Making clinical decisions based on measurable residual disease improves the outcome in multiple myeloma.

The assessment of measurable residual disease (MRD) in bone marrow has proven of prognostic relevance in patients with multiple myeloma (MM). Nevertheless, and unlike other hematologic malignancies, the use of MRD results to make clinical decisions in MM has been underexplored to date. In this retrospective study, we present the results from a multinational and multicenter series of 400 patients with MRD monitoring during front-line therapy with the aim of exploring how clinical decisions made based on those MRD results affected outcomes. As expected, achievement of MRD negativity at any point was associated with improved PFS versus persistent MRD positivity (median PFS 104 vs. 45 months, p < 0.0001). In addition, however, 67 out of 400 patients underwent a clinical decision (treatment discontinuation, intensification or initiation of a new therapy) based on MRD results. Those patients in whom a treatment change was made showed a prolonged PFS in comparison with those 333 patients in which MRD results were not acted upon (respectively, mPFS 104 vs. 62 months, p = 0.005). In patients who achieved MRD negativity during maintenance (n = 186) on at least one occasion, stopping therapy in 24 patients vs. continuing in 162 did not alter PFS (mPFS 120 months vs. 82 months, p = 0.1). Most importantly, however, in patients with a positive MRD during maintenance (n = 214), a clinical decision (either intensification or change of therapy) (n = 43) resulted in better PFS compared to patients in whom no adjustment was made (n = 171) (mPFS NA vs. 39 months, p = 0.02). Interestingly, there were no significant differences when MRD was assessed by flow cytometry or by next-generation sequencing. Herein, we find that MRD is useful in guiding clinical decisions during initial therapy and has a positive impact on PFS in MM patients. This potentially opens a new dimension for the use of MRD in MM, but this role still remains to be confirmed in prospective, randomized clinical trials.

Regional variations in Helicobacter pylori infection, gastric atrophy and gastric cancer risk: The ENIGMA study in Chile.

BACKGROUND: Regional variations in gastric cancer incidence are not explained by prevalence of Helicobacter pylori, the main cause of the disease, with several areas presenting high H. pylori prevalence but low gastric cancer incidence. The IARC worldwide H. pylori prevalence surveys (ENIGMA) aim at systematically describing age and sex-specific prevalence of H. pylori infection around the world and generating hypotheses to explain regional variations in gastric cancer risk. METHODS: We selected age- and sex-stratified population samples in two areas with different gastric cancer incidence and mortality in Chile: Antofagasta (lower rate) and Valdivia (higher rate). Participants were 1-69 years old and provided interviews and blood for anti-H. pylori antibodies (IgG, VacA, CagA, others) and atrophy biomarkers (pepsinogens). RESULTS: H. pylori seroprevalence (Age-standardized to world population) and antibodies against CagA and VacA were similar in both sites. H. pylori seroprevalence was 20% among children <10 years old, 40% among 10-19 year olds, 60% in the 20-29 year olds and close to or above 80% in those 30+ years. The comparison of the prevalence of known and potential H. pylori cofactors in gastric carcinogenesis between the high and the low risk area showed that consumption of chili products was significantly higher in Valdivia and daily non-green vegetable consumption was more common in Antofagasta. Pepsinogen levels suggestive of gastric atrophy were significantly more common and occurred at earlier ages in Valdivia, the higher risk area. In a multivariate model combining both study sites, age, chili consumption and CagA were the main risk factors for gastric atrophy. CONCLUSIONS: The prevalence of H. pylori infection and its virulence factors was similar in the high and the low risk area, but atrophy was more common and occurred at younger ages in the higher risk area. Dietary factors could partly explain higher rates of atrophy and gastric cancer in Valdivia. IMPACT: The ENIGMA study in Chile contributes to better understanding regional variations in gastric cancer incidence and provides essential information for public health interventions.

Diagnóstico microbiológico y vigilancia epidemiológica de la campilobacteriosis en Chile: situación actual y desafíos futuros / Microbial diagnosis and epidemiological surveillance of campylobacteriosis in Chile: present state and further challenges

Resumen Campylobacter spp. es considerado el primer agente etiológico de diarrea en países desarrollados, y el segundo o tercero en países en vías de desarrollo. La elevada incidencia de gastroenteritis por Campylobacter spp. y sus posibles secuelas post-infección (artritis reactiva, el síndrome de Miller-Fisher o el síndrome de Guillain-Barré) le confieren gran importancia desde el punto de vista socio-económico. Sin embargo, en la mayoría de los países en vías de desarrollo no existe diagnóstico microbiológico rutinario de este patógeno. En Chile, la campilobacteriosis es notificable desde 1983. Sin embargo, la falta de diagnóstico rutinario por parte de los laboratorios clínicos ha dificultado conocer la verdadera prevalencia de este patógeno, tanto en infecciones intestinales como extra-intestinales. Además, a pesar que la campilobacteriosis es una enfermedad zoonótica, el diagnóstico de este patógeno no está considerado dentro del Reglamento Sanitario de los Alimentos de Chile. Todo esto se traduce en una falta de conocimiento sobre la epidemiología de la enfermedad por Campylobacter spp en Chile. Por lo tanto, es objetivo de esta revisión analizar la situación de la campilobacteriosis en las últimas dos décadas en Chile y determinar cuáles son los desafíos que quedan para lograr un diagnóstico y vigilancia efectivos en el país.

Abstract Campylobacter spp. is considered as the first etiologic agent of diarrhea in developed countries and the second or third in developing countries. The high incidence of Campylobacter gastroenteritis and its possible post-infection sequelae (reactive arthritis, Miller-Fisher syndrome or Guillain-Barré syndrome) give it great importance from the socioeconomic point of view. However, in most developing countries there is no routine microbial diagnosis of this pathogen. In Chile, campylobacteriosis is notifiable since 1983. However, the lack of routine diagnosis by clinical laboratories has made it difficult to know the true prevalence of this pathogen in both intestinal and extra-intestinal infections. In addition, although campylobacteriosis is a zoonotic disease, the diagnosis of this pathogen is not considered within the Chilean Food Sanitary Regulations. All this results in a lack of knowledge about the epidemiology of Campylobacter spp disease in Chile. Therefore, the objective of this review is to analyze the situation of campylobacteriosis in the last two decades in Chile and to determine the challenges that remain to achieve an effective microbial diagnosis and epidemiologic surveillance.

Concurrent progressive multifocal leukoencephalopathy and central nervous system infiltration by multiple myeloma: A case report.

Progressive multifocal leukoencephalopathy rarely occurs in patients with multiple myeloma. Intracranial central nervous system invasion is also an uncommon event in multiple myeloma, occurring in less than 1% of cases. We describe herein an exceptional case of coexisting progressive multifocal leukoencephalopathy and intraparenchymal central nervous system myeloma infiltration. A 73-year-old woman with relapsed multiple myeloma was treated with 15 cycles of lenalidomide and dexamethasone, but therapy had to be stopped because of a hip fracture after a fall. During hospitalization, the patient developed progressive multifocal leukoencephalopathy caused by John Cunningham virus, and a prominent intra-parenchymal CD138-positive infiltrate was detected. VDJ rearrangements of the immunoglobulin heavy chain gene and the mutational profile of plasma cells in bone marrow at the time of diagnosis and in brain biopsy after progression were analyzed by next generation sequencing, showing genetic differences between medullary and extramedullary myeloma cells. The role of long-term treatment with lenalidomide and dexamethasone in the development progressive multifocal leukoencephalopathy or intraparenchymal central nervous system myeloma infiltration remains unknown. However, our results suggest that both events may have arisen as a consequence of treatment-related immunosuppression. Thus, an appropriate clinical approach compatible with the simultaneous treatment of progressive multifocal leukoencephalopathy and multiple myeloma should be developed.

A Polyphasic and Taxogenomic Evaluation Uncovers Arcobacter cryaerophilus as a Species Complex That Embraces Four Genomovars.

The species Arcobacter cryaerophilus is found in many food products of animal origin and is the dominating species in wastewater. In addition, it is associated with cases of farm animal and human infectious diseases,. The species embraces two subgroups i.e., 1A (LMG 24291T = LMG 9904T) and 1B (LMG 10829) that can be differentiated by their 16S rRNA-RFLP pattern. However, some authors, on the basis of the shared intermediate levels of DNA-DNA hybridization, have suggested abandoning the subgroup classification. This contradiction indicates that the taxonomy of this species is not yet resolved. The objective of the present study was to perform a taxonomic evaluation of the diversity of A. cryaerophilus. Genomic information was used along with a Multilocus Phylogenetic Analysis (MLPA) and phenotypic characterization on a group of 52 temporally and geographically dispersed strains, coming from different types of samples and hosts from nine countries. The MLPA analysis showed that those strains formed four clusters (I-IV). Values of Average Nucleotide Identity (ANI) and in silico DNA-DNA Hybridization (isDDH) obtained between 13 genomes representing strains of the four clusters were below the proposed cut-offs of 96 and 70%, respectively, confirming that each of the clusters represented a different genomic species. However, none of the evaluated phenotypic tests enabled their unequivocal differentiation into species. Therefore, the genomic delimited clusters should be considered genomovars of the species A. cryaerophilus. These genomovars could have different clinical importance, since only the cluster I included strains isolated from human specimens. The discovery of at least one stable distinctive phenotypic character would be needed to define each cluster or genomovar as a different species. Until then, we propose naming them "A. cryaerophilus gv. pseudocryaerophilus" (Cluster I = LMG 10229T), "A. cryaerophilus gv. crypticus" (Cluster II = LMG 9065T), "A. cryaerophilus gv. cryaerophilus" (Cluster III = LMG 24291T) and "A. cryaerophilus gv. occultus" (Cluster IV = LMG 29976T).

Genomic and clinical evidence uncovers the enterohepatic species Helicobacter valdiviensis as a potential human intestinal pathogen.

BACKGROUND: Helicobacter valdiviensis is a recently described enterohepatic species isolated from wild bird's fecal samples. Currently, its pathogenic potential and clinical significance are unknown mainly due to the lack of whole-genome sequences to compare with other helicobacters and the absence of specific screenings to determine its prevalence in humans. MATERIALS AND METHODS: The species type strain (WBE14T ) was whole-genome-sequenced, and comparative analyses were carried out including the genomes from other Helicobacter species to determine the exact phylogenetic position of H. valdiviensis and to study the presence and evolution of virulence determinants. In parallel, stools from diarrheic patients and healthy individuals were screened by PCR to assess the clinical incidence of H. valdiviensis. RESULTS: Helicobacter valdiviensis belongs to a monophyletic clade conformed by H. canadensis, H. pullorum, H. winghamensis, H. rodentium, and H. apodemus. Its predicted genome size is 2 176 246 bp., with 30% of G+C content and 2064 annotated protein-coding genes. The patterns of virulence factors in H. valdiviensis were similar to other enterohepatic species, but evidence of horizontal gene transfer from Campylobacter species was detected for key genes like those coding for the CDT subunits. Positive PCR results confirmed the presence of H. valdiviensis in 2 of 254 (0.78%) stools of patients with acute diarrhea while not a single sample was positive in healthy individuals. CONCLUSIONS: Horizontal gene transfer has contributed to shape the gene repertory of H. valdiviensis, which codes for virulence factors conserved in other pathogens that are well-known human pathogens. Additionally, the detection of H. valdiviensisDNA in diarrheic patients supports its role as a potential emergent intestinal pathogen. Further, sampling efforts are needed to uncover the clinical relevance of this species, which should be accomplished by the isolation of H. valdiviensis from ill humans and the obtention of whole genomes from clinical isolates.

Description of Helicobacter valdiviensis sp. nov., an Epsilonproteobacteria isolated from wild bird faecal samples.

Two Gram-stain-negative, gently curved rod-shaped isolates (WBE14(T) and WBE19), recovered from wild bird faecal samples in the city of Valdivia (Southern Chile) were subjected to a polyphasic taxonomic study. Results of a genus-specific PCR indicated that these isolates belonged to the genus Helicobacter. This was further confirmed by a phylogenetic analyses based on the 16S rRNA, 60 kDa heat-shock protein (cpn60) and gyrase subunit B (gyrB) genes, where both strains formed a novel phylogenetic line within this genus. The 16S rRNA gene sequence similarity of strain WBE14(T) to the type strains of all other species of the genus Helicobacter examined ranged from 89.4 to 97.0%; Helicobacter brantae and Helicobacter pametensis were the most closely related species. However, on the basis of the protein-coding genes Helicobacter pullorum and Helicobacter canadensis are the most closely related species. These data, together with their different morphological and biochemical characteristics, revealed that these strains represent a novel species, for which the name Helicobacter valdiviensis sp. nov. is proposed, with the type strain WBE14(T) ( = CECT 8410(T) = LMG 27920(T)).

Arcobacter defluvii sp. nov., isolated from sewage samples.

A study employing a polyphasic taxonomic approach was undertaken to clarify the position of 12 isolates recovered from sewage samples. These isolates were recognized as a potential novel species because a new and specific pattern was produced with the 16S rRNA-RFLP Arcobacter identification method. The sequences of the 16S rRNA gene not only supported the classification of these novel strains as members of the genus Arcobacter, but also showed that they formed a separate phylogenetic line. Strain SW28-11(T), chosen as the representative of these strains, showed 16S rRNA gene sequence similarity of 95.6 % with the closest related species Arcobacter nitrofigilis. The phylogenetic position of the novel strains was further confirmed by analysis of the housekeeping genes hsp60, rpoB and, for the first time, gyrB. The latter proved to be an excellent additional gene for establishing the phylogeny of this genus. These data, together with phenotypic characterization, revealed that this group of isolates represent a novel species of the genus Arcobacter. The name Arcobacter defluvii sp. nov., is proposed, with the type strain SW28-11(T) ( = CECT 7697(T) = LMG 25694(T)).