluation of the standard and the name of the standard was agreed upon «Q-PEX¼, as well as, the registration of the intellectual property of said standard in July-2020. CONCLUSIONS: The standard for certification of the quality of pharmaceutical care for outpatients developed aims to help the continuous advancement of Hospital Pharmacy services.

Effects of Bacillus thuringiensis Cry1Ab and Cry3Aa endotoxins on predatory Coleoptera tested through artificial diet-incorporation bioassays.

Traditional approaches to studying the effects of genetically modified (GM) crops on beneficial insects involve either field assays, comparing insect population levels between control and GM crops or tritrophic bioassays with contaminated insects - usually larvae or eggs of Lepidoptera - as preys. Here, we report the results of a bioassay using an artificial diet, suitable for predatory Coleoptera, to supply Bacillus thuringiensis (Bt) solubilized Cry1Ab and Cry3Aa as well as trypsin-activated Cry1Ab to Atheta coriaria and Cryptolaemus montrouzieri adults and young larvae of Adalia bipunctata. Water, solubilization buffer and trypsin-treated solubilization buffer were used as controls. In total, 1600 insects were assayed. Assays showed a relatively low mortality rate in the controls, ranging from as low as 7% after 15 days (C. montrouzieri) to about 15-20% after five days (A. bipunctata) or 15 days (A. coriaria). For all three predators, there were no statistical differences between the mortality recorded in any of the treatment groups and the corresponding controls. These results indicate a lack of short- (A. bipunctata) and long-term (A. coriaria and C. montrouzieri) mortality associated with oral ingestion of Cry1Ab and Cry3Aa at the high dose tested (50 microg ml-1). We discuss the relevance of these findings for the ecology of beneficial Coleoptera and compatibility with Bt and GM Bt crops.

Biofilm in milking equipment on a dairy farm as a potential source of bulk tank milk contamination with Listeria monocytogenes.

The objective of this study was to assess the presence of a Listeria monocytogenes-containing biofilm in milking equipment as a potential source of bulk tank milk contamination on a dairy farm where milk contamination had been previously documented. Samples were collected from milking equipment and milking parlor premises on 4 occasions and analyzed for the presence of L. monocytogenes. Pulsed-field gel electrophoresis (PFGE) typing was conducted on L. monocytogenes isolates from the milking equipment, parlor and storage room floors, bulk tank milk, and in-line milk filters. Pieces from milk meters and rubber liners were obtained to visually assess the presence of a biofilm using scanning electron microscopy. A total of 6 (15%), 4 (25%), and 1 (6%) samples were culture-positive for L. monocytogenes in the first, second, and third sample collection, respectively. Two samples were L. monocytogenes hly PCR-positive but were culture-negative in the fourth sample collection. Combined AscI and ApaI restriction analysis yielded 6 PFGE types for 15 L. monocytogenes isolates obtained from milking equipment, parlor, bulk tank milk, and milk filters. A predominant and persistent PFGE type (PFGE type T) was observed among these L. monocytogenes isolates (9/15 isolates). Scanning electron microscopy of samples from the bottom cover of 2 milk meters showed the presence of individual and clusters of bacteria, mainly associated with surface scratches. The presence of a bacterial biofilm was observed on the bottom covers of the 2 milk meters. Prevention of the establishment of biofilms in milking equipment is a crucial step in fulfilling the requirement of safe, high-quality milk.

Evidence for Succession and Putative Metabolic Roles of Fungi and Bacteria in the Farming Mutualism of the Ambrosia Beetle Xyleborus affinis.

The bacterial and fungal community involved in ambrosia beetle fungiculture remains poorly studied compared to the famous fungus-farming ants and termites. Here we studied microbial community dynamics of laboratory nests, adults, and brood during the life cycle of the sugarcane shot hole borer, Xyleborus affinis We identified a total of 40 fungal and 428 bacterial operational taxonomic units (OTUs), from which only five fungi (a Raffaelea fungus and four ascomycete yeasts) and four bacterial genera (Stenotrophomonas, Enterobacter, Burkholderia, and Ochrobactrum) can be considered the core community playing the most relevant symbiotic role. Both the fungal and bacterial populations varied significantly during the beetle's life cycle. While the ascomycete yeasts were the main colonizers of the gallery early on, the Raffaelea and other filamentous fungi appeared after day 10, at the time when larval hatching happened. Regarding bacteria, Stenotrophomonas and Enterobacter dominated overall but decreased in foundresses and brood with age. Finally, inferred analyses of the putative metabolic capabilities of the bacterial microbiome revealed that they are involved in (i) degradation of fungal and plant polymers, (ii) fixation of atmospheric nitrogen, and (iii) essential amino acid, cofactor, and vitamin provisioning. Overall, our results suggest that yeasts and bacteria are more strongly involved in supporting the beetle-fungus farming symbiosis than previously thought.IMPORTANCE Ambrosia beetles farm their own food fungi within tunnel systems in wood and are among the three insect lineages performing agriculture (the others are fungus-farming ants and termites). In ambrosia beetles, primary ambrosia fungus cultivars have been regarded essential, whereas other microbes have been more or less ignored. Our KEGG analyses suggest so far unknown roles of yeasts and bacterial symbionts, by preparing the tunnel walls for the primary ambrosia fungi. This preparation includes enzymatic degradation of wood, essential amino acid production, and nitrogen fixation. The latter is especially exciting because if it turns out to be present in vivo in ambrosia beetles, all farming animals (including humans) are dependent on atmospheric nitrogen fertilization of their crops. As previous internal transcribed spacer (ITS) metabarcoding approaches failed on covering the primary ambrosia fungi, our 18S metabarcoding approach can also serve as a template for future studies on the ambrosia beetle-fungus symbiosis.

Integral urban solid waste management program in a Mexican university.

The Azcapotzalco campus of the Universidad Autónoma Metropolitana (UAM-A) has implemented an Integral Urban Solid Waste Management Program, "Segregation for a Better UAM Environment" (Separacción por un mejor UAMbiente). This program is directed to create awareness and involve the academic community of the UAM-A concerning the problem of solid wastes, at the same time fulfilling the local environmental legislation. The program consists in separating solid wastes into two classes: (1) recoverable wastes (glass and PET bottles, aluminum cans, Tetrapak packages) and (2) other wastes (non-recoverable). During the past three years, thanks to this program, the amount of solid wastes delivered monthly to municipal collecting services has been considerably reduced. In this period, UAM-A has sent to recycling: 2.2 tons of glass bottles; 2.3 tons of PET bottles; 1.2 tons of Tetrapak packages and 27.5 kg of aluminum cans.

Severe renal failure and thrombotic microangiopathy induced by malignant hypertension successfully treated with spironolactone.

Malignant hypertension can cause thrombotic microangiopathy (TMA) characterized by hemolytic anemia and thrombocytopenia. On the other hand, severe hypertension is sometimes associated with hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP). Distinguishing these entities is important because of therapeutic implications. Plasmapheresis should be initiated as soon as possible if we are dealing with TTP. We describe the case of a 30-year-old man referred to our hospital with malignant hypertension, severe renal failure and TMA: haemoglobin=9g/dL, total bilirubin=0.4mg/dL, haptoglobin≤10mg/dL, platelet count=59,000/µL and schistocytes on peripheral smear. He required initiation of hemodialysis. Additionally, we considered that the possible cause of TMA was malignant hypertension according to the presence of hypertensive retinopathy and thrombocytopenia which remitted only with blood pressure control, hence, plasmapheresis was not given. Renal function did not improve and the patient remained chronic hemodialysis. Intensive therapy for hypertension with a combination of antihypertensive drugs including spironolactone successfully lowered his blood pressure without developing hyperkalemia.

Genome size reduction through multiple events of gene disintegration in Buchnera APS.

The evolution of the endosymbiont Buchnera during its adaptation to intracellular life involved a massive reduction in its genome. By comparing the orthologous genes of Buchnera, Escherichia coli and Vibrio cholerae, we show that the minimal genome size of Buchnera arose from multiple events of gene disintegration dispersed over the whole genome. The elimination of the genes was a continuous process that began with gene inactivation and progressed until the DNA corresponding to the pseudogenes were completely deleted.

The effects of prebiotics on microbial dysbiosis, butyrate production and immunity in HIV-infected subjects.

Altered interactions between the gut mucosa and bacteria during HIV infection seem to contribute to chronic immune dysfunction. A deeper understanding of how nutritional interventions could ameliorate gut dysbiosis is needed. Forty-four subjects, including 12 HIV+ viremic untreated (VU) patients, 23 antiretroviral therapy-treated (ART+) virally suppressed patients (15 immunological responders and 8 non-responders) and 9 HIV- controls (HIV-), were blindly randomized to receive either prebiotics (scGOS/lcFOS/glutamine) or placebo (34/10) over 6 weeks in this pilot study. We assessed fecal microbiota composition using deep 16S rRNA gene sequencing and several immunological and genetic markers involved in HIV immunopathogenesis. The short dietary supplementation attenuated HIV-associated dysbiosis, which was most apparent in VU individuals but less so in ART+ subjects, whose gut microbiota was found more resilient. This compositional shift was not observed in the placebo arm. Significantly, declines in indirect markers of bacterial translocation and T-cell activation, improvement of thymic output, and changes in butyrate production were observed. Increases in the abundance of Faecalibacterium and Lachnospira strongly correlated with moderate but significant increases of butyrate production and amelioration of the inflammatory biomarkers soluble CD14 and high-sensitivity C-reactive protein, especially among VU. Hence, the bacterial butyrate synthesis pathway holds promise as a viable target for interventions.

Oral vinorelbine plus capecitabine (oral vincap) combination in patients with advanced breast cancer (ABC). A phase II study of the GOIM (Gruppo Oncologico dell'Italia Meridionale).

BACKGROUND: Vinorelbine i.v. and capecitabine are two of the most effective single agents in previously treated advanced breast cancer (ABC). A number of studies have been reported with the combination of these agents. Actually, the availability of oral formulation for vinorelbine allows a full oral combination of the two agents. The aim of this study was to evaluate the activity and toxicity of this novel combination. PATIENTS AND METHODS: Thirty-eight advanced breast cancer patients refractory to anthracyclines and taxanes were included in this study. Treatment consisted of vinorelbine 60 mg/m(2) (days 1 + 8), and capecitabine 2000 mg/m(2) (days 2-7 and 9-16) every 3 weeks. RESULTS: A total of 228 courses were given with a mean of three cycles/patient (range 1-12). Five patients (13.1%) had no toxicity at all. Hematologic side-effects were: neutropenia grade 2-3 in seven patients (18.9%) and grade 4 in one patient (2.7%), anemia grade 1 in 11 patients (29.7%), grade 2-3 in five patients (13.5%), thrombocytopenia grade 1 in six patients (16.2%) and grade 3 in one patient (2.7%). Non-hematologic side-effects were: fatigue grade 1 in five patients (13.5%), hand-foot syndrome grade 1 in two patients (5.4%) and grade 2 in two patients (5.4%), nausea/vomiting grade 1 in two patients (5.4%), grade 2 in three patients (8.1%) and grade 3 in one patient (2.7%), constipation grade 1 in two patients (5.4%), peripheral neurotoxicity grade 1 in three patients (8.1%) and grade 2 in one patient (2.7%), gastric pain grade 1 in two patients (5.4%), stomatitis grade 1 in three patients (8.1%) and grade 2 in one patient (2.7%). Out of 38 patients assessable, we observed two (5.4%) CR, 13 (34 %) PR, 14 (37.8%) SD and nine (26.3%) PD. The median time to progression was 4.5 months (range 1-18 months), the median response duration was 7 months (range 2-18 months) and the median survival duration was 10 months (range 2-26+). CONCLUSIONS: The oral vincap should be considered as an alternative to single agent capecitabine or vinorelbine in ABC refractory to antra-taxane combination.