19 research outputs found
Recommended from our members
Intersphincteric epidermoid inclusion cyst: report of a rare case.
Epidermoid inclusion cysts of the perineal region are a rare entity, which require appropriate diagnosis and management. Here we describe the unusual case of a large protruding epidermoid inclusion cyst originating from the intersphincteric anal plane, which was mobilized and excised successfully. Essential investigations to ensure accurate diagnosis in addition to surgical technique to reduce recurrence and patient morbidity are described in this case report
Oncogenic <i>PIK3CA</i> promotes cellular stemness in an allele dose-dependent manner
The PIK3CA gene, which encodes the p110α catalytic subunit of PI3 kinase (PI3K), is mutationally activated in cancer and in overgrowth disorders known as PIK3CA-related overgrowth spectrum (PROS). To determine the consequences of genetic PIK3CA activation in a developmental context of relevance to both PROS and cancer, we engineered isogenic human induced pluripotent stem cells (iPSCs) with heterozygous or homozygous knockin of PIK3CA H1047R While heterozygous iPSCs remained largely similar to wild-type cells, homozygosity for PIK3CA H1047R caused widespread, cancer-like transcriptional remodeling, partial loss of epithelial morphology, up-regulation of stemness markers, and impaired differentiation to all three germ layers in vitro and in vivo. Genetic analysis of PIK3CA-associated cancers revealed that 64% had multiple oncogenic PIK3CA copies (39%) or additional PI3K signaling pathway-activating "hits" (25%). This contrasts with the prevailing view that PIK3CA mutations occur heterozygously in cancer. Our findings suggest that a PI3K activity threshold determines pathological consequences of oncogenic PIK3CA activation and provide insight into the specific role of this pathway in human pluripotent stem cells
Six versus 12 months' adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT
Background
The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes in human epidermal growth factor receptor 2 (HER2) positive early, potentially curable breast cancer. Twelve monthsâ trastuzumab tested in the registration trials was adopted for standard adjuvant treatment in 2006. Subsequently similar outcomes were demonstrated using 9 weeks trastuzumab. Shorter durations were therefore tested for non-inferiority.
Objectives
To establish whether 6 monthsâ adjuvant trastuzumab is non-inferior to 12 months in HER2-positive early breast cancer using a primary endpoint of 4-year disease-free-survival (DFS).
Design
Phase III randomised, controlled, non-inferiority trial.
Setting
152 NHS Hospitals.
Participants
4088 patients with HER2-positive early breast cancer planned to receive both chemotherapy and trastuzumab.
Intervention
Randomisation (1:1) between six monthsâ or twelve monthsâ trastuzumab.
Main outcomes
Primary endpoint was DFS four years after diagnosis. Secondary endpoints were overall survival (OS), cost effectiveness, and cardiac function during trastuzumab. Assuming a 4-year DFS rate of 80% with 12 months, 4000 patients were required to demonstrate non-inferiority of 6-months (5% 1-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life years (QALYs) were estimated by within-trial analysis and a lifetime decision-analytic model.
Results
Between 4th October 2007 and 31st July 2015, 2045 patients were randomised to 12-monthsâ trastuzumab and 2043 to 6-months. Sixty-nine percent had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% had trastuzumab sequentially after chemotherapy; 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years median follow-up with 389 (10%) deaths, and 566 (14%) DFS events, 4-year DFS rates for the 4088 patients were 89.5% (95% CI, 88.1-90.8) in the 6-month group and 90.3% (95% CI 88.9- 91.5) in the 12-month group (Hazard Ratio 1.10; 90% CI 0.96â1.26, non-inferiority p=0.01), demonstrating non-inferiority of 6-monthsâ trastuzumab. Congruent results were found for OS (non-inferiority p=0.0003), and landmark analyses 6 months from starting trastuzumab (non-inferiority p=0.03 (DFS) and p=0.006 (OS)). 6-monthsâ trastuzumab resulted in fewer patients reporting adverse events of severe grade (365/1929 (19%) versus 460/1935 (24%) 12-month patients, p=0.0003) or stopping early because of cardiotoxicity (61/1977 (3%) versus 146/1941 (8%) 12-month patients, p<0.0001). Health economic analysis showed significantly lower lifetime costs and similar lifetime QALYs, and thus a high probability that 6 months is cost-effective compared to 12 months. Patient reported experiences on the trial highlighted fatigue, and aches and pains most frequently.
Limitations
The type of chemotherapy and timing of trastuzumab changed through the recruitment phase of the study as standard practice altered.
Conclusions
PERSEPHONE demonstrated that in HER2-positive early breast cancer 6 monthsâ adjuvant trastuzumab was non-inferior to 12 months. There was significantly less cardiac toxicity and fewer severe adverse events with 6 monthsâ treatment.
Future work
On-going translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned.
Trial registration
ISRCTN 52968807
Funding
National Institute for Health Research, Health Technology Assessment Programme (HTA Project: 06/303/98).National Institute for Health Research, Health Technology Assessment Programme (HTA Project: 06/303/98)
CD or not CD, that is the question - a digital interobserver agreement study in coeliac disease
OBJECTIVE: Coeliac disease (CD) diagnosis generally depends on histological examination of duodenal biopsies. We present the first study analysing the concordance in examination of duodenal biopsies using digitised whole-slide images (WSIs). We further investigate whether the inclusion of IgA tTG and haemoglobin (Hb) data improves the inter-observer agreement of diagnosis.DESIGN: We undertook a large study of the concordance in histological examination of duodenal biopsies using digitised WSIs in an entirely virtual reporting setting. Our study was organised in two phases: in phase one, 13 pathologists independently classified 100 duodenal biopsies (40 normal; 40 CD; 20 indeterminate enteropathy) in the absence of any clinical or laboratory data. In phase two, the same pathologists examined the (re-anonymised) WSIs with the inclusion of IgA tTG and Hb data.RESULTS: We found the mean probability of two observers agreeing in the absence of additional data to be 0.73 (±0.08) with a corresponding Cohen's kappa of 0.59 (±0.11). We further showed that the inclusion of additional data increased the concordance to 0.80 (±0.06) with a Cohen's kappa coefficient of 0.67 (±0.09).CONCLUSION: We showed that the addition of serological data significantly improves the quality of CD diagnosis. However, the limited inter-observer agreement in CD diagnosis using digitised WSIs, even after the inclusion of IgA tTG and Hb data, indicates the important of interpreting duodenal biopsy in the appropriate clinical context. It further highlights the unmet need for an objective means of reproducible duodenal biopsy diagnosis, such as the automated analysis of WSIs using AI.<br/
Opportunistic internal mammary lymph node biopsy during microvascular free flap breast reconstruction: A useful technique?
Achieving margin clearance following oncoplastic breast surgery in comparison with simple wide local excision: a threeâdimensional specimen assessment
Recommended from our members
Six versus 12 months' adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT
Background
The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes in human epidermal growth factor receptor 2 (HER2) positive early, potentially curable breast cancer. Twelve monthsâ trastuzumab tested in the registration trials was adopted for standard adjuvant treatment in 2006. Subsequently similar outcomes were demonstrated using 9 weeks trastuzumab. Shorter durations were therefore tested for non-inferiority.
Objectives
To establish whether 6 monthsâ adjuvant trastuzumab is non-inferior to 12 months in HER2-positive early breast cancer using a primary endpoint of 4-year disease-free-survival (DFS).
Design
Phase III randomised, controlled, non-inferiority trial.
Setting
152 NHS Hospitals.
Participants
4088 patients with HER2-positive early breast cancer planned to receive both chemotherapy and trastuzumab.
Intervention
Randomisation (1:1) between six monthsâ or twelve monthsâ trastuzumab.
Main outcomes
Primary endpoint was DFS four years after diagnosis. Secondary endpoints were overall survival (OS), cost effectiveness, and cardiac function during trastuzumab. Assuming a 4-year DFS rate of 80% with 12 months, 4000 patients were required to demonstrate non-inferiority of 6-months (5% 1-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life years (QALYs) were estimated by within-trial analysis and a lifetime decision-analytic model.
Results
Between 4th October 2007 and 31st July 2015, 2045 patients were randomised to 12-monthsâ trastuzumab and 2043 to 6-months. Sixty-nine percent had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% had trastuzumab sequentially after chemotherapy; 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years median follow-up with 389 (10%) deaths, and 566 (14%) DFS events, 4-year DFS rates for the 4088 patients were 89.5% (95% CI, 88.1-90.8) in the 6-month group and 90.3% (95% CI 88.9- 91.5) in the 12-month group (Hazard Ratio 1.10; 90% CI 0.96â1.26, non-inferiority p=0.01), demonstrating non-inferiority of 6-monthsâ trastuzumab. Congruent results were found for OS (non-inferiority p=0.0003), and landmark analyses 6 months from starting trastuzumab (non-inferiority p=0.03 (DFS) and p=0.006 (OS)). 6-monthsâ trastuzumab resulted in fewer patients reporting adverse events of severe grade (365/1929 (19%) versus 460/1935 (24%) 12-month patients, p=0.0003) or stopping early because of cardiotoxicity (61/1977 (3%) versus 146/1941 (8%) 12-month patients, p<0.0001). Health economic analysis showed significantly lower lifetime costs and similar lifetime QALYs, and thus a high probability that 6 months is cost-effective compared to 12 months. Patient reported experiences on the trial highlighted fatigue, and aches and pains most frequently.
Limitations
The type of chemotherapy and timing of trastuzumab changed through the recruitment phase of the study as standard practice altered.
Conclusions
PERSEPHONE demonstrated that in HER2-positive early breast cancer 6 monthsâ adjuvant trastuzumab was non-inferior to 12 months. There was significantly less cardiac toxicity and fewer severe adverse events with 6 monthsâ treatment.
Future work
On-going translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned.
Trial registration
ISRCTN 52968807
Funding
National Institute for Health Research, Health Technology Assessment Programme (HTA Project: 06/303/98).National Institute for Health Research, Health Technology Assessment Programme (HTA Project: 06/303/98)