Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study.

BACKGROUND: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial. PATIENTS AND METHODS: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion. RESULTS: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy. CONCLUSIONS: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.

Is unicentric familial papillary thyroid microcarcinoma different from multicentric?

BACKGROUND: Familial papillary thyroid microcarcinoma (FPTMC) appears to be more aggressive than sporadic papillary thyroid microcarcinoma (SPTMC). However, there are authors who indicate that unicentric FPTMC has a similar prognosis to SPTMC. The objective is to analyze whether unicentric FPTMC has a better prognosis than multicentric FPTMC. DESIGN AND METHODS: Type of study: National multicenter longitudinal analytical observational study. STUDY POPULATION: Patients with FPTMC. STUDY GROUPS: Two groups were compared: Group A (unicentric FPTMC) vs. Group B (multicentric FPTMC). STUDY VARIABLES: It is analyzed whether between the groups there are: a) differentiating characteristics; and b) prognostic differences. STATISTICAL ANALYSIS: Cox regression analysis and survival analysis. RESULTS: Ninety-four patients were included, 44% (n = 41) with unicentric FPTMC and 56% (n = 53) with multicentric FPTMC. No differences were observed between the groups according to socio-familial, clinical or histological variables. In the group B a more aggressive treatment was performed, with higher frequency of total thyroidectomy (99 vs. 78%; p = 0.003), lymph node dissection (41 vs. 15%; p = 0.005) and therapy with radioactive iodine (96 vs. 73%; p = 0.002). Tumor stage was similar in both groups (p = 0.237), with a higher number of T3 cases in the group B (24 vs. 5%; p = 0.009). After a mean follow-up of 90 ± 68.95 months, the oncological results were similar, with a similar disease persistence rate (9 vs. 5%; p = 0.337), disease recurrence rate (21 vs. 8%; p = 0.159) and disease-free survival (p = 0.075). CONCLUSIONS: Unicentric FPTMC should not be considered as a SPTMC due to its prognosis is similar to multicentric FPTMC.

Biological behavior of familial papillary thyroid microcarcinoma: Spanish multicenter study.

PURPOSE: Familial papillary thyroid microcarcinoma (FPTMC) can present a more aggressive behavior than the sporadic microcarcinoma. However, few studies have analyzed this situation. The objective is to analyze the recurrence rate of FPTMC and the prognostic factors which determine that recurrence in Spain. METHODS: Spanish multicenter longitudinal analytical observational study was conducted. Patients with FPTMC received treatment with curative intent and presented cure criteria 6 months after treatment. Recurrence rate and disease-free survival (DFS) were analyzed. Two groups were analyzed: group A (no tumor recurrence) vs. group B (tumor recurrence). RESULTS: Ninety-four patients were analyzed. During a mean follow-up of 73.3 ± 59.3 months, 13 recurrences of FPTMC (13.83%) were detected and mean DFS was 207.9 ± 11.5 months. There were multifocality in 56%, bilateral thyroid involvement in 30%, and vascular invasion in 7.5%; that is to say, they are tumors with histological factors of poor prognosis in a high percentage of cases. The main risk factors for recurrence obtained in the multivariate analysis were the tumor size (OR: 2.574, 95% CI 1.210-5.473; p = 0.014) and the assessment of the risk of recurrence of the American Thyroid Association (ATA), both intermediate risk versus low risk (OR: 125, 95% CI 10.638-1000; p < 0.001) and high risk versus low risk (OR: 45.454, 95% CI 5.405-333.333; p < 0.001). CONCLUSION: FPTMC has a recurrence rate higher than sporadic cases. Poor prognosis is mainly associated with the tumor size and the risk of recurrence of the ATA.

Current treatment landscape for oligometastatic non-small cell lung cancer.

The management of patients with advanced non-small cell lung carcinoma (NSCLC) has undergone major changes in recent years. On the one hand, improved sensitivity of diagnostic tests, both radiological and endoscopic, has altered the way patients are staged. On the other hand, the arrival of new drugs with antitumoral activity, such as targeted therapies or immunotherapy, has changed the prognosis of patients, improving disease control and prolonging survival. Finally, the development of radiotherapy and surgical and interventional radiology techniques means that radical ablative treatments can be performed on metastases in any location in the body. All of these advances have impacted the treatment of patients with advanced lung cancer, especially in a subgroup of these patients in which all of these treatment modalities converge. This poses a challenge for physicians who must decide upon the best treatment strategy for each patient, without solid evidence for one optimal mode of treatment in this patient population. The aim of this article is to review, from a practical and multidisciplinary perspective, published evidence on the management of oligometastatic NSCLC patients. We evaluate the different alternatives for radical ablative treatments, the role of primary tumor resection or radiation, the impact of systemic treatments, and the therapeutic sequence. In short, the present document aims to provide clinicians with a practical guide for the treatment of oligometastatic patients in routine clinical practice.

First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update.

BACKGROUND: To further characterize survival benefit with first-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone, we report updated data from the phase III CheckMate 9LA trial with a 2-year minimum follow-up. PATIENTS AND METHODS: Adult patients were treatment naïve, with stage IV/recurrent non-small-cell lung cancer, no known sensitizing EGFR/ALK alterations, and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with two cycles of chemotherapy, or four cycles of chemotherapy. Updated efficacy and safety outcomes are reported, along with progression-free survival (PFS) after next line of treatment (PFS2), treatment-related adverse events (TRAEs) by treatment cycle, and efficacy outcomes in patients who discontinued all treatment components in the experimental arm due to TRAEs. RESULTS: With a median follow-up of 30.7 months, nivolumab plus ipilimumab with chemotherapy continued to prolong overall survival (OS) versus chemotherapy. Median OS was 15.8 versus 11.0 months [hazard ratio 0.72 (95% confidence interval 0.61-0.86)]; 2-year OS rate was 38% versus 26%. Two-year PFS rate was 20% versus 8%. ORR was 38% versus 25%, respectively; 34% versus 12% of all responses were ongoing at 2 years. Median PFS2 was 13.9 versus 8.7 months. Improved efficacy outcomes in the experimental versus control arm were observed across most subgroups, including by programmed death-ligand 1 and histology. No new safety signals were observed; onset of grade 3/4 TRAEs was mostly observed during the first two treatment cycles in the experimental arm. In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy treatment due to TRAEs (n = 61) median OS was 27.5 months; 56% of responders had an ongoing response ≥1 year after discontinuation. CONCLUSIONS: With a 2-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy provided durable efficacy benefits over chemotherapy with a manageable safety profile and remains an efficacious first-line treatment of advanced non-small-cell lung cancer.

Second-line nivolumab in relapsed small-cell lung cancer: CheckMate 331☆.

BACKGROUND: Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC. PATIENTS AND METHODS: CheckMate 331 is a randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS). RESULTS: Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy [median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P = 0.11]. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score ≥1% versus <1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%. CONCLUSION: Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.

Treatment strategy optimization for patients with non-small-cell lung cancer harboring EGFR mutation: a Delphi consensus.

AIM: To stablish a consensus on the treatment strategy for advanced non-small-cell lung cancer (aNSCLC) with epidermal growth factor receptor mutation (EGFRm) in Spain. METHODS: After a systematic literature review, the scientific committee developed 33 statements in 4 fields: molecular diagnosis (10 items); histologic profile and patient clinical characteristics (7 items); first-line (1L) treatment in EGFRm aNSCLC (8 items); and subsequent-line treatment (8 items). A panel of 31 experts completed 2 Delphi online questionnaires rating their degree of agreement/disagreement for each statement through a 1-9 range scale (1-3 = disagree, 7-9 = agree). Consensus was reached if 2/3 of the participants are in the median range. RESULTS: In the first Delphi round consensus was achieved for 24/33 of the statements. One of the assertions was deleted, proceeding to a second round with the eight remaining questions with no consensus or in the range of indeterminacy. Determination of the EGFR status from tissue and analysis of the different biomarkers are two important variables that influenced treatment decision in patients with aNSCLC. 1L treatment should be the best therapeutic option, independently of the subsequent lines of treatment. For patients with the most common activating mutations osimertinib was considered the most efficient and safe 1L option. In case of disease progression, a new biopsy was needed. CONCLUSIONS: A consensus document is proposed to optimize the treatment strategy for untreated patients with a NSCLC with EGFR sensitizing mutations.

Genome-wide profiling of non-smoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors.

BACKGROUND: The etiology and the molecular basis of lung adenocarcinomas (LuADs) in nonsmokers are currently unknown. Furthermore, the scarcity of available primary cultures continues to hamper our biological understanding of non-smoking-related lung adenocarcinomas (NSK-LuADs). PATIENTS AND METHODS: We established patient-derived cancer cell (PDC) cultures from metastatic NSK-LuADs, including two pairs of matched EGFR-mutant PDCs before and after resistance to tyrosine kinase inhibitors (TKIs), and then performed whole-exome and RNA sequencing to delineate their genomic architecture. For validation, we analyzed independent cohorts of primary LuADs. RESULTS: In addition to known non-smoker-associated alterations (e.g. RET, ALK, EGFR, and ERBB2), we discovered novel fusions and recurrently mutated genes, including ATF7IP, a regulator of gene expression, that was inactivated in 5% of primary LuAD cases. We also found germline mutations at dominant familiar-cancer genes, highlighting the importance of genetic predisposition in the origin of a subset of NSK-LuADs. Furthermore, there was an over-representation of inactivating alterations at RB1, mostly through complex intragenic rearrangements, in treatment-naive EGFR-mutant LuADs. Three EGFR-mutant and one EGFR-wild-type tumors acquired resistance to EGFR-TKIs and chemotherapy, respectively, and histology on re-biopsies revealed the development of small-cell lung cancer/squamous cell carcinoma (SCLC/LuSCC) transformation. These features were consistent with RB1 inactivation and acquired EGFR-T790M mutation or FGFR3-TACC3 fusion in EGFR-mutant tumors. CONCLUSIONS: We found recurrent alterations in LuADs that deserve further exploration. Our work also demonstrates that a subset of NSK-LuADs arises within cancer-predisposition syndromes. The preferential occurrence of RB1 inactivation, via complex rearrangements, found in EGFR-mutant tumors appears to favor SCLC/LuSCC transformation under growth-inhibition pressures. Thus RB1 inactivation may predict the risk of LuAD transformation to a more aggressive type of lung cancer, and may need to be considered as a part of the clinical management of NSK-LuADs patients.

Clinical utility of plasma-based digital next-generation sequencing in patients with advance-stage lung adenocarcinomas with insufficient tumor samples for tissue genotyping.

BACKGROUND: Approximately 30% of tumor biopsies from patients with advanced-stage lung adenocarcinomas yield insufficient tissue for successful molecular subtyping. We have analyzed the clinical utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) in patients with inadequate tumor samples for tissue genotyping. PATIENTS AND METHODS: We conducted the study in a multi-institutional prospective cohort of clinically unselected patients with advanced-stage lung adenocarcinomas with insufficient tissue for EGFR, ALK or ROS1 genotyping across 12 Spanish institutions (n = 93). ctDNA NGS was carried out by Guardant Health (Guardant360, Redwood City, CA), using a hybrid-capture-based 73-gene panel. Variants were deemed actionable if they were part of the OncoKB precision oncology knowledge database and classified in four levels of actionability based on their clinical or preclinical evidence for drug response. RESULTS: Eighty-three out of 93 patients (89%) had detectable levels of ctDNA. Potentially actionable level 1-4 genomic alterations were detected in 53 cases (57%), of which 13 (14%) had level 1-2A alterations (Food and Drug Administration-approved and standard-care biomarkers according to lung cancer guidelines). Frequencies of each genomic alteration in ctDNA were consistent with those observed in unselected pulmonary adenocarcinomas. The majority of the patients (62%), particularly those with actionable alterations (87%), had more than one pathogenic variant in ctDNA. The median turnaround time to genomic results was 13 days. Twelve patients (13%) received genotype-matched therapies based on ctDNA results, deriving the expected clinical benefit. Patients with co-occurring pathogenic alterations had a significantly shorter median overall survival as compared with patients without co-occurring pathogenic alteration (multivariate hazard ratio = 5.35, P = 0.01). CONCLUSION: Digital NGS of ctDNA in lung cancers with insufficient tumor samples for tissue sequencing detects actionable variants that frequently co-occur with other potentially clinically relevant genomic alterations, allowing timely initiation of genotype-matched therapies.

Correction to: Predictive and prognostic clinical and pathological factors of nivolumab efficacy in non-small-cell lung cancer patients.

Clinical and Translational Oncology.

Predictive and prognostic clinical and pathological factors of nivolumab efficacy in non-small-cell lung cancer patients.

BACKGROUND: Immunotherapy increases overall response rate (ORR) and overall survival (OS) in patients with non-small-cell lung cancer (NSCLC). Prognostic and predictive factors are a high need. PATIENTS AND METHODS: Retrospective review of NSCLC patients treated with nivolumab was performed. Analyzed variables included age, sex, stage, performance status (PS), location of metastases, presence of tumour-related symptoms and comorbidities, number of metastasis locations, previous chemotherapy, anti-angiogenic and radiotherapy treatments, and analytical data from the standard blood count and biochemistry. RESULTS: A total of 175 patients were included. Median age was 61.5 years, 73.1% were men, 77.7% were ECOG-PS 0-1, and 86.7% were included with stage IV disease. Histology was non-squamous in 77.1%. Sixty-five received nivolumab in second line (37.1%). Thirty-eight patients had brain metastasis (22%), and 39 (22.3%) liver metastasis and 126 (72%) had more than one metastatic location. The ORR was 15.7% with median Progression free survival (PFS) 2.8 months and median OS 5.81 months. Stage III vs IV and time since the beginning of the previous line of treatment ≥ 6 vs < 6 months were associated with better response. PS 2, time since the previous line of treatment < 6 vs ≥ 6 months, and more than one metastatic location were independently associated with shorter OS in multivariable analysis (7.8 vs 2.7 months, 11.2 vs 4.6 months, and 9.4 vs 5.1 month). Finally, time since the previous treatment < 6 vs ≥ 6 months and more than one metastatic location were independently associated with shorter PFS in multivariable analysis (4.3 vs 2.3 months and 4.7 vs 2.3 months). CONCLUSION: Poor PS, short period of time since the previous treatment, and more than one metastatic location were associated with poorer prognostic.

Mitochondrial ascorbate-glutathione cycle and proteomic analysis of carbonylated proteins during tomato (Solanum lycopersicum) fruit ripening.

In non-photosynthetic tissues, mitochondria are the main source of energy and of reactive oxygen species. Accumulation of high levels of these species in the cell causes damage to macromolecules including several proteins and induces changes in different metabolic processes. Fruit ripening has been characterized as an oxidative phenomenon; therefore, control of reactive oxygen species levels by mitochondrial antioxidants plays a crucial role on this process. In this work, ascorbate-glutathione cycle components, hydrogen peroxide levels and the proteomic profile of carbonylated proteins were analyzed in mitochondria isolated from tomato (Solanum lycopersicum) fruit at two ripening stages. A significant increase on most ascorbate-glutathione cycle components and on carbonylated proteins was observed in mitochondria from breaker to light red stage. Enzymes and proteins involved in diverse cellular and mitochondrial metabolic pathways were identified among the carbonylated proteins. These results suggest that protein carbonylation is a post-translational modification involved in tomato fruit ripening regulation.

Postoperative complications do not impact on recurrence and survival after curative resection of gastric cancer.

BACKGROUND: We assessed the impact of complications on recurrence and survival after curative gastric cancer resection. METHODS: Patients undergoing R0 resections between 1990 and 2009 were identified in a prospectively maintained database and were categorized by presence of any complication Clavien-Dindo (CD) ≥ II, sepsis or intra-abdominal sepsis. Cox regression analyses to relate complications and clinico-pathological variables to time to recurrence (TTR) and overall survival (OS) were performed. RESULTS: A total of 271 patients were included with a median follow-up of 149.9 months (range 140.1-159.9). Complications CD ≥ II occurred in 162 (59.8%) patients, sepsis in 66 (22.5%), and intra-abdominal sepsis in 37 (13.6%). Recurrence developed in 88 (32.4%) patients. Independent predictors of short TTR were pTNM stage (IIIB-IIIC vs. IA-IIA) (hazard ratio [HR] = 37.55, 95% confidence interval [CI] 17.57-80.24; p < 0.001), D1 lymphadenectomy (HR = 3.14, 95% CI 1.94-5.07; p < 0.001), and male gender (HR = 1.65, 95% CI 1.06-2.57; p = 0.026). pTNM stage (IIIB-IIIC vs. IA-IIA, HR = 10.28, 95% CI 6.51-16.23; p < 0.001), male gender (HR = 1.64, 95% CI 1.17-2.31; p = 0.005), age (HR = 1.03, 95% CI 1.02-1.05; p < 0.001), and adjuvant therapy (HR = 0.55, 95% CI 0.37-0.83; p = 0.004) were identified as independent predictors of OS.. CONCLUSIONS: Evidence provided by this study does not support a negative impact of postoperative complications CD ≥ II, sepsis, and intra-abdominal sepsis on the oncologic outcome after curative gastric cancer resection.

Technical note: Advantages and limitations of authenticating Palmera goat dairy products by pyrosequencing the melanocortin 1 receptor (MC1R) gene.

Inferring the breed of origin of dairy products can be achieved through molecular analysis of genetic markers with a population-specific pattern of segregation. The goal of the current work was to generate such markers in goats by resequencing several pigmentation genes [melanocortin 1 receptor (MC1R), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), tyrosinase (TYR), and tyrosinase-related protein 2 (TYRP2)]. This experiment revealed 10 single nucleotide polymorphisms (SNP), including 5 missense mutations and 1 nonsense mutation. These markers were genotyped in 560 goats from 18 breeds originally from Italy, the Iberian Peninsula, the Canary Islands, and North Africa. Although the majority of SNP segregated at moderate frequencies in all populations (including 2 additional markers that were used as a source of information), we identified a c.764G>A SNP in MC1R that displayed highly divergent allelic frequencies in the Palmera breed compared with the Majorera and Tinerfeña breeds from the Canary Islands. Thus, we optimized a pyrosequencing-based technique that allowed us to estimate, very accurately, the allele frequencies of this marker in complex DNA mixtures from different individuals. Once validated, we applied this method to generating breed-specific DNA profiles that made it possible to detect fraudulent cheeses in which Palmero cheese was manufactured with milk from Majorera goats. One limitation of this approach, however, is that it cannot be used to detect illegal manufacturing where Palmero dairy products are produced by mixing milk from Palmera and Majorera goats, because the c.764G>A SNP segregates in both breeds.

Nocardiosis cerebral parvosintomática, en pacientes inmunocomprometidos / Parvosymptomatic cerebral nocardiosis in immunocompromised patients

Antecedentes: La nocardiosis es originada por distintas cepas de Nocardia, bacterias Gram positivas que afecta a humanos y animales. Pueden producir infecciones sistémicas de ingreso cutáneo o pulmonar, que llegan a comprometer el Sistema Nervioso Central. Se afectan especialmente pacientes inmunosuprimidos que pueden desarrollar abscesos cerebrales, visibles en la Resonancia Magnética (RM), pero que no expresan síntomas de las lesiones focales o son parvosintomáticos. Pacientes y Método: Queremos comunicar dos mujeres con trasplante renal en tratamiento inmunosupresor, que desarrollaron cuadros pulmonares agudos que obligaron a su hospitalización, en cuyo contexto la paciente (A) presentó una convulsión y la (B) cefalea y compromiso de conciencia, que obligaron a una RM de cerebro. En ambos casos se encontraron múltiples abscesos cerebrales de distinta ubicación y tamaño que no habían dado síntomas focales. La nocardiosis se identificó en la paciente (A) con la biopsia de un micetoma cutáneo y en la (B) con la resolución quirúrgica de un absceso cerebeloso. En ambas se inició tratamiento específico con adecuada respuesta. Sin embargo, las reacciones adversas a la antibioterapia obligaron a suspenderla. Esta suspensión reactivó la infección que complicó y llevó al fallecimiento de las pacientes. Conclusiones: La publicación de varios casos de nocardiosis cerebral parvosintomática en pacientes inmunosuprimidos sugiere que para las infecciones cerebrales por Nocardia la pérdida de la inmunidad celular resulta muy significativa, porque permitiría el ingreso y proliferación de la bacteria al interior del SNC sin generar respuestas clínicas inmediatas. La aparición de síntomas se relacionaría con una tardía alteración de la barrera hematoencefálica, más que con el lento proceso lesional de la Nocardia. Lo que condicionaría su diagnóstico oportuno.

Background: Nocardiosis is caused by several strains of Nocardia, Gram-positive bacteria that infects humans and animals likewise. They develop a systemic infection of pulmonary or cutaneous origin that can spread to the Central Nervous System. It frequently affects immunosupresed patients, in which parvosymptomatic cerebral abscess has been described, visible in magnetic resonance imaging but without focal symptoms. Patients and Methods: We want to communicate two women with renal transplant in immunosupresor treatment who were admitted to our hospital for acute pulmonar disease, during which patient A presented a convulsive episode and patient B headache and stupor, after which CT and MR were obtained. In both cases multiple cerebral abscesses were found, of different sizes and location, with no clinical manifestations. Nocardia diagnosis was made in patient A by biopsy from a cutaneous mycetoma and in patient B after surgery of a cerebellar abscess. In both cases antimicrobial treatment was initiated with good response, but had to be interrupted due to adverse effects. This reactivated the infection, which had a complicated course and finally lead to the death of both patients. Conclusions: The fact that several cases of parvosymtomatic cerebral Nocardiosis in immunosupresed patients have been published suggest that cellular immunosupresion is key in the development of cerebral infections by Nocardia. It probably allows the access and multiplication of the bacteria inside the encephalon without an immediate clinical response. The development of symptoms is probably related to a late alteration of the blood-brain barrier rather than to the slow progression of Nocardia disease.

Copy number variation in the genomes of domestic animals.

Copy number variation (CNV) might be one of the main contributors to phenotypic diversity and evolutionary adaptation in animals and plants, employing a wide variety of mechanisms, such as gene dosage and transcript structure alterations, to modulate organismal plasticity. In the past 4 years, considerable advances have been made in the characterization of the genomic architecture of CNV in domestic species. First, low-resolution CNV maps were produced for cattle, goat, sheep, pig, dog, chicken, duck and turkey, showing that these structural polymorphisms comprise a significant part of these genomes. Furthermore, CNVs have been associated with several pigmentation (white coat in horse, pig and sheep) and morphological (late feathering and pea comb in chicken) traits, as well as with susceptibility to a wide array of diseases and developmental disorders, for example osteopetrosis, anhidrotic ectodermal dysplasia, copper toxicosis, intersexuality, cone degeneration, periodic fever and dermoid sinus, among others. In the future, development of high-resolution tools for CNV detection and typing combined with the implementation of databases integrating CNV, QTL and gene expression data will be essential to identify and measure the impact of this source of structural variation on the many phenotypes that are relevant to animal breeders and veterinary practitioners.

High preoperative serum vascular endothelial growth factor levels predict poor clinical outcome after curative resection of gastric cancer.

BACKGROUND: Tumour vascular endothelial growth factor (VEGF) and tumour urokinase-type plasminogen activator (uPA) are prognostic factors in gastric cancer but surgical specimens are required for testing. The prognostic value of preoperative serum VEGF (s-VEGF) and serum uPA (s-uPA) levels was evaluated in patients undergoing potentially curative (R0) gastric cancer resection. METHODS: Concentrations of s-VEGF and s-uPA were measured 97 patients with gastric cancer and 20 controls. Angiogenesis was measured in vitro based on human endothelial cell tube formation. RESULTS: Levels of s-VEGF were higher in patients with gastric cancer than controls (median 288 versus 189 pg/ml respectively; P = 0.002). They were associated with pathological tumour node metastasis (pTNM) stage, pT, pN, lymph node ratio and perineural invasion, and correlated with platelet counts. In multivariable analysis, s-VEGF over 320 pg/ml was the only preoperative predictor of both recurrence and disease-specific survival. Serum from patients with raised s-VEGF levels enhanced angiogenesis in vitro significantly more than serum from those with a s-VEGF level of 320 pg/ml or less. CONCLUSION: High preoperative s-VEGF level is an independent prognostic factor for recurrence and survival after R0 resection of gastric cancer. This may provide a useful guide to decision making regarding neoadjuvant and adjuvant therapies.

[Prevalence of malnutrition in medical and surgical wards of a university hospital]. / Prevalencia de malnutrición en los servicios médicos y quirúrgicos de un hospital universitario.

INTRODUCTION: Malnutrition is frequently found in hospitals, where is related to poor outcomes. There are contradictory data about if prevalence of malnutrition is greater in surgical or medical patients. The aim of this study is to know the prevalence of malnutrition in both groups of patients. METHODS: The nutritional status of 189 patients from medical and surgical wards was assessed with Subjective Global Assessment, and data about sex, age, length of hospital stay, mortality, diseases, and wards of admission were collected. Qualitative variables were compared with chi-square test, and independent quantitative variables with Student's t test. P < 0.05 was accepted as significative. RESULTS: The prevalence of malnutrition was 40.2%. Malnourished patients have lost 7.3% of their weight, 67.1% referred a diminished oral intake, and 53.9% anorexia. Malnutrition was significatively associated to male sex, greater length of stay, and cancer. Prevalence and severity of malnutrition were similar in medical and surgical wards, and malnourished patients just differed in diseases (chronic diseases in medical; surgical procedures and cancer in surgery). CONCLUSIONS: Malnutrition is equally prevalent in medical and surgical wards, probably due to different but highly frequent risk factors, and is related to a longer hospital stay.

[Chronic diarrhea with uncommon etiology]. / Diarrea crónica de causa infrecuente.

Chronic diarrhea is a common syndrome. An etiological diagnosis is often reached through clinical history, physical examination and simple tests. In some cases, when the etiology is not found, the syndrome is called functional diarrhea, even though established criteria are often not fulfilled. We present the case of a patient with diarrhea for several months. The most common causes were ruled out through clinical history, physical examination, radiographic studies and laboratory tests, and the patient was diagnosed with functional diarrhea. Three months later, the patient presented a neck mass, and biopsy revealed medullary carcinoma of the thyroid. A review of recommendations for the systematic evaluation of chronic diarrhea is presented. A general approach should include careful history taking characteristics of diarrhea (onset, associated symptoms, epidemiological factors, iatrogenic causes such as laxative ingestion), a thorough physical examination with special attention to the anorectal region, and routine laboratory tests (complete blood count and serum chemistry). In addition, stool analysis including electrolytes (fecal osmotic gap), leukocytes, fecal occult blood, excess stool fat and laxative screening can yield important objective information to classify the diarrhea as: osmotic (osmotic gaps > 125 mOsm/Kg), secretory (osmotic gaps < 50 mOsm/Kg), inflammatory or steatorrheic. At this point in the evaluation, a specific diagnosis may be made. However, if diagnosis is not reached further specific examinations should be performed for each of the 4 types of diarrhea described above. A systematic approach to the evaluation of chronic diarrhea is warranted. Medullary thyroid carcinoma and other endocrine syndromes causing chronic diarrhea are very rare. Measurement of serum peptide concentrations should only be performed when clinical presentation and findings in stool or radiographic studies suggest this etiology.