Dissection of PIK3CA Aberration for Cervical Adenocarcinoma Outcomes.
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ABSTRACT:
SUBMITTER: Chung TKH
PROVIDER: S-EPMC8269188 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
Publications
Dissection of <i>PIK3CA</i> Aberration for Cervical Adenocarcinoma Outcomes.
Chung Tony K H TKH Doran Graeme G Cheung Tak-Hong TH Yim So-Fan SF Yu Mei-Yung MY Worley Michael J MJ Elias Kevin M KM Thorner Aaron R AR Pedamallu Chandra Sekhar CS Ojesina Akinyemi I AI Lau Kei-Man KM Ducar Matthew D MD Wong Raymond R Y RRY Wang Vivian W VW Nag Anwesha A Wollison Bruce M BM Dalgarno Audrey A Lee Jacqueline H S JHS Yeung Suet-Ying SY Wong Lo L Horowitz Neil S NS Davis Michelle R MR Leung Shuk-On A SA Mu Yi Y Mok Samuel C SC Chan Paul K S PKS Lawrence Michael S MS Crum Christopher P CP Chiu Rossa W K RWK Berkowitz Ross S RS Wong Yick-Fu YF
Cancers 20210628 13
Personalized treatment of genetically stratified subgroups has the potential to improve outcomes in many malignant tumors. This study distills clinically meaningful prognostic/predictive genomic marker for cervical adenocarcinoma using signature genomic aberrations and single-point nonsynonymous mutation-specific droplet digital PCR (ddPCR). Mutations in <i>PIK3CA</i> E542K, E545K, or H1047R were detected in 41.7% of tumors. <i>PIK3CA</i> mutation detected in the patient's circulating DNA collec ...[more]
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Project description:BackgroundActivation of the phosphatidylinositol 3-kinase (PI3K) through mutational inactivation of PTEN tumour suppressor gene is common in diverse cancer types, but rarely reported in gastric cancer. Recently, mutations in PIK3CA, which encodes the p110alpha catalytic subunit of PI3K, have been identified in various human cancers, including 3 of 12 gastric cancers. Eighty percent of these reported mutations clustered within 2 regions involving the helical and kinase domains. In vitro study on one of the "hot-spot" mutants has demonstrated it as an activating mutation.MethodsBased on these data, we initiated PIK3CA mutation screening in 94 human gastric cancers by direct sequencing of the gene regions in which 80% of all the known PIK3CA mutations were found. We also examined PIK3CA expression level by extracting data from the previous large-scale gene expression profiling study. Using Significance Analysis of Microarrays (SAM), we further searched for genes that show correlating expression with PIK3CA.ResultsWe have identified PIK3CA mutations in 4 cases (4.3%), all involving the previously reported hotspots. Among these 4 cases, 3 tumours demonstrated microsatellite instability and 2 tumours harboured concurrent KRAS mutation. Data extracted from microarray studies showed an increased expression of PIK3CA in gastric cancers when compared with the non-neoplastic gastric mucosae (p < 0.001). SAM further identified 2910 genes whose expression levels were positively associated with that of PIK3CA.ConclusionOur data suggested that activation of the PI3K signalling pathway in gastric cancer may be achieved through up-regulation or mutation of PIK3CA, in which the latter may be a consequence of mismatch repair deficiency.
| S-EPMC1079799 | biostudies-literature
Project description:BACKGROUND AND STUDY AIMS: The clinical benefit of endoscopic submucosal dissection (ESD) for superficial duodenal neoplasias has not yet been verified. The aims of this study were to validate the feasibility and long-term outcomes of ESD for nonampullary superficial duodenal neoplasias, larger than 20 mm. PATIENTS AND METHODS: 41 patients, with 41 nonampullary large superficial duodenal neoplasias, who underwent ESD between April 2005 to March 2013 were included in the study. The short- and long-term outcomes were retrospectively evaluated, related to tumor size, resection size, histological type, invasion depth, complete resection rate, operation time, perforation rate, delayed bleeding rate, local recurrence rate, distant metastasis, and survival rate. RESULTS: ESD was successfully completed in 38 of 41 patients (92.7 %). The median sizes of tumors and resected specimens were, respectively, 26 mm (range 20 - 70 mm) and 36.5 mm (range 23 - 80 mm). Histopathological findings showed 13 adenocarcinomas (12 mucosal, 1 submucosal) and 28 adenomas (26 high grade dysplasia, 2 low grade dysplasia). The complete resection rate was 89.5 % (34 /38 tumors). The mean operation time was 128.3minutes. Perforation during ESD occurred in 39 % and delayed bleeding occurred in 18.4 %. The median observation period was 48 months (range 3.2 - 94.1 months), and no local recurrence or distant metastasis was seen during this time, representing a disease-free survival rate of 100 %. CONCLUSIONS: ESD for nonampullary large superficial duodenal adenocarcinoma/adenoma is feasible with favorable long-term outcomes. However, because of the high complication rate due to its technical difficulty, experience and skill of the operator, along with adequate perioperative management, are essential.
| S-EPMC4440373 | biostudies-other
Project description:The aim of this study was to evaluate the clinicopathological and prognostic relevance of PIK3CA mutations in Chinese patients with surgically resected cervical cancer. PIK3CA mutations were screened in 771 cervical cancer specimens using reverse transcription polymerase chain reaction and Sanger sequencing. In total, 13.6% (105 of 771) of patients harbored non-synonymous PIK3CA mutations. Patients harboring PIK3CA mutations were older than patients with wild-type PIK3CA (mean age: 50.7 years vs. 47.0 years, P < 0.01). PIK3CA mutations were more commonly observed in postmenopausal patients than in premenopausal patients (19.6% vs. 10.2%, P < 0.01). PIK3CA mutations were more common in squamous cell carcinomas than in non-squamous cell tumors (15.3% vs 7.3%, of P < 0.01). The 3-year relapse-free survival was 90.2% for PIK3CA mutant patients and 80.9% for PIK3CA wild-type patients (P = 0.03). PIK3CA mutation was confirmed as an independent predictor for better treatment outcome in the multivariate analyses (HR = 0.54, 95% CI: 0.29-0.99, P = 0.048). PIK3CA mutations were significantly associated with less distant metastases (mutant-type: 8/105, wild-type: 98/666, p = 0.048). Thus, patients with mutant PIK3CA had distinct characteristics in age, menopausal status, and histological subtype and have better treatment outcome and less distant metastasis after surgery-based multimodal therapy.
| S-EPMC4566086 | biostudies-literature
Project description:Few studies have explored HER2 status in cervical adenocarcinoma, particularly in the gastric-type adenocarcinoma (GAC), a nonhuman-papillomavirus-related subtype with poor clinical outcomes. In this study, we investigated HER2 expression and amplification by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in 209 well annotated cervical adenocarcinomas diagnosed using the International Endocervical Adenocarcinoma Criteria and Classification. IHC identified HER2 protein expression in 57.4% (123/209) of adenocarcinomas, of which 62 were IHC 1+ (negative), 38 2+ (equivocal) and 23 3+ (positive). HER2 amplification was found in 13 cases (6.2%) including 10 with IHC 3+ and 3 with IHC 2+. Among all the major histotypes of cervical adenocarcinoma, HER2 amplification was most common in GAC cases with a frequency of 14.7% (5/34). Moreover, HER2 amplification was more frequently associated with 2018 International Federation of Gynecology & Obstetrics (FIGO) stage III/IV, perineural involvement and ovarian spread (p < 0.05) while IHC 3+ was more common in patients with lymphovascular invasion and ovarian involvement (p < 0.05). Survival analysis indicated that FIGO stage III/IV, GAC, and p53 overexpression were associated with poor disease-specific survival and tumor recurrence (p < 0.05). In conclusion, HER2 amplification was present in a subset of adenocarcinomas, and more common in GAC, pointing to a potential benefit from trastuzumab treatment. HER2 overexpression does not identify gene amplification status in cervical adenocarcinoma; therefore, FISH is suggested for both IHC positive and equivocal cases. Further investigation on more cases with longer follow-up times is required to consolidate these findings.
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Project description:IntroductionCervical artery dissection (CeAD) is considered a non-atherosclerotic arteriopathy, but atherosclerosis of the cervical arteries may co-exist. We explored the frequency and clinical importance of co-existent atherosclerosis in patients with CeAD.Patients and methodsSingle-center exploratory study from the Stroke Center Basel, Switzerland. We re-reviewed duplex ultrasound images at (i) baseline and (ii) last follow-up visit for the presence versus absence of the following atherosclerotic manifestations in the carotid arteries: (i) abnormal carotid intima-media thickness, (ii) plaques, and (iii) atherosclerotic stenosis. We investigated whether CeAD patients with versus without co-existing atherosclerosis differ regarding (a) recurrence of CeAD and (b) occurrence of vascular events (myocardial infarction, peripheral artery disease, or ischemic stroke) using logistic regression with adjustment for age and follow-up time.ResultsAmong 294 CeAD patients (median age 46 [IQR 37-53], 41.8% women), 35 (12%) had any atherosclerotic signs at baseline. Among 196 patients with available follow-up, another 21/196 (11%) patients developed atherosclerosis during a median follow-up of 55.7 months. Patients with atherosclerosis had decreased odds of recurrent CeADs when compared to patients without atherosclerosis (OR 0.03, 95% CI = 0.00-0.30). During follow-up, 6 (15%) vascular events occurred among 40 CeAD patients with atherosclerosis and 13 (8.5%) among 153 patients without atherosclerosis (OR 1.38, 95% CI = 0.39-4.55, data for 3 patients were missing).Discussion and conclusionSigns of atherosclerosis in the carotid artery were detectable in 12% of CeAD patient at baseline. Additionally, 11% of CeAD patients developed new signs of atherosclerosis within the following 5 years. The presence of atherosclerosis may suggest a lower risk for recurrent CeAD. Whether it might indicate an increased risk for late clinical vascular events deserves further studies.
| S-EPMC11569546 | biostudies-literature
Project description:BACKGROUND:Cervical artery dissection (CAD) and stroke are serious harms that are sometimes associated with cervical spinal manipulation therapy (cSMT). Because of the relative rarity of these adverse events, studying them prospectively is challenging. As a result, systematic review of reports describing these events offers an important opportunity to better understand the relation between adverse events and cSMT. Of note, the quality of the case report literature in this area has not yet been assessed. PURPOSE:1) To systematically collect and synthesize available reports of CAD that have been associated with cSMT in the literature and 2) assess the quality of these reports. METHODS:A systematic review of the literature was conducted using several databases. All clinical study designs involving CADs associated with cSMT were eligible for inclusion. Included studies were screened by two independent reviewers for the presence/absence of 11 factors considered to be important in understanding the relation between CAD and cSMT. RESULTS:Overall, 43 articles reported 901 cases of CAD and 707 incidents of stroke reported to be associated with cSMT. The most common type of stroke reported was ischemic stroke (92%). Time-to-onset of symptoms was reported most frequently (95%). No single case included all 11 factors. CONCLUSIONS:This study has demonstrated that the literature infrequently reports useful data toward understanding the association between cSMT, CADs and stroke. Improving the quality, completeness, and consistency of reporting adverse events may improve our understanding of this important relation.
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Project description:This study aims to reveal the risk factors associated with recurrence or new-onset high-grade squamous intraepithelial lesions (HSILs) or more severe lesions (HSILs +) and analyze obstetrical outcomes in patients with adenocarcinoma in situ (AIS) or stage IA1 cervical cancer patients after conization. A retrospective cohort study was developed from January 1, 2002, and July 1, 2018, in a single center, where all patients with AIS or stage IA1 cervical cancer who accepted conization for primary surgery were reviewed and followed up until July 1, 2019, for the pathological findings of HSILs + and obstetric outcomes. Two hundred and seventeen patients were identified, including 114 cases of AIS, 76 cases of stage IA1 squamous cell carcinoma (SCC) and 27 cases of stage IA1 adenocarcinoma (ADC). A total of 88 (40.6%) patients had an intact uterus without radiotherapy. Five patients experienced HSIL+ recurrence. The cumulative 3-, 5- and 10-year incidence rates of HSILs + were 1.0%, 1.5% and 2.0%, respectively. No significant risk factors, including primary disease, margin status and hysterectomy, were associated with recurrence. Twenty (66.7%) of 30 patients who attempted pregnancy had 23 successful pregnancies, which result in 7 miscarriages, 16 live births and 5 preterm births. Age at conization was the only independent risk factor associated with pregnancy, live births and preterm births. In conclusion, conization is safe for young women with AIS, stage IA1 SCC and ADC who desire future fertility, and the associated HSIL recurrence rate is low. Increased age significantly lowered the conception or live birth rate.
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Project description:PIK3CA mutations are frequently diagnosed in diverse cancers and may predict response to PI3K/AKT/mTOR inhibitors. It remains unclear whether they are associated with other characteristics. We analyzed characteristics and outcome of 90 consecutive patients with diverse advanced tumors and PIK3CA mutations and 180 wild-type PIK3CA controls matched by tumor type, gender, and age referred to the Clinical Center for Targeted Therapy. PIK3CA and MAPK mutations (KRAS, NRAS, and BRAF) were analyzed using polymerase chain reaction-based DNA sequencing. The most frequent PIK3CA mutations were E545K (31/90, 34%), E542K (16/90, 18%) in exon 9, and H1047R (20/90, 22%) in exon 20. PIK3CA mutations compared to wild-type PIK3CA were associated with simultaneous KRAS (p=0.047) and MAPK mutations (p=0.03), but only MAPK mutations were confirmed as having an independent association in multivariate analysis. Rates of lung, bone, liver and brain metastases were similar in PIK3CA-mutant and wild-type patients. Patients with PIK3CA mutations treated on trials with PI3K/AKT/mTOR inhibitors had a higher partial/complete response (PR/CR) rate than wild-type PIK3CA patients treated with their best phase I therapy (10/56, 18% vs. 12/152, 8%; p=0.045), but not a prolonged progression-free survival. Patients with H1047R PIK3CA mutations had higher PR/CR rate with PI3K/AKT/mTOR inhibitors compared to wild-type PIK3CA patients treated with their best phase I therapy (6/16, 38% vs. 12/152, 8%; p=0.003). In conclusion, PIK3CA mutations in diverse cancers were not associated with clinical characteristics, but were correlated with MAPK mutations. PIK3CA mutations, especially, H1047R, were associated with attaining a PR/CR to PI3K/AKT/mTOR pathway inhibitors.
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Project description:To compare the effects of curative surgery and curative definitive concurrent chemoradiotherapy (CCRT) on cervical adenocarcinoma (AC) by conducting a national cohort study with a large sample size, we enrolled women with cervical AC and categorized them into two groups according to treatment modality to compare treatment outcomes: group 1, comprising patients who received curative surgery, and group 2, comprising patients who received curative definitive CCRT. Data of 1,621 patients with cervical AC were extracted from the Taiwan Cancer Registry database. Univariate and multivariate Cox regression analysis results indicated that high American Society of Anesthesiologists scores, advanced American Joint Committee on Cancer (AJCC) clinical stage, and curative definitive CCRT were significant independent poor prognostic factors. The adjusted hazard ratio (aHR; 95% confidence interval [CI]) for overall mortality in early invasive clinical stages (IB-IIA) was 1.27 (0.77-2.69) in group 2 compared with group 1, whereas that for overall mortality at AJCC clinical stage IIB was 2.46 (1.34-4.53) in group 2 compared with group 1. The aHR (95% CI) for overall mortality at advanced clinical stages (III and IV) was 1.47 (1.09-1.97) in group 2 compared with group 1. Curative surgery improves survival in cervical AC at advanced clinical stages. Either curative surgery or definitive CCRT is an option in the early invasive clinical stages of cervical AC.
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Project description:Raw data of exome sequencing of 17 paired samples and 1 orphan tumor sample, total 18 samples
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