15 research outputs found
Effectively sampling rectal mucus and assessing the validity of a DNA methylation assay in the detection of colorectal cancer.
No full textColorectal cancer (CRC) is one of the most common cancers in the Western world. Screening for
CRC using faecal occult blood test (FOBT) is well established. There is evidence that DNA based
stool tests may be more effective than FOBT.
Hypothesis
The hypothesis is that in patients with CRC, rectal mucus may contain DNA derived from colonic
tumours. It is speculated that quantitative or qualitative assessment of DNA in rectal mucus may
permit an improved method of CRC screening.
Aims
Using surgically resected specimens of colonic tumours:
To assess the feasibility and reliability of measuring DNA in mucus samples
To compare different devices to measure mucus DNA
To assess the amount of mucus DNA at various distances from colonic tumours
In patients with CRC and controls:
To compare the amount of DNA in rectal mucus
Using a panel of 3 DNA methylation markers, to compare the rectal mucus DNA
methylation profile between patients with CRC and controls
Methods
Surgical colectomy specimens were obtained from 25 patients with CRC. The feasibility and
repeatability of measuring mucus DNA amounts was established using different buffer solutions,
different storage techniques and different sampling devices. Mucus DNA amounts were measured at
tumour sites and various distances proximal and distal to the tumour. 58 patients referred to a
colorectal outpatient clinic with suspected CRC were assessed. Rectal mucus samples were
obtained using a balloon device introduced through a proctoscope. All patients were investigated by
colonoscopy to clarify the presence or absence of a CRC. The amount of DNA in the mucus
samples was measured. The presence of three DNA methylation markers (NDRG4, TFP12 and
GATA4) was assessed in all samples. All studies were approved by the local ethics committee.
Results
Reliable measurement of DNA from mucus samples was established using balloon, foam and brush
devices and a cell lysate buffer. Higher amounts of DNA in surgical specimens were found distal to
tumours compared to proximally. In patients with CRC the amount of DNA in rectal mucus was
higher than in controls (no disease or benign polyps). The three DNA methylation marker panel had
a sensitivity of 87% and specificity of 27.5% for the detection of CRC.
Conclusions
The results are consistent with the hypothesis that DNA detected in rectal mucus is derived from
proximal tumours. Higher levels of rectal mucus DNA are obtained from patients with CRC than
from controls. The selected DNA methylation panel was not sufficiently useful in our sample group
to be of use as a screening technique, due to poor specificity. Further work is in progress to compare
DNA abnormalities in resected tumour tissue with DNA from rectal mucus in the same patients.
Future work may be required to improve the panel of DNA abnormalities assessed
The concept of “Obstruction-Free Survival” as an outcome measure in advanced colorectal cancer management
No full textTargeted genetic sequencing analysis of 223 cases of pseudomyxoma peritonei treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy shows survival related to GNAS and KRAS status
No full textBackground and aim: pseudomyxoma peritonei (PMP) is an unusual condition with unique behaviour caused by a mucinous neoplasm, usually arising from the appendix. The aim of this study was to evaluate the prevalence of genomic alterations in clinical specimens of PMP using a targeted assay and correlate the findings with clinical, pathological and outcome data. Sequencing data from 223 patients were analysed. Results: the median follow-up interval was 48 months. The primary neoplasm was appendiceal in 216 patients, ovarian in 4, urachal in 2 and renal in one. We confirmed common mutations in GNAS and KRAS (42% each) with significant co-occurrence of variants in these genes. TP53 mutations were found in 8%. Other mutations were rare but included novel mutations in BAP1 and ERBB4. Of 17 patients with acellular peritoneal mucin, 6 (35%) were positive for DNA mutations. The non-appendiceal cases generally showed a similar mutational landscape to the appendiceal lesions with GNAS and KRAS commonly mutated, although one urachal lesion showed multi-hit TP53 mutation without variants in either GNAS or KRAS. Survival was significantly associated with the grade of the primary neoplasm, the grade of the peritoneal disease, the completeness of cytoreduction score and with mutation in either GNAS, KRAS or both. The hazard ratio (HR) associated with mutation in GNAS and/or KRAS was 1.87 (p = 0.004). Conclusions: survival outcome was more closely associated with the grade of the peritoneal disease than with the grade of the primary neoplasm. Our findings support the developing concept that mutational analysis may provide prognostic information in patients with PMP.</p
Efficacy of fibrinogen concentrate in major abdominal surgery – A prospective, randomized, controlled study in cytoreductive surgery for pseudomyxoma peritonei
No full textBackground: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei (PMP) is associated with excessive bleeding and acquired fibrinogen deficiency. Maintaining plasma fibrinogen may support hemostasis. Objectives: To compare hemostatic efficacy and safety of human fibrinogen concentrate (HFC) vs cryoprecipitate as fibrinogen sources for bleeding patients with acquired fibrinogen deficiency undergoing PMP CRS. Methods: FORMA-05 was an off-label single-center, prospective, randomized, controlled phase 2 study. Patients undergoing PMP surgery with predicted intraoperative blood loss ≥2 L received human fibrinogen concentrate (HFC; 4 g) or cryoprecipitate (two pools of 5 units, containing approximately 4.0-4.6 g fibrinogen), repeated as needed. The primary endpoint was a composite of intraoperative and postoperative efficacy, graded using objective 4-point scales and adjudicated by an independent committee. Results: One hundred percent of patients receiving HFC (95% confidence interval: 83.9-100.0, n = 21) or cryoprecipitate (84.6-100.0, n = 22) achieved hemostatic success. HFC demonstrated noninferior efficacy (P =.0095; post hoc) and arrived in the operating room 46 minutes faster. There were significantly greater mean increases with HFC vs cryoprecipitate in plasma fibrinogen (0.78 vs 0.35 g/L; P <.0001) and FIBTEM A20 (3.33 vs 0.93 mm; P =.003). Factor XIII, factor VIII, and von Willebrand factor activity were maintained throughout surgery. Only red blood cells were transfused intraoperatively (median units: HFC group, 1.0; cryoprecipitate group, 0.5). Thromboembolic events were detected with cryoprecipitate only. Safety was otherwise comparable between groups. Conclusions: Human fibrinogen concentrate was hemostatically efficacious in patients undergoing major abdominal PMP surgery, with a favorable safety profile. These results are relevant to other surgical settings where bleeding and acquired fibrinogen deficiency occur.</p
Spinal cord injury patients benefit from laparoscopic hartmann's procedure, for bowel dysmotility disorder
No full textOutcomes of home parenteral nutrition in 34 patients with intestinal failure from recurrent or progressive peritoneal malignancy of gastro-intestinal tract origin
No full textPatients undergoing cytoreductive surgery for peritoneal malignancy of appendiceal origin should be consented for umbilical excision as 30% have umbilical infiltration
No full textComplete pathological response after ceritinib for anaplastic lymphoma kinase-rearranged epithelioid peritoneal mesothelioma
No full textPublished version, accepted version (12 month embargo), submitted versionRD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
