Staff Publication

Gefitinib and EGFR gene copy number aberrations in esophageal cancer (2017)

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Type of publication:
Conference abstract

Author(s):
Petty R.D.; Dahle-Smith A.; Stevenson D.A.J.; Osborne A.; Massie D.; Clark C.; Miedzybrodzka Z.; Murray G.I.; Dutton S.J.; Roberts C.; Chong I.Y.; Mansoor W.; Thompson J.; Harrison M.; *Chatterjee A.; Falk S.J.; Elyan S.; Garcia-Alonso A.; Fyfe D.W.; Wadsley J.; Chau I; Ferry D.R.; Miedzybrodzka Z.

Citation:
Journal of Clinical Oncology; Jul 2017; vol. 35 (no. 20); p. 2279-2287

Abstract:
Purpose The Cancer Esophagus Gefitinib trial demonstrated improved progression-free survival with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib relative to placebo in patients with advanced esophageal cancer who had disease progression after chemotherapy. Rapid and durable responses were observed in a minority of patients. We hypothesized that genetic aberration of the EGFR pathway would identify patients benefitting from gefitinib. Methods A prespecified, blinded molecular analysis of Cancer Esophagus Gefitinib trial tumors was conducted to compare efficacy of gefitinib with that of placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF, and PIK3CA mutation status. EGFR CNG was determined by fluorescent in situ hybridization (FISH) using prespecified criteria and EGFR FISH-positive status was defined as high polysomy or amplification. Results Biomarker data were available for 340 patients. In EGFR FISH-positive tumors (20.2%), overall survival was improved with gefitinib compared with placebo (hazard ratio [HR] for death, 0.59; 95% CI, 0.35 to 1.00; P = .05). In EGFR FISH-negative tumors, there was no difference in overall survival with gefitinib compared with placebo (HR for death, 0.90; 95% CI, 0.69 to 1.18; P = .46). Patients with EGFR amplification (7.2%) gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI, 0.07 to 0.64; P = .006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF, and PIK3CA mutations, or for any mutation versus none. Conclusion EGFR CNG assessed by FISH appears to identify a subgroup of patients with esophageal cancer who may benefit from gefitinib as a secondline treatment. Results of this study suggest that anti- EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FISH-positive and, in particular, EGFR-amplified esophageal cancer.

VIPoma: A rare cause of life threatening diarrhoea (2017)

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Type of publication:
Conference abstract

Author(s):
*Bevis M.

Citation:
Anaesthesia; Jul 2017; vol. 72 ; p. 30

Abstract:
VIPomas are rare neuroendocrine tumours that secrete excessive vasoactive intestinal peptide causing refractory diarrhoea, hypokalaemia and metabolic acidosis. This case describes the difficulties in diagnosing a rare cause of diarrhoea on the ITU. A 76-year-old male, with a background of type 2 diabetes, presented to hospital with a 3-day history of confusion, muscle weakness, lethargy and profuse diarrhoea. The patient had been having diarrhoea for two months but colonoscopy was unremarkable. On examination the patient was dehydrated and had a heart rate of 110 min-1, otherwise no abnormality was found. Blood tests showed metabolic acidosis (pH 7.17, base excess -15.4 mmol.L-1, bicarbonate 12.9 mmol.L-1) and severe hypokalaemia (K+ 1.3 mmol.L-1). He was admitted to ITU for aggressive fluid resuscitation and electrolyte correction. The patient had large volumes of watery diarrhoea (8 l every 24 h) which was unresponsive to loperamide and codeine. Stool cultures were negative. CT of the abdomen revealed a solitary focal liver lesion and a possible focal abnormality in the pancreatic tail. A gut hormone profile was sent for analysis. Although the diagnosis was unclear, the patient was started on octreotide which slowed the diarrhoea after a few days. Histology of the liver lesion confirmed neuroendocrine tumour, and both vasoactive intestinal peptide and pancreatic polypeptide were raised in the blood, therefore a diagnosis of pancreatic VIPoma was made. Discussion VIPomas are very rare, affecting less than 1 in 1,000,000 patients each year in the UK [1]. The cause of most VIPomas is unknown; however multiple endocrine neoplasia type 1 is a risk factor [1]. VIPomas are slow growing and are often malignant. Patients often develop symptoms slowly and may have diarrhoea for years before a diagnosis is made. The diarrhoea is large-volume, has a dilute tea appearance, and is not affected by fasting. Tests for VIPoma include serum vasoactive intestinal peptide (however this needs to be processed at a specialist centre), CT, MRI and octreoscan [1, 2]. Initial treatment focuses on fluid and electrolyte replacement as untreated severe electrolyte imbalance can lead to arrhythmias, cardiovascular collapse and death. Somatostatin analogues, such as octreotide, help control the symptoms of diarrhoea; however, the main treatment is surgical [2]. In conclusion, although VIPomas are rare they should be suspected in patients that present with profuse chronic diarrhoea with no obvious cause.

Abiraterone for prostate cancer not previously treated with hormone therapy (2017)

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Type of publication:
Randomised controlled trial

Author(s):
James, Nicholas D. Ph.D.; de Bono, Johann S. Ph.D.; Spears, Melissa R. M.Sc.; Clarke, Noel W. Ch.M.; Mason, Malcolm D. F.R.C.R.; Dearnaley, David P. F.R.C.R.; Ritchie, Alastair W.S. M.D.; Amos, Claire L. Ph.D.; Gilson, Clare M.R.C.P.; Jones, Rob J. M.B., Ch.B.; Matheson, David Ph.D.; Millman, Robin; Attard, Gerhardt M.D.; Chowdhury, Simon Ph.D.; Cross, William R. F.R.C.S.; Gillessen, Silke M.D.; Parker, Christopher C. M.D.; Russell, Martin J. F.R.C.R.; Berthold, Dominik R. M.D.; Brawley, Chris M.Sc.; Adab, Fawzi F.R.C.R.; Aung, San M.R.C.P.; Birtle, Alison J. F.R.C.R.; Bowen, Jo F.R.C.R.; Brock, Susannah F.R.C.R.; Chakraborti, Prabir F.R.C.R.; Ferguson, Catherine F.R.C.R.; Gale, Joanna B.M.; Gray, Emma F.R.C.R.; Hingorani, Mohan Ph.D.; Hoskin, Peter J. F.R.C.R.; Lester, Jason F. F.R.C.R.; Malik, Zafar I. F.R.C.R.; McKinna, Fiona F.R.C.R.; McPhail, Neil F.R.C.R.; Money-Kyrle, Julian F.R.C.R.; O'Sullivan, Joe Ph.D.; Parikh, Omi F.R.C.R.; Protheroe, Andrew F.R.C.P.; Robinson, Angus F.R.C.R.; *Srihari, Narayanan N. F.R.C.R.; Thomas, Carys M.R.C.P.; Wagstaff, John Ch.B.; Wylie, James F.R.C.R.; Zarkar, Anjali F.R.C.R.; Parmar, Mahesh K.B. D.Phil.; Sydes, Matthew R. M.Sc.; the STAMPEDE Investigators

Citation:
New England Journal of Medicine; Jul 2017; vol. 377 (no. 4); p. 338-351

Abstract:
BACKGROUND: Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. METHODS: We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostatespecific
antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). RESULTS: A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events). CONCLUSIONS: Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476, and Current Controlled Trials number, ISRCTN78818544.)

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Is routine embryo culture to day 6 beneficial? (2013)

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Type of publication:
Conference abstract

Author(s):
*Nash K.; *Gittins V.; *Hatton A.; *Binnersley S.; *Hughes G.; *Kasraie J.

Citation:
Human Fertility; 2013; vol. 16 (no. 3)

Abstract:
Introduction : Following the HFEA's 'Multiple Birth, Single Embryo Transfer Policy'in 2008, blastocyst culture has become routine practice in many clinics. In our clinic, patients unable to transfer on day 5 (D5) due to failed blastocyst development or poor quality, are cultured to day 6 (D6). Supernumerary embryos not suitable for freezing on D5 are cultured to D6 and frozen if viable. We compared biochemical and clinical pregnancy rates for D5 and D6 blastocyst transfers to determine whether routine culture to D6 is beneficial. Method: Biochemical (BPR) and Clinical (CPR) pregnancy rates were compared for D5 and D6 transfers between 01/01/09 and 31/05/12. Results were analysed using Fisher's Exact test . We distinguished D6 blastocysts that were 'true'D6 from those that might have been later developing D5 blastocysts. Results: There was no significant difference in BPR (51.7%) and CPR (41.4%) for D5 (n=203) and D6 (43.5% and 30.4%, n=23) (BPR p=0.51, CPR p=0.37). One patient definitely had a 'true'D6 blastocyst. Conclusion: Culture to D6 appears beneficial as D5 and D6 pregnancy rates are similar. However, small numbers mean the D6 group results may be unreliable. One patient out of 23 had a definate D6 blastocyst making it possible that the other 22 developed late on D5. To truly distinguish D5 and 6 blastocysts we could perform transfers later on D5, but this may be impractical, particularly with blastocysts developing after 5 pm. Alternatively time-lapse technology would allow precise timing of blastulation. With these results in mind, it is likely that our policy of culturing to and freezing blastocysts on D6 regardless of the day of transfer is beneficial and will improve cumulative pregnancy rates. The number of fresh cycles a patient requires will also be reduced, ultimately benefiting the patient through reduced risk/cost, and the clinic/NHS healthcare economy.*

Should embryos be cultured on to day 6 following embryo transfer if there are no embryos suitable for cryopreservation on (2013)

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Type of publication:
Conference abstract

Author(s):
*Hughes G.; *Binnersley S.; *Wallbutton S.; *Gittins V.; *Parry S.; *Hatton A.; *Lavender A.; *Kasraie J.

Citation:
Human Fertility; 2013; vol. 16 (no. 3)

Abstract:
Introduction : Risks and costs associated with stimulation/egg collection mean that storage of excess viable embryos and maximisation of cumulative pregnancy rates from a single egg collection are a priority for clinics.  Should we culture all embryos not suitable for cryopreservation on day 3 (D3) and day 5 (D5) onwards to allow us to assess their viability for cryopreservation over an extended period? Materials and Methods: Retrospective  analysis of the development of 457 embryos from 89 patients that were allocated for training from D3 (n=71) and D5 (n=18) transfer patients that did not meet cryopreservation criteria on D3 (6C 15% fragmentation, 70 hours post insemination/injection) or D5 ( <= 3BB (Gardner and Schoolcraft) 118 hours post insemination). The  embryos allocated were cultured at 6% CO2 to D6 and graded each day. Results: Blastulation rates for D5 transfer patients were significantly greater than D3 transfer patients (43.04% vs 26.42%, p <= 0.0005). 1.88%  of embryos from D3 patients with 0 frozen developed to <= 3BB on D5 vs 8.57% of embryos from D3 patients with 1 frozen (p <= 0.0142). 6.29% of embryos from D3 patients with 0 frozen developed <= 3BB on D6 vs 11.43% of embryos from D3 patients with 1 frozen (p=0.1498). 11.39% of embryos from D5 transfer patients developed to <= 3BB on D6. Conclusions : This small retrospective study, in suboptimal culture conditions,  appears to show it may be beneficial to routinely culture embryos not meeting our cryopreservation criteria on D3 or D5 to D6. At present our biochemical success rates (53% vs 41%, p=0.3671) and clinical success rates for D5 vs D6 transfers (43% vs 32%, p=0.658) suggest that D6 blastocysts are as viable as D5 blastocysts. Practical
and financial implications must be taken into account but this practice may reduce 'fresh'egg collections and maximise cumulative success, thereby reducing risk and cost to the healthcare economy.

Routine culture and cryopreservation of day 6 blastocysts-is it worthwhile? A National Survey (2013)

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Type of publication:
Conference abstract

Author(s):
*Hatton A.; *Gittins V.; *Binnersley S.; *Hughes G.; *Lavender A.; *Kasraie J.

Citation:
Human Fertility; 2013; vol. 16 (no. 3)

Abstract:
Introduction : Blastocyst culture is now routine, but national practice is not uniform. Extended culture to day 6 (D6) may be considered controversial due to possible associated epigenetic factors and a perceived decrease in  viability of D6 blastocysts. Conversely, cryopreservation on D6 may reduce the number of fresh egg collections required, minimising risk to patients and cost to the healthcare economy, but do the benefits outweigh the  potential risks? Method : National survey of practice, protocol and outcome. Results: 40 clinics responded 7.5% did not culture to blastocyst. 92.5% cultured to blastocyst in 5-80% of treatment cycles. 59.5% cultured to D6 if  blastocysts were unavailable for transfer on day 5(D5) and between 0 and <= 90% of patients had fresh D6 transfers. Average clinical pregnancy rates (CPRs) for fresh D5 vs D6 transfers were 44.3% vs 25.7%. All clinics culturing to blastocyst cryopreserved. 89% cultured to D6 if no cryopreservation occurred on D5. 83.5% cultured remaining embryos to D6 whether or not cryopreservation occurred on D5. Average CPRs for cryopreserved D5 vs D6 blastocysts were 31% vs 28.3%. 89% believed culturing to D6 was worthwhile. Other data (e.g. culture system, cryopreservation method, carrier, media) were also collected and analysed. Conclusions : The majority of respondents cultured to, and cryopreserved, on D6. CPRs varied greatly between  centres but were generally lower in fresh D6 vs D5 transfers. Nevertheless, results suggest that D6 transfer is worthwhile for patients without D5 blastocysts. Additionally, CPRs for cryopreserved D6 blastocysts were very similar to D5 and appeared slightly higher than fresh D6. Whilst it remains to be seen whether cryopreserved D6 blastocysts are more viable than fresh, it certainly appears that cryopreservation of D6 blastocysts is effective and beneficial to both patients and the healthcare economy by reducing risks from stimulation/ egg  collections and overall costs whilst maximising cumulative success.

Vitrification of lower grade cleavage stage embryos and pregnancy outcome (2013)

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Type of publication:
Conference abstract

Author(s):
*Binnersley S.; *Hughes G.; *Hatton A.; *Gittins V.; *Kasraie J.

Citation:
Human Fertility; 2013; vol. 16 (no. 3)

Abstract:
Introduction : Conservation of viable embryos minimises risk to patients from repeated stimulation/egg collection, reduces costs and maximises cumulative success rates, but national practice varies greatly. Many clinics only cryopreserve top quality embryos, potentially leading to the disposal of viable embryos and unnecessary further cycles of IVF. Our clinics experience of survival rates from traditional 'slow'freezing, where fragmentation may provide additional foci for ice crystal formation, meant that, when our clinic introduced Vitrification in 2008, we continued to cryopreserve only embryos with < 5% fragmentation. However survival and pregnancy rates using vitrification were such that from May 2010, following validation of survival rates, criteria were relaxed to allow embryos with 15% fragmentation to be stored. Materials and Methods: Retrospective analysis of 156 frozen (vitrified) embryo transfer cycles. Embryos were classified as top (<=5% fragmentation) or non-top (5 to 15% fragmentation) quality. Two embryos were transferred in all cycles. Three groups were compared: 1 < Two top quality (n=109), 2=One top and one non-top (n=20), 3=two non-top (n=27) quality transferred. Vitrification cooling/warming utilised Origio media and Cryo-Bio system sealed straws. Results: There was no significant difference for patient age (p=0.48), survival rates of blastomeres in each group (97.9% vs 96.7% and 98.1%, p=0.62), biochemical pregnancy rate (36.7% vs 30.0% vs 33.3%, p=0.62), clinical pregnancy rate (20.2% vs 10.0% vs 22.2%, p=0.36), or implantation rate (12.8% vs 5% vs 12.96%, p=0.19) in all groups. Conclusion: This small retrospective study appears to show that vitrication of lower grade embryos (15% fragmentation) results in similar pregnancy rates to the vitrification of only top quality embryos. The resultant increase in the number of stored embryos and frozen embryo transfers decreases risk to the patient and cost to the healthcare economy whilst increasing the cumulative pregnancy rate from single 'fresh'IVF cycles

Medical student's perceptions of forensic pathology (2017)

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Type of publication:
Conference abstract

Author(s):
*Iles K.L.

Citation:
Journal of Pathology; Mar 2017; vol. 241, Supplement 1, Page S6

Abstract:
Forensic pathology is an important sub-specialty of pathology which requires a variety skills that are relevant and transferable to many other areas of medicine. Despite this, it does not feature in the undergraduate curriculum of most medical schools meaning that knowledge specific to forensic medicine such as wound terminology may not be taught. A lack of formal teaching and an ever increasing dramatised presence of the  specialty in the media may lead to a misrepresentation of the role of forensic pathologists. As a result this study  aimed to examine final year medical student's perceptions of the role of the forensic pathologists and their confidence in knowledge of important aspects of forensic medicine. An online survey was developed to assess these areas which was distributed to final year medical students at a UK institution via email. From the  respondents, the overall perception of the job role was correct, however there appeared to be some misconceptions regarding the role of a forensic scientist, or crime scene investigator in comparison to a forensic  pathologist. The study also highlighted that students did not feel confident in differentiating between wound  types using the correct terminology. This is important as injuries are common presentations in many clinical areas, and incorrect terminology may have mediocolegal implications. This study has highlighted the need for clarification of the job role of the forensic pathologist. There is a greater need for forensic pathology in the undergraduate curriculum, which should focus on description and terminology of wounds and injuries.

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Clinical risk factors predicting genital fungal infections with sodium–glucose cotransporter 2 inhibitor treatment: The ABCD nationwide dapagliflozin audit (2017)

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Type of publication:
Journal article

Author(s):
Ken Yan Thong, Mahender Yadagiri, Dennis Joseph Barnes, *David Stuart Morris, Tahseen Ahmad Chowdhury, Ling Ling Chuah, Anthony Michael Robinson, Stephen Charles Bain, Karen Ann Adamson, Robert Elford John Ryder, ABCD Nationwide Dapagliflozin Audit contributors

Citation:
Primary Care Diabetes 2017 [published online 29th June 2017]

Abstract:
Introduction

Treatment of type 2 diabetes with sodium–glucose cotransporter 2 (SGLT2) inhibitors may result in genital fungal infections. We investigated possible risk factors for developing such infections among patients treated with the SGLT2 inhibitor dapagliflozin.

Methods

The Association of British Clinical Diabetologists (ABCD) collected data on patients treated with dapagliflozin in routine clinical practice from 59 diabetes centres. We assessed possible associations of patient’s age, diabetes duration, body mass index, glycated haemoglobin, renal function, patient sex, ethnicity and prior genital fungal infection, urinary tract infection, urinary incontinence or nocturia, with the occurrence of ≥1 genital fungal infection within 26 weeks of treatment.

Results

1049 out of 1116 patients (476 women, 573 men) were analysed. Baseline characteristics were, mean ± SD, age 56.7 ± 10.2 years, BMI 35.5 ± 6.9 kg/m2 and HbA1c 9.4 ± 1.5%. Only patient sex (13.2% women vs 3.3% men) and prior history of genital fungal infection (21.6% vs 7.3%) were found to be associated with occurrence of genital fungal infections after dapagliflozin treatment, adjusted OR 4.22 [95%CI 2.48,7.19], P < 0.001 and adjusted OR 2.41 [95% CI 1.04,5.57], P = 0.039, respectively.

Conclusion

Women and patients with previous genital fungal infections had higher risks of developing genital fungal infections with dapagliflozin treatment.

Lack of risk factors predicting the development of genital mycotic infections among patients treated with dapagliflozin: the ABCD Nationwide Dapagliflozin Audit (2017)

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Type of publication:
Poster presentation

Author(s):
Thong KY, Yadagiri M, Tong P, Barnes D, *Morris D et al.

Citation:
American Diabetes Association annual meeting June 2017, San Diego.

Abstract:

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