Pathologic complete response (pCR) after multimodal treatment for locally advanced rectal cancer (LARC) is used as surrogate marker of success as it is assumed to correlate with improved oncologic ...outcome. However, long-term oncologic data are scarce.
This retrospective, multicentre study updated the oncologic follow-up of prospectively collected data from the Spanish Rectal Cancer Project database. pCR was described as no evidence of tumour cells in the specimen. Endpoints were distant metastases-free survival (DMFS) and overall survival (OS). Multivariate regression analyses were run to identify factors associated with survival.
Overall, 32 different hospitals were involved, providing data on 815 patients with pCR. At a median follow-up of 73.4 (IQR 57.7–99.5) months, distant metastases occurred in 6.4% of patients. Abdominoperineal excision (APE) (HR 2.2, 95%CI 1.2–4.1, p = 0.008) and elevated CEA levels (HR = 1.9, 95% CI 1.0–3.7, p = 0.049) were independent risk factors for distant recurrence. Age (years) (HR 1.1; 95%-CI 1.05–41.09; p < 0.001) and ASA III-IV (HR = 2.0; 95%-CI 1.4–2.9; p < 0.001), were the only factors associated with OS. The estimated 12, 36 and 60-months DMFS rates were 96.9%, 91.3%, and 86.8%. The estimated 12, 36 and 60-months OS rates were 99.1%, 94.9% and 89.3%.
The incidence of metachronous distant metastases is low after pCR, with high rates of both DMFS and OS. The oncologic prognosis in LARC patients that achieve pCR after neoadjuvant chemo-radiotherapy is excellent in the long term.
Pyridoxine-dependent epilepsy (PDE) is a rare disorder of the lysine metabolism, characterized by a pharmacoresistant epileptic encephalopathy that usually begins in the neonatal period. However, its ...phenotypic spectrum is wide and not limited to seizures. We report a new case of PDE who developed hydrocephalus, along with an exhaustive review of the literature.
Our patient presented with seizures at 13 h of life. Antiepileptic drugs, vitamins and cofactors were required to achieve seizure control. Laboratory tests were congruent with PDE. She remained seizure-free until age five months, when seizures reappeared in the context of increasing head size and irritability. A cranial ultrasound showed hydrocephalus, for which she underwent ventriculoperitoneal shunting.
Seven other patients with same features have been previously reported. Seizure onset occurred within the first 7 days in all patients. Most of the children developed hydrocephalus at 6–7 months of age. In 4 out of 7 a genetic mutation was identified, despite the accurate etiology of hydrocephalus was unknown in most of them. The case we report behaved similarly to the others previously described. We postulate that the pathogenesis of this complication could be related to the high expression of antiquitin in choroid plexus epithelium, where the cerebrospinal fluid is produced.
patients with PDE should be closely monitored, since they may present severe complications. We highlight the development of hydrocephalus, an uncommon but potentially life-threatening problem reported in 8 patients up to present time.
FPR2 DNA Aptamers for Targeted Therapy of Wound Repair Arriba, María del Carmen de; Fernández, Gerónimo; Chacón-Solano, Esteban ...
Journal of investigative dermatology,
08/2022, Letnik:
142, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Chronic wounds represent a major health problem worldwide. Some of the available therapies based on recombinant proteins usually fail owing to the hostile environment found at the wound bed. Aptamers ...appear as an attractive alternative to recombinant factors owing in part to their stability, sensitivity, specificity, and low-cost production. In this study, the Cell-Systematic Evolution of Ligands by EXponential Enrichment technology was employed to generate aptamers that specifically recognize and modulate the function of the FPR2, a receptor expressed in a variety of cells involved in wound repair. Three aptamers were obtained that specifically bound to FPR2 stable transfectants generated in HaCaT cells. The targeted aptamers were shown to act as FPR2 agonists in different in vitro functional assays, including wound healing assays, and elicited a similar pattern of response to that obtained with other known FPR2 peptide agonists, such as the human LL37 cathelicidin. We have also obtained in vivo evidence for the prohealing activities of one of these FPR2 aptamers in a skin-humanized mouse model developed by us, previously shown to accurately recreate the main phases of physiological human wound repair process. In conclusion, we provide evidence of the potential therapeutic value of FPR2 aptamers for cutaneous repair.
Very few surveys have been carried out of oncosurgical decisions made in patients with pancreatic cancer (PC), or of the possible differences in therapeutic approaches between low/medium and ...high-volume centers. A survey was sent out to centers affiliated to the Spanish Group of Pancreatic Surgery (GECP) asking about their usual pre-, intra- and post-operative management of PC patients and describing five imaginary cases of PC corresponding to common scenarios that surgeons regularly assess in oncosurgical meetings. A consensus was considered to have been reached when 80% of the answers coincided. We received 69 responses from the 72 GECP centers (response rate 96%). Pre-operative management: consensus was obtained on 7/16 questions (43.75%) with no significant differences between low- vs high-volume centers. Intra-operative: consensus was obtained on 11/28 questions (39.3%). D2 lymphadenectomy, biliary culture, intra-operative biliary margin study, pancreatojejunostomy, and two loops were significantly more frequent in high-volume hospitals (
p
< 0.05). Post-operative: consensus was obtained on 2/8 questions (25%). No significant differences were found between low-/medium- vs high-volume hospitals. Of the 41 questions asked regarding the cases, consensus was reached on 22 (53.7%). No differences in the responses were found according to the type of hospital. Management and cases: consensus was reached in 42/93 questions (45.2%). At GECP centers, consensus was obtained on 45% of the questions. Only 5% of the answers differed between low/medium and high-volume centers (all intra-operative). A more specific assessment of why high-volume centers obtain the best results would require the design of complex prospective studies able to measure the therapeutic decisions made and the effectiveness of their execution.
Clinicaltrials.gov identifier
:
NCT04755036.
We report the clinical and genetic features of a Caucasian girl who presented a severe neurodevelopmental disorder with drug‐resistant epilepsy, hypotonia, severe gastro‐esophageal reflux and brain ...magnetic resonance imaging anomalies. WES uncovered a novel variant in homozygosis (g.197092814_197092824delinsC) in HECW2 gene that encodes the E3 ubiquitin‐protein ligase HECW2. This protein induces ubiquitination and is implicated in the regulation of several important pathways involved in neurodevelopment and neurogenesis. Furthermore, de novo heterozygous missense variants in this gene have been associated with neurodevelopmental disorder with hypotonia, seizures, and absent language (NDHSAL). The homozygous variant of our patient disrupts the splice donor site of intron 22 and causes the elimination of exon 22 (r.3766_3917+1del) leading to an in‐frame deletion of the protein (p.Leu1256_Trp1306del). Functional studies showed a twofold increase of its RNA expression, while the protein expression level was reduced by 60%, suggesting a partial loss‐of‐function mechanism of pathogenesis. Thus, this is the first patient with NDHSAL caused by an autosomal recessive splicing variant in HECW2.
This study identified the first patient with NDHSAL caused by an autosomal recessive splicing variant in HECW2 gene. The novel variant in homozygosis (g.197092814_197092824delinsC) produces the elimination of exon 22 (r.3765_3917del) leading to an in‐frame deletion of the protein (p.Leu1256_Trp1306del) and a 60% reduction in its expression level.
Abstract Cholinergic striatal interneurons (ChIs) express the vesicular glutamate transporter 3 (VGLUT3) which allows them to regulate the striatal network with glutamate and acetylcholine (ACh). In ...addition, VGLUT3-dependent glutamate increases ACh vesicular stores through vesicular synergy. A missense polymorphism, VGLUT3-p.T8I, was identified in patients with substance use disorders (SUDs) and eating disorders (EDs). A mouse line was generated to understand the neurochemical and behavioral impact of the p.T8I variant. In VGLUT3 T8I/T8I male mice, glutamate signaling was unchanged but vesicular synergy and ACh release were blunted. Mutant male mice exhibited a reduced DA release in the dorsomedial striatum but not in the dorsolateral striatum, facilitating habit formation and exacerbating maladaptive use of drug or food. Increasing ACh tone with donepezil reversed the self-starvation phenotype observed in VGLUT3 T8I/T8I male mice. Our study suggests that unbalanced dopaminergic transmission in the dorsal striatum could be a common mechanism between SUDs and EDs.
To validate a prognostic score predicting major complications in patients with solid tumors and seemingly stable episodes of febrile neutropenia (FN). The definition of clinical stability implies the ...absence of organ dysfunction, abnormalities in vital signs, and major infections.
We developed the Clinical Index of Stable Febrile Neutropenia (CISNE), with six explanatory variables associated with serious complications: Eastern Cooperative Oncology Group performance status ≥ 2 (2 points), chronic obstructive pulmonary disease (1 point), chronic cardiovascular disease (1 point), mucositis of grade ≥ 2 (National Cancer Institute Common Toxicity Criteria; 1 point), monocytes < 200 per μL (1 point), and stress-induced hyperglycemia (2 points). We integrated these factors into a score ranging from 0 to 8, which classifies patients into three prognostic classes: low (0 points), intermediate (1 to 2 points), and high risk (≥ 3 points). We present a multicenter validation of CISNE.
We prospectively recruited 1,133 patients with seemingly stable FN from 25 hospitals. Complication rates in the training and validation subsets, respectively, were 1.1% and 1.1% in low-, 6.1% and 6.2% in intermediate-, and 32.5% and 36% in high-risk patients; mortality rates within each class were 0% in low-, 1.6% and 0% in intermediate-, and 4.3% and 3.1% in high-risk patients. Areas under the receiver operating characteristic curves in the validation subset were 0.652 (95% CI, 0.598 to 0.703) for Talcott, 0.721 (95% CI, 0.669 to 0.768) for Multinational Association for Supportive Care in Cancer (MASCC), and 0.868 (95% CI, 0.827 to 0.903) for CISNE (P = .002 for comparison between CISNE and MASCC).
CISNE is a valid model for accurately classifying patients with cancer with seemingly stable FN episodes.
Background
Current evidence suggests that local anesthetic wound infiltration should be employed as part of multimodal postoperative pain management. There is scarce data concerning the benefits of ...this anesthetic modality in laparoscopic weight loss surgery. Therefore, we analyzed the influence of trocar site infiltration with bupivacaine on the management of postoperative pain in laparoscopic bariatric surgery.
Methods
This retrospective randomized study included 47 patients undergoing primary obesity surgery between January and September 2014. Laparoscopic gastric bypass was performed in 39 cases and sleeve gastrectomy in 8 cases. Patients were stratified into two groups depending on whether preincisional infiltration with bupivacaine and epinephrine was performed (study group, 27 patients) or not (control group, 20 patients). Visual analogue scale (VAS), International Pain Outcomes questionnaire, and rescue medication records were reviewed to assess postoperative pain.
Results
VAS scores in the study group and sleeve gastrectomy group were lower than those in the control and gastric bypass groups in the first 4 h postoperatively without reaching statistical significance (
p
> 0.05). VAS scores did not differ in any other period of time. No statistically significant differences in pain perception were registered according to the patient’s pain outcomes questionnaire or the need for rescue medication.
Conclusions
The present study did not conclusively prove the efficacy of bupivacaine infiltration by any of the three evaluation methods analyzed. Nevertheless, preincisional infiltration provides good level of comfort in the immediate postoperative period when analgesia is most urgent.
Cellular cobalamin defects are a locus and allelic heterogeneous disorder. The gold standard for coming to genetic diagnoses of cobalamin defects has for some time been gene-by-gene Sanger sequencing ...of individual DNA fragments. Enzymatic and cellular methods are employed before such sequencing to help in the selection of the gene defects to be sought, but this is time-consuming and laborious. Furthermore some cases remain undiagnosed because no biochemical methods have been available to test for cobalamin absorption and transport defects.
This paper reports the use of massive parallel sequencing of DNA (exome analysis) for the accurate and rapid genetic diagnosis of cobalamin-related defects in a cohort of affected patients. The method was first validated in an initial cohort with different cobalamin defects. Mendelian segregation, the frequency of mutations, and the comprehensive structural and functional analysis of gene variants, identified disease-causing mutations in 12 genes involved in the absorption and synthesis of active cofactors of vitamin B
(22 cases), and in the non-cobalamin metabolism-related genes ACSF3 (in four biochemically misdiagnosed patients) and SUCLA2 (in one patient with an unusual presentation). We have identified thirteen new variants all classified as pathogenic according to the ACGM recommendation but four were classified as variant likely pathogenic in MUT and SUCLA2. Functional and structural analysis provided evidences to classify them as pathogenic variants.
The present findings suggest that the technology used is sufficiently sensitive and specific, and the results it provides sufficiently reproducible, to recommend its use as a second-tier test after the biochemical detection of cobalamin disorder markers in the first days of life. However, for accurate diagnoses to be made, biochemical and functional tests that allow comprehensive clinical phenotyping are also needed.
We report the case of a Caucasian Spanish origin female who showed severe psychomotor developmental delay, hypotonia, strabismus, epilepsy, short stature, and poor verbal language development. Brain ...magnetic resonance imaging scans showed thickened corpus callosum, cortical malformations, and dilated and abnormal configuration of the lateral ventricles without hydrocephalus. Whole‐exome sequence uncovered a de novo variant in the microtubule associated serine/threonine kinase 1 gene (MAST1; NM_014975.3:c.1565G>A:p.(Gly522Glu)) that encodes for the MAST1. Only 12 patients have been identified worldwide with 10 different variants in this gene: six patients with mega‐corpus‐callosum syndrome with cerebellar hypoplasia and cortical malformations; two patients with microcephaly and cerebellar hypoplasia; two patients with autism, one patient with diplegia, and one patient with microcephaly and dysmorphism. Our patient shows a new phenotypic subtype defined by mega‐corpus‐callosum syndrome with cortical malformations without cerebellar hypoplasia. In conclusion, our data expand the phenotypic spectrum associated to MAST1 gene variants.
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