27 research outputs found
A case of distal extrahepatic cholangiocarcinoma with two positive resection margins
Cholangiocarcinoma is an uncommon primary malignancy of the biliary tract that is challenging to diagnose and treat effectively due to its relatively silent and late clinical presentation. The present study reports a case of a 60-year-old male with distal extrahepatic cholangiocarcinoma with a 3-week history of painless obstructive jaundice symptoms and subjective weight loss. Imaging revealed an obstructing lesion in the common bile duct, just distal to the entrance of the cystic duct. Pathology revealed moderately differentiated cholangiocarcinoma with two positive proximal resection margins. The two positive resection margins presented a challenge during surgery and points to an urgent need for further studies to better illuminate diagnostic and therapeutic options for patients with similar clinicopathological presentation
A Multi-Factorial Observational Study on Sequential Fecal Microbiota Transplant in Patients with Medically Refractory Clostridioides difficile Infection
Fecal microbiota transplantation (FMT) is highly effective in recurrent Clostridioides difficile infection (CDI); increasing evidence supports FMT in severe or fulminant Clostridioides difficile infection (SFCDI). However, the multifactorial mechanisms that underpin the efficacy of FMT are not fully understood. Systems biology approaches using high-throughput technologies may help with mechanistic dissection of host-microbial interactions. Here, we have undertaken a deep phenomics study on four adults receiving sequential FMT for SFCDI, in which we performed a longitudinal, integrative analysis of multiple host factors and intestinal microbiome changes. Stool samples were profiled for changes in gut microbiota and metabolites and blood samples for alterations in targeted epigenomic, metabonomic, glycomic, immune proteomic, immunophenotyping, immune functional assays, and T-cell receptor (TCR) repertoires, respectively. We characterised temporal trajectories in gut microbial and host immunometabolic data sets in three responders and one non-responder to sequential FMT. A total of 562 features were used for analysis, of which 78 features were identified, which differed between the responders and the non-responder. The observed dynamic phenotypic changes may potentially suggest immunosenescent signals in the non-responder and may help to underpin the mechanisms accompanying successful FMT, although our study is limited by a small sample size and significant heterogeneity in patient baseline characteristics. Our multi-omics integrative longitudinal analytical approach extends the knowledge regarding mechanisms of efficacy of FMT and highlights preliminary novel signatures, which should be validated in larger studies
In search of stool donors: a multicenter study of prior knowledge, perceptions, motivators, and deterrents among potential donors for fecal microbiota transplantation
Introduction: Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent Clostridium difficile infection. Stool donors are essential, but difficult to recruit and retain. We identified factors influencing willingness to donate stool.Methods: A 32-item questionnaire targeted young adults and health care workers via social media and university email lists in Edmonton and Kingston, Canada; London and Nottingham, England; and Indianapolis and Boston, USA. Items included baseline demographics and FMT knowledge and perception. Investigated motivators and deterrents included economic compensation, screening process, time commitment, and stool donation logistics. Logistic regression and linear regression models estimated associations of study variables with self-assessed willingness to donate stool.Results: 802 respondents completed our questionnaire: 387 (48.3%) age 21–30 years, 573 (71.4%) female, 323 (40%) health care workers. Country of residence, age and occupation were not associated with willingness to donate stool. Factors increasing willingness to donate were: already a blood donor (OR 1.64), male, altruism, economic benefit, knowledge of how FMT can help patients (OR 1.32), and positive attitudes towards FMT (OR 1.39). Factors decreasing willingness to donate were: stool collection unpleasant (OR 0.92), screening process invasive (OR 0.92), higher donation frequency, negative social perceptions of stool, and logistics of collecting/transporting feces.Discussion: Blood donors and males are more willing to consider stool donation. Altruism, economic compensation, and positive feedback are motivators. Screening process, high donation frequency, logistics of collecting/transporting feces, lack of public awareness, and negative social perception are deterrents. Considering these variables could maximize donor recruitment and retention
Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples
Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts
Mo1957 – Eeffect of Lyophilized Sterile Fecal Filtrate Vs Lyophilized Donor Stool on Recurrent Clostridoides Difficile Infection: Preliminary Results from a Randomized, Double-Blind Pilot Study
Tu1881 – Economic Evaluation of a Fecal Microbiota Transplantation Program for Recurrent Clostridioides Difficile Infection
Metabolic Profiling Directly from the Petri Dish Using Nanospray Desorption Electrospray Ionization Imaging Mass Spectrometry
Understanding
molecular interaction pathways in complex biological
systems constitutes a treasure trove of knowledge that might facilitate
the specific, chemical manipulation of the countless microbiological
systems that occur throughout our world. However, there is a lack
of methodologies that allow the direct investigation of chemical gradients
and interactions in living biological systems, in real time. Here,
we report the use of nanospray desorption electrospray ionization
(nanoDESI) imaging mass spectrometry for in vivo metabolic profiling
of living bacterial colonies directly from the Petri dish with absolutely
no sample preparation needed. Using this technique, we investigated
single colonies of <i>Shewanella oneidensis</i> MR-1, <i>Bacillus subtilis</i> 3610, and <i>Streptomyces coelicolor</i> A3(2) as well as a mixed biofilm of <i>S. oneidensis</i> MR-1 and <i>B. subtilis</i> 3610. Data from <i>B.
subtilis</i> 3610 and <i>S. coelicolor</i> A3(2) provided
a means of validation for the method while data from <i>S. oneidensis</i> MR-1 and the mixed biofilm showed a wide range of compounds that
this bacterium uses for the dissimilatory reduction of extracellular
metal oxides, including riboflavin, iron-bound heme and heme biosynthetic
intermediates, and the siderophore putrebactin
Chemical Analysis of Complex Organic Mixtures Using Reactive Nanospray Desorption Electrospray Ionization Mass Spectrometry
Reactive nanospray desorption electrospray ionization
(nano-DESI)
combined with high-resolution mass spectrometry was utilized for the
analysis of secondary organic aerosol produced through ozonolysis
of limonene (LSOA). Previous studies have shown that LSOA constituents
are multifunctional compounds containing at least one aldehyde or
ketone groups. In this study, we used the selectivity of the Girard’s
reagent T (GT) toward carbonyl compounds to examine the utility of
reactive nano-DESI for the analysis of complex organic mixtures. In
these experiments, 1–100 μM GT solutions were used as
the working solvents for reactive nano-DESI analysis. Abundant products
from the single addition of GT to LSOA constituents were observed
at GT concentrations in excess of 10 μM. We found that LSOA
dimeric and trimeric compounds react with GT through a simple addition
reaction resulting in formation of the carbinolamine derivative. In
contrast, reactions of GT with monomeric species result in the formation
of both the carbinolamine and the hydrazone derivatives. In addition,
several monomers did not react with GT on the time scale of our experiment.
These molecules were characterized by relatively high values of the
double bond equivalent and low oxygen content. Furthermore, because
addition of a charged GT tag to a neutral molecule eliminates the
discrimination against the low proton affinity compounds in the ionization
process, reactive nano-DESI analysis enables quantification of individual
compounds in the complex mixture. For example, we were able to estimate
for the first time the amounts of dimers and trimers in the LSOA mixture.
Specifically, we found that the most abundant LSOA dimer was detected
at the ∼0.5 pg level and the total amount of dimers and trimers
in the analyzed sample was ∼11 pg. Our results indicate that
reactive nano-DESI is a valuable approach for examining the presence
of specific functional groups and for the quantification of compounds
possessing these groups in complex mixtures
MR-guided radiation therapy with concurrent gemcitabine / nab-paclitaxel chemotherapy in inoperable pancreatic cancer: a TITE-CRM phase I trial
BACKGROUND: Ablative radiation therapy for borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA-PDAC) may limit concurrent chemotherapy dosing and usually is only safely deliverable to tumors distant from gastrointestinal organs. MR-guided radiation therapy (MRgRT) may safely permit radiation and chemotherapy dose escalation.
METHODS: We conducted a single-arm phase I study to determine the maximum tolerated dose (MTD) of ablative hypofractionated radiation with full-dose gemcitabine/nab-paclitaxel in patients with BR/LA-PDAC. Patients were treated with gemcitabine/nab-paclitaxel (1000/125 mg/m(2)) x 1c then concurrent gemcitabine/nab-paclitaxel and radiation. Gemcitabine/nab-paclitaxel and radiation doses were escalated per time-to-event continual reassessment method from 40-45 Gy / 25 fxs with chemotherapy (600-800/75 mg/m(2)) to 60-67.5 Gy / 15 fractions and concurrent gemcitabine/nab-paclitaxel (1000/100 mg/m(2)). The primary endpoint was MTD of radiation as defined by 60-day dose limiting toxicity (DLT). DLT was treatment-related G5, G4 hematologic or G3 gastrointestinal requiring hospitalization \u3e3 days. Secondary endpoints included resection rates, local progression free survival (LPFS), distant metastasis free survival (DMFS), and overall survival (OS).
RESULTS: Thirty patients enrolled (3/2015-2/2019), with 26 evaluable patients (2 progressed before radiation, 1 determined ineligible for radiation during planning, 1 withdrew consent). One DLT was observed. The DLT rate was 14.1% [3.3%-24.9%] with a maximum tolerated dose of gemcitabine/nab-paclitaxel (1000/100 mg/m(2)) and 67.5 Gy / 15 fractions. At a median follow-up of 40.6 months for living patients the median OS was 14.5 months (95% CI, 10.9-28.2 months). The median OS for patients with ECOG 0 and CA 19-9 \u3c90 were 34.1 (95% CI, 13.6-54.1) and 43.0 (95% CI, 8.0-not reached) months, respectively. 2-year LPFS and DMFS were 85% (95% CI, 63-94%) and 57% (95% CI, 34-73%), respectively.
CONCLUSIONS: Full-dose gemcitabine/nab-paclitaxel with ablative MRgRT dosing is safe in patients with BR/LA-PDAC, with promising LPFS and DMFS.
CLINICALTRIALS: gov NCTXXXXXXXX