Cross-sectional and longitudinal associations of adherence to WCRF/AICR cancer prevention recommendations with health-related quality of life in breast cancer survivors. Health-EpiGEICAM study.

OBJECTIVES: Adherence to healthy lifestyle recommendations has been reported to improve health-related quality of life (HRQL) in breast cancer (BC) patients, but the influence of long-term behavioral changes remains unknown. We evaluated the association between adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations and HRQL both, at BC diagnosis and the change 7-12 years later. DESIGN: Prospective cohort study. SETTINGS AND PARTICIPANTS: A total of 406 breast cancer survivors, from the EpiGEICAM study, were recruited in 16 Spanish hospitals. MEASUREMENTS: Epidemiological, clinical, dietary, physical activity and HRQL information was collected both at recruitment and 7-12 years later. A 7-item score to measure compliance with recommendations was assessed according to the 2018 WCRF/AICR scoring criteria. HRQL was evaluated using SF-36 questionnaire. Linear mixed models for longitudinal data were used to assess the cross-sectional and longitudinal association between adherence score and the physical and mental component summary scores. RESULTS: At diagnosis, for each unit increase in WCRF/AICR score adherence, the HRQL physical domain increased 0.78 points (95%CI: -0.04 to 1.60; P trend:0.06). The mean change in physical HRQL from diagnosis to follow-up per unit increase in within-subject adherence score was 0.73 points (95%CI: -0.18 to 1.65; P trend: 0.12). For the mental domain, no association was observed with compliance with the recommendations at diagnosis, nor with changes in adherence over time. CONCLUSIONS: Our results suggest that Increased adherence to WCRF/AICR cancer prevention recommendations over time could contribute to slightly improved long-term physical HRQoL in BC survivors.

Clinical, Pathological Characteristics and Progression of Urothelial Bladder Cancer in Young Adult Patients. Our Experience and Literature Review.

BACKGROUND: Bladder cancer is highly prevalent even though its incidence is considerably lower in patients younger than 40 years, thus raising the issue of the influence of age at diagnosis on the natural history of this disease. This study aimed to evaluate the characteristics and progression of young patients with urothelial bladder carcinoma with at least 10 years of follow-up and to compare the results with those of previously reported studies. MATERIAL AND METHODS: A retrospective study between 1990 and 2007 was conducted. The medical records and tissue samples of patients with urothelial bladder tumours were reviewed, and patients with a first diagnosis of urothelial carcinoma of the bladder at age 40 years or younger were selected. Their clinical and pathological data and disease-free survival were analysed. RESULTS: This study included 43 patients, with a median follow-up of 152 months (interquartile range (IQR): 96-222) and a mean age at diagnosis of 34 years (SD: 4.6). Thirty-five patients (81.4%) had non-muscle invasive tumours at diagnosis, and 53.5%, 27.9% and 18.6% had tumour grades of G1, G2 and G3, respectively. Fifteen patients (34.9%) experienced recurrence, and eight (18.6%) progressed. At 24 and 60 months, the recurrence-free survival rates were 84.8% (95% confidence interval (CI): 69.2%-92.9%) and 68.9% (95% CI: 51.7%-81%), respectively, and the progression-free survival rates were 94.9% (95% CI: 81%-98.7%) and 92.2% (95% CI: 77.8%-97.4%), respectively. CONCLUSIONS: Bladder cancer is an uncommon disease in young patients. In most cases, it consists of non-muscle-invasive tumours, with a low rate of recurrence and progression. The prognosis is based on the tumour's characteristics and not on the patient's age.

Birthmode and environment-dependent microbiota transmission dynamics are complemented by breastfeeding during the first year.

The composition and maturation of the early-life microbiota are modulated by a number of perinatal factors, whose interplay in relation to microbial vertical transmission remains inadequately elucidated. Using recent strain-tracking methodologies, we analyzed mother-to-infant microbiota transmission in two different birth environments: hospital-born (vaginal/cesarean) and home-born (vaginal) infants and their mothers. While delivery mode primarily explains initial compositional differences, place of birth impacts transmission timing-being early in homebirths and delayed in cesarean deliveries. Transmission patterns vary greatly across species and birth groups, yet certain species, like Bifidobacterium longum, are consistently vertically transmitted regardless of delivery setting. Strain-level analysis of B. longum highlights relevant and consistent subspecies replacement patterns mainly explained by breastfeeding practices, which drive changes in human milk oligosaccharide (HMO) degrading capabilities. Our findings highlight how delivery setting, breastfeeding duration, and other lifestyle preferences collectively shape vertical transmission, impacting infant gut colonization during early life.

Collagen peptides affect collagen synthesis and the expression of collagen, elastin, and versican genes in cultured human dermal fibroblasts.

Background: Collagen is one of the major proteins of the skin and it is particularly important for its strength and resilience. Skin aging is a natural process that is characterized by the decrease and fragmentation of collagen in the dermis. Oral supplementation with collagen peptides has been clinically shown to have a positive effect on the skin condition. However, the mechanisms of aging-related changes synthesized by cells exposed to collagen are currently not well understood. Therefore, in this in vitro study, the mechanisms associated with collagen, elastin, and versican in human dermal fibroblasts were investigated after exposure to collagen peptides. Methods: The effects of different concentrations of collagen peptides on cell viability and metabolism were analyzed. For gene expression analysis, human dermal fibroblasts were treated with collagen peptides. This was then followed by RNA extraction and DNA synthesis. Gene expressions of collagen type 1 (COL1A1), elastin (ELN), and versican (VCAN) were quantified by quantitative reverse transcription polymerase chain reaction (RT-qPCR). In addition, collagen levels were analyzed by confocal scanning laser microscopy using immunostaining. Results: Collagen peptides tested in the study increased the expression of the relevant COL1A1, ELN, and VCAN genes in human dermal fibroblasts (p < 0.005). Furthermore, confocal microscopy showed increased collagen expression in the dermal fibroblast culture after treatment with the collagen peptides (p < 0.005). Conclusion: These data provide cell-based evidence for the beneficial effects of exposure to collagen peptides on the skin's collagen content and on the molecules that provide firmness and elasticity. This may support the hypothesis that collagen peptides are important for maintaining extracellular matrix (ECM) structure and skin regeneration.

Human fecal alpha-glucosidase activity and its relationship with gut microbiota profiles and early stages of intestinal mucosa damage.

OBJECTIVES: We investigated potential relationships among initial lesions of the intestinal mucosa, fecal enzymatic activities and microbiota profiles. METHODS: Fecal samples from 54 volunteers were collected after recruitment among individuals participating in a colorectal cancer (CRC) screening program in our region (Northern Spain) or attending for consultation due to clinical symptoms; intestinal mucosa samples were resected during colonoscopy. Enzymatic activities were determined in fecal supernatants by a semi-quantitative method. The fecal microbiota composition was determined by 16S rRNA gene-based sequencing. The results were compared between samples from clinical diagnosis groups (controls and polyps), according with the type of polyp (hyperplastic polyps or conventional adenomas) and considering the grade of dysplasia for conventional adenomas (low and high grade dysplasia). RESULTS: High levels of α-glucosidase activity were more frequent among samples from individuals diagnosed with intestinal polyps, reaching statistical significance for conventional adenomas and for low grade dysplasia adenomas when compared to controls. Regarding the microbiota profiles, higher abundance of Christensenellaceae_R-7 group and Oscillospiraceae_UCG-002 were found in fecal samples displaying low α-glucosidase activity as compared with those with higher activity as well as in controls with respect to conventional adenomas. A relationship was evidenced among intestinal mucosal lesions, gut glucosidase activities and intestinal microbiota profiles. CONCLUSIONS: Our findings suggest a relationship among altered fecal α-glucosidase levels, the presence of intestinal mucosal lesions, which can be precursors of CRC, and shifts in defined microbial groups of the fecal microbiota.

Potentiation of the M 1 muscarinic acetylcholine receptor normalizes neuronal activation patterns and improves apnea severity in Mecp2+/- mice.

Rett syndrome (RTT) is a neurodevelopmental disorder that is caused by loss-of-function mutations in the methyl-CpG binding protein 2 ( MeCP2 ) gene. RTT patients experience a myriad of debilitating symptoms, which include respiratory phenotypes that are often associated with lethality. Our previous work established that expression of the M 1 muscarinic acetylcholine receptor (mAchR) is decreased in RTT autopsy samples, and that potentiation of the M 1 receptor improves apneas in a mouse model of RTT; however, the population of neurons driving this rescue is unclear. Loss of Mecp2 correlates with excessive neuronal activity in cardiorespiratory nuclei. Since M 1 is found on cholinergic interneurons, we hypothesized that M 1 -potentiating compounds decrease apnea frequency by tempering brainstem hyperactivity. To test this, Mecp2 +/- and Mecp2 +/+ mice were screened for apneas before and after administration of the M 1 positive allosteric modulator (PAM) VU0453595 (VU595). Brains from the same mice were then imaged for c-Fos, ChAT, and Syto16 using whole-brain light-sheet microscopy to establish genotype and drug-dependent activation patterns that could be correlated with VU595's efficacy on apneas. The vehicle-treated Mecp2 +/- brain exhibited broad hyperactivity when coupled with the phenotypic prescreen, which was significantly decreased by administration of VU595, particularly in regions known to modulate the activity of respiratory nuclei (i.e. hippocampus and striatum). Further, the extent of apnea rescue in each mouse showed a significant positive correlation with c-Fos expression in non-cholinergic neurons in the striatum, thalamus, dentate gyrus, and within the cholinergic neurons of the brainstem. These results indicate that Mecp2 +/- mice are prone to hyperactivity in brain regions that regulate respiration, which can be normalized through M 1 potentiation.

Telomerase Reverse Transcriptase-Promoter Mutation in Young Patients with Bladder Tumors.

The TERT (Telomerase Reverse Transcriptase) gene promoter mutation is one of the most prevalent mutations in urothelial bladder tumors and this mutation is related to bladder tumor progression. Our purpose was to evaluate the presence of this mutation in a population of patients who were first diagnosed at age ≤ 40 years and to examine its relationship with tumor characteristics and progression. A molecular study was performed to detect the two most prevalent mutations in the TERT promoter (C228T and C250T). The study included 29 patients, with a mean follow-up of 152 months. There were no statistically significant differences in the clinical or tumor characteristics according to the presence or absence of the mutation. Although the mutation group showed poorer recurrence-free survival (RFS), there was no statistically significant difference and there was no difference in progression-free survival by group (p > 0.05). The pTERT mutations in bladder tumor cells occurred less frequently in younger patients than in older patients, a finding that could indicate different mechanisms of carcinogenesis. The trend towards lower RFS in patients with mutated pTERT needs to be confirmed by further studies, given the small number of patients included in these studies due to the low incidence of bladder tumors in this age group.

Role of the intestinal microbiota and diet in the onset and progression of colorectal and breast cancers and the interconnection between both types of tumours.

Colorectal cancer (CRC) is among the leading causes of mortality in adults of both sexes worldwide, while breast cancer (BC) is among the leading causes of death in women. In addition to age, gender, and genetic predisposition, environmental and lifestyle factors exert a strong influence. Global diet, including alcohol consumption, is one of the most important modifiable factors affecting the risk of CRC and BC. Western dietary patterns promoting high intakes of xenobiotics from food processing and ethanol have been associated with increased cancer risk, whereas the Mediterranean diet, generally leading to a higher intake of polyphenols and fibre, has been associated with a protective effect. Gut dysbiosis is a common feature in CRC, where the usual microbiota is progressively replaced by opportunistic pathogens and the gut metabolome is altered. The relationship between microbiota and BC has been less studied. The estrobolome is the collection of genes from intestinal bacteria that can metabolize oestrogens. In a dysbiosis condition, microbial deconjugating enzymes can reactivate conjugated-deactivated oestrogens, increasing the risk of BC. In contrast, intestinal microorganisms can increase the biological activity and bioavailability of dietary phytochemicals through diverse microbial metabolic transformations, potentiating their anticancer activity. Members of the intestinal microbiota can increase the toxicity of xenobiotics through metabolic transformations. However, most of the microorganisms involved in diet-microbiota interactions remain poorly characterized. Here, we provide an overview of the associations between microbiota and diet in BC and CRC, considering the diverse types and heterogeneity of these cancers and their relationship between them and with gut microbiota.

National expert consensus on home-administered oncologic therapies in Spain.

The diagnosis and treatment of cancer impose a significant emotional and psychological burden on patients, families, and caregivers. Patients undergo several interventions in a hospital setting, and the increasing number of patients requiring extended care and follow-up is driving the demand for additional clinical resources to address their needs. Hospital at Home (HaH) teams have introduced home-administered oncologic therapies that represent a new model of patient-centered cancer care. This approach can be integrated with traditional models and offers benefits to both patients and healthcare professionals (HCPs). Home-administered treatment programs have been successfully piloted globally, demonstrated as a preferred option for most patients and a safe alternative that could reduce costs and hospital burden. The document aims to establish the minimum recommendations for the home administration of oncologic therapies (ODAH) based on a national expert agreement. The expert panel comprised seven leading members from diverse Spanish societies and three working areas: clinical and healthcare issues, logistical and administrative issues, and economic, social, and legal issues. The recommendations outlined in this article were obtained after a comprehensive literature review and thorough discussions. This document may serve as a basis for the future development of home-administered oncologic therapy programs in Spain. .

Strict versus Liberal Use of Sentinel Node Biopsy in Breast Cancer Surgery: Any Clinical Outcome Differences? A 20-Year Clinical Experience.

Introduction: As applied to early breast cancer (BC) patients, sentinel node biopsy (SNB) has undergone major changes over the years, especially concerning the widening of indication criteria or skipping systematic axillary lymph node dissection (ALND) after a positive SN. We aimed to ascertain whether a strict versus a more liberal use of SNB resulted in different clinical outcomes in our clinical experience. Methods: We studied consecutive BC patients undergoing SNB between January 1, 2000, and March 31, 2020. There were 1,587 patients and 1,634 SNB procedures. Cases were divided into two study groups: the "strict" SNB group (unifocal tumors up to 35 mm in which ALND was always performed for a positive SN, amounting to 1,183 SNBs), and the "liberal" SNB group (extended tumor size up to selected T3 cases, as well as multifocal or bilateral disease, and patients with previous contralateral BC, not always followed by ALND after a positive SN, amounting to 451 SNBs). Patients were closely followed up to the end of the study. Results: Clinico-pathological variables were strikingly different between study groups, with the liberal group showing a higher risk profile. Cox regression analysis for disease recurrence did not show significant differences in axillary, lymph node, or locoregional recurrence rates or distant relapse. There were no differences in survival between groups. Conclusion: It seems reasonable to adopt the liberal SNB approach, as the goal of surgical management in early BC patients must be attaining optimal locoregional disease control, no matter the differences in distant metastatic spread rates across different BC risk profiles.

Protective Potential of a Botanical-Based Supplement Ingredient against the Impact of Environmental Pollution on Cutaneous and Cardiopulmonary Systems: Preclinical Study.

Air pollution is a growing threat to human health. Airborne pollution effects on respiratory, cardiovascular and skin health are well-established. The main mechanisms of air-pollution-induced health effects involve oxidative stress and inflammation. The present study evaluates the potential of a polyphenol-enriched food supplement ingredient comprising Lippia citriodora, Olea europaea, Rosmarinus officinalis, and Sophora japonica extracts in mitigating the adverse effects of environmental pollution on skin and cardiopulmonary systems. Both in vitro and ex vivo studies were used to assess the blend's effects against pollution-induced damage. In these studies, the botanical blend was found to reduce lipid peroxidation, inflammation (by reducing IL-1α), and metabolic alterations (by regulating MT-1H, AhR, and Nrf2 expression) in human skin explants exposed to a mixture of pollutants. Similar results were also observed in keratinocytes exposed to urban dust. Moreover, the ingredient significantly reduced pollutant-induced ROS production in human endothelial cells and lung fibroblasts, while downregulating the expression of apoptotic genes (bcl-2 and bax) in lung fibroblasts. Additionally, the blend counteracted the effect of urban dust on the heart rate in zebrafish embryos. These results support the potential use of this supplement as an adjuvant method to reduce the impact of environmental pollution on the skin, lungs, and cardiovascular tissues.

New Paradigms in the Diet and Microbiome Relationship.

Decades of extensive scientific research have led to a consensus on the modulatory effect of diet in shaping the composition and activity of the gut microbiota [...].

Human milk miRNAs associate to maternal dietary nutrients, milk microbiota, infant gut microbiota and growth.

BACKGROUND: Maternal diet influences the milk composition, yet little information is available on the impact of maternal diet on milk miRNAs expression. Further, the association of human milk miRNAs to maternal diet and milk microbiota is not explored. In addition, the role of milk miRNAs on the infant gut microbiota, infant growth and development has not been investigated. METHODS: Milk samples were collected from 60 healthy lactating women at ≤15d post-partum, HTG transcriptome assay was performed to examine milk miRNA profile. Maternal clinical and dietary clusters information were available and infant anthropometric measures were followed up to one year of age. Milk and infant microbiota were analyzed by 16S rRNA gene sequencing and integrative multi-omics data analysis was performed to identify potential association between microRNA, maternal dietary nutrients and microbiota. RESULTS: Discriminant analysis revealed that the milk miRNAs were clustered into groups according to the maternal protein source. Interestingly, 31 miRNAs were differentially expressed (P adj < 0.05) between maternal dietary clusters (Cluster 1: enriched in plant protein and fibers and Cluster 2: enriched in animal protein), with 30 miRNAs downregulated in the plant protein group relative to animal protein group. Pathway analysis revealed that the top enriched pathways (P adj < 0.01) were involved in cell growth and proliferation processes. Furthermore, significant features contributing to the clustering were associated with maternal dietary nutrients and milk microbiota (r > 0.70). Further, miR-378 and 320 family miRNAs involved in adipogenesis were positively correlated to the infant BMI-z-scores, weight, and weight for length-z-scores at 6 months of age. CONCLUSIONS: Maternal dietary source impacts the milk miRNA expression profile. Further, miRNAs were associated with maternal dietary nutrients, milk microbiota and to the infant gut microbiota and infant growth and development. CLINICAL TRIAL: The study is registered in ClinicalTrials.gov. The identification number is NCT03552939.

Immunometabolic Profile Associated with Progressive Damage of the Intestinal Mucosa in Adults Screened for Colorectal Cancer: Association with Diet.

Environmental factors such as diet and lifestyle have been shown to influence the development of some intestinal mucosal lesions that may be precursors of colorectal cancer (CRC). The presence of these alterations seems to be associated with misbalanced immunological parameter levels. However, it is still unclear as to which immunological parameters are altered in each phase of CRC development. In this work, we aimed to study the potential relationships of immunological and metabolic parameters with diet in a CRC-related lesion context. Dietary information was obtained using an annual semi-quantitative food-frequency questionnaire (FFQ) from 93 volunteers classified via colonoscopy examination according to the presence of intestinal polyps or adenocarcinoma. Cytokines, chemokines, and adipokines were determined from serum samples. We observed a reduction in adiponectin according to the damage to the mucosa, accompanied by an increase and decrease in C-X-C motif chemokine ligand 10 (CXCL10) and resistin, respectively, in CRC cases. The presence of aberrant crypt foci (ACF) in the polyp group was associated with higher tumor necrosis factor-alpha (TNF-α) concentrations. Vegetables were directly correlated with adiponectin and resistin levels, while the opposite occurred with red meat. A bioactive compound, soluble pectin, showed a negative association with TNF-α. Future dietary strategies could be developed to modulate specific immunological parameters in the context of CRC.

Small Molecule Pytren-4QMn Metal Complex Slows down Huntington's Disease Progression in Male zQ175 Transgenic Mice.

Huntington's disease (HD) is an inherited neurodegenerative disorder considered a rare disease with a prevalence of 5.7 per 100,000 people. It is caused by an autosomal dominant mutation consisting of expansions of trinucleotide repeats that translate into poly-glutamine enlarged mutant huntingtin proteins (mHTT), which are particularly deleterious in brain tissues. Since there is no cure for this progressive fatal disease, searches for new therapeutic approaches are much needed. The small molecule pytren-4QMn (4QMn), a highly water-soluble mimic of the enzyme superoxide dismutase, has shown in vivo beneficial anti-inflammatory activity in mice and was able to remove mHTT deposits in a C. elegans model of HD. In this study, we assessed 4QMn therapeutic potential in zQ175 neo-deleted knock-in mice, a model of HD that closely mimics the heterozygosity, genetic injury, and progressive nature of the human disease. We provide evidence that 4QMn has good acute and chronic tolerability, and can cross the blood-brain barrier, and in male, but not female, zQ175 mice moderately ameliorate HD-altered gene expression, mHtt aggregation, and HD disease phenotype. Our data highlight the importance of considering sex-specific differences when testing new therapies using animal models and postulate 4QMn as a potential novel type of small water-soluble metal complex that could be worth further investigating for its therapeutic potential in HD, as well as in other polyglutamine diseases.

Associations of dietary factors and xenobiotic intake with faecal microbiota composition according to the presence of intestinal mucosa damage.

Diet is a major modulator of gut microbiota, which plays a key role in the health status, including colorectal cancer (CRC) development. Several studies and meta-analyses have evidenced an association of certain dietary factors and xenobiotic intake with the incidence of CRC. Nevertheless, how these dietary factors impact the first stages of intestinal mucosa damage is still uncertain. This study aimed at exploring the associations of relevant dietary factors with the gut microbiota of control individuals and subjects diagnosed with intestinal polyps. A total of 60 volunteers were recruited, clinically classified according to colonoscopy criteria and interviewed using food frequency questionnaires (FFQs). The nutritional status of each volunteer was determined and the intake of dietary xenobiotics was quantified. The relative abundance of faecal microbiota taxonomic groups was obtained through 16S rRNA gene sequencing. The association of dietary factors and xenobiotics with faecal microbiota composition showed differences according to the clinical diagnosis group. Our results showed that the intake of red meat (≥50 g day-1) and total polycyclic aromatic hydrocarbons (PAHs) (≥0.75 µg day-1) was associated with a decreased abundance of the family Bacteroidaceae and an increased abundance of Coriobacteriaceae in control subjects. The intake of the heterocyclic amines 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) (≥40 ng day-1) and 2-amino-3,8 dimethylimidazo(4,5,f) quinoxaline (MeIQx) (≥50 ng day-1) was associated with a decreased abundance of Akkermansiaceae in the control diagnosis group. Moreover, N-nitroso compounds (NOCs), nitrites (≥1.69 mg day-1) and N-nitrosodimethylamine (NDMA) (≥0.126 µg day-1) were associated with a decreased abundance of Bifidobacteriaceae. The intake of ethanol (≥12 g day-1) in the polyps group was associated with an increased abundance of Peptostreptococcaceae and a decreased abundance of Veillonellaceae. Moreover, linear regression analyses allowed us to identify ethanol, calcium, bioactive compounds such as flavonoids, stilbenes, cellulose, phenolic acids or total polyphenols, and dietary xenobiotics such as PhIP and MeIQx, the NOC N-nitrosopyrrolidine (NPYR) or the total PAHs as potential predictors of faecal microbiota group abundances. These results indicated that the consumption of milk, red meat, processed meat and ethanol and the intake of polyphenols, dietary PAHs, HAs and NOCs are associated with specific groups of the intestinal microbiota, depending on the clinical diagnosis group.

Impact on Fecal Microbiota and Health-Related Markers of an Intervention Focused on Improving Eating Behavior in People at Risk of Food Insecurity.

Non-communicable diseases are particularly prevalent among low-income individuals and are associated with the consumption of processed foods, fat, and sugars. This work aims to evaluate the impacts of a nutrition education intervention for low socio-economic individuals on sensory perception, health-related parameters and gut microbiota. Twenty low-income adults underwent a 4-week intervention. Dietary information (three 24 h recalls), detection thresholds and discrimination scores (salty and sweet), and severity of depressive symptoms (Beck Depression Inventory-II (BDI-II)) were collected. Fecal microbial composition and short chain fatty acids were determined by 16S ribosomal RNA-gene sequencing and gas chromatography, respectively. After the intervention, 35% of subjects presented higher compliance with dietary recommendations, increased consumption of vegetables and lignans and reduced consumption of processed meats and nitrosamines, together with depleted levels of Actinomycetota. Higher discrimination for salty and sweet and lower BDI-II scores were also obtained. This nutrition education intervention entailed changes in dietary intake towards healthier food options, reduced potentially carcinogenic compounds and improved scores for discrimination and severity of depressive symptoms. The confirmation of these results in future studies would enable the design of strategic policies contributing to the optimal nutrition of materially deprived families through affordable healthy plant-based interventions.

Randomized phase II study of weekly carfilzomib 70 mg/m2 and dexamethasone with or without cyclophosphamide in relapsed and/or refractory multiple myeloma patients.

In this randomized phase II study (GEM-KyCyDex, clinicaltrials gov. Identifier: NCT03336073), the combination of weekly carfilzomib 70 mg/m2, cyclophosphamide and dexamethasone (KCd) was compared to carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM) after 1-3 prior lines (PL). One hundred and ninety-seven patients were included and randomized 1:1 to receive KCd (97 patients) or Kd (100 patients) in 28-day cycles until progressive disease or unacceptable toxicity occurred. Patient median age was 70 years, and the median number of PL was one (range, 1-3). More than 90% of patients had previously been exposed to proteasome inhibitors, approximetely 70% to immunomodulators, and approximetely 50% were refractory to their last line (mainly lenalidomide) in both groups. After a median follow-up of 37 months, median progression-free survival (PFS) was 19.1 and 16.6 months in KCd and Kd, respectively (P=0.577). Of note, in the post hoc analysis of the lenalidomide-refractory population, the addition of cyclophosphamide to Kd resulted in a significant benefit in terms of PFS: 18.4 versus 11.3 months (hazard ratio =1.7, 95% confidence interval: 1.1-2.7; P=0.043). The overall response rate and the percentage of patients who achieved complete response was around 70% and 20% in both groups. The addition of cyclophosphamide to Kd did not result in any safety signal, except for severe infections (7% vs. 2%). In conclusion, the combination of cyclophosphamide with Kd 70 mg/m2 weekly does not improve outcomes as compared with Kd alone in RRMM after 1-3 PL, but a significant benefit in PFS was observed with the triplet combination in the lenalidomide-refractory population. The administration of weekly carfilzomib 70 mg/m2 was safe and convenient, and, overall, the toxicity was manageable in both arms.

Commensal Fecal Microbiota Profiles Associated with Initial Stages of Intestinal Mucosa Damage: A Pilot Study.

Progressive intestinal mucosal damage occurs over years prior to colorectal cancer (CRC) development. The endoscopic screening of polyps and histopathological examination are used clinically to determine the risk and progression of mucosal lesions. We analyzed fecal microbiota compositions using 16S rRNA gene-based metataxonomic analyses and the levels of short-chain fatty acids (SCFAs) using gas chromatography in volunteers undergoing colonoscopy and histopathological analyses to determine the microbiota shifts occurring at the early stages of intestinal mucosa alterations. The results were compared between diagnosis groups (nonpathological controls and polyps), between samples from individuals with hyperplastic polyps or conventional adenomas, and between grades of dysplasia in conventional adenomas. Some microbial taxa from the Bacillota and Euryarchaeota phyla were the most affected when comparing the diagnosis and histopathological groups. Deeper microbiota alterations were found in the conventional adenomas than in the hyperplastic polyps. The Ruminococcus torques group was enriched in both the hyperplastic polyps and conventional adenomas, whereas the family Eggerthellaceae was enriched only in the hyperplastic polyps. The abundance of Prevotellaceae, Oscillospiraceae, Methanobacteriaceae, Streptococcaceae, Christensenellaceae, Erysipelotrichaceae, and Clostridiaceae shifted in conventional adenomas depending on the grade of dysplasia, without affecting the major SCFAs. Our results suggest a reorganization of microbial consortia involved in gut fermentative processes.