2023

Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial (2023)

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Type of publication:
Journal article

Author(s):
Joharatnam-Hogan N.; Hatem D.; Cafferty F.H.; Petrucci G.; Cameron D.A.; Ring A.; Kynaston H.G.; Gilbert D.C.; Wilson R.H.; Hubner R.A.; Swinson D.E.B.; Cleary S.; Robbins A.; MacKenzie M.; Scott-Brown M.W.G.; Sothi S.; Dawson L.K.; Capaldi L.M.; Churn M.; Cunningham D.; Khoo V.; Armstrong A.C.; Ainsworth N.L.; Horan G.; Wheatley D.A.; Mullen R.; Lofts F.J.; Walther A.; Herbertson R.A.; Eaton J.D.; O'Callaghan A.; Eichholz A.; Kagzi M.M.; Patterson D.M.; Narahari K.; Bradbury J.; Stokes Z.; Rizvi A.J.; Walker G.A.; Kunene V.L.; *Srihari N.; Gentry-Maharaj A.; Meade A.; Patrono C.; Rocca B.; Langley R.E.

Citation:
British Journal of Cancer. 129(4):706-720, 2023 Sep.

Abstract:
Background: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. Method(s): Urinary 11-dehydro-thromboxane B2(U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. Result(s): In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. Conclusion(s): Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin.

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Novel case report of primary osteosarcoma of the maxilla in an adult: An important differential diagnosis (2023)

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Type of publication:
Journal article

Author(s):
*Venkatasami M.; *Harrison K.

Citation:
Advances in Oral and Maxillofacial Surgery. 2023. Article Number: 100423. Date of Publication: September 2023. [epub ahead of print]

Abstract:
Craniofacial osteosarcoma accounts for 10% of osteosarcoma malignancies, typically affecting the 4-5th decade of life, with the maxilla being the second-most common site. We report a 58-year-old male, non-smoker, with a lump of his upper jaw which occasionally bled during mastication. Clinical examination revealed an exophytic mass in the upper left tuberosity of the maxilla and no lymphadenopathy, where initial differential diagnosis was squamous cell carcinoma. Radiological investigations revealed a metabolically active left maxillary lesion with maxillary sinus destruction, representing primary malignancy. Histological analyses initially suggested a fibro-osseous lesion; further immunohistochemistry showed cytokeratin AE1/AE3/CK(MNF.116) positivity with 60% ki67 proliferation index; diagnostic of grade 2-3 osteosarcoma. Management included neoadjuvant chemotherapy prior to total maxillectomy and dental prosthetic rehabilitation. We report a novel case of primary osteosarcoma of the maxilla in an adult. Osteosarcoma is challenging to diagnose and an important differential to consider where the mainstay of treatment is early invention.

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Dysphagia-optimised intensity-modulated radiotherapy versus standard intensity-modulated radiotherapy in patients with head and neck cancer (DARS): a phase 3, multicentre, randomised, controlled trial (2023)

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Type of publication:
Journal article

Author(s):
Nutting C.; Finneran L.; Roe J.; Sydenham M.A.; Beasley M.; Bhide S.; Boon C.; Cook A.; De Winton E.; Emson M.; Foran B.; Frogley R.; Petkar I.; *Pettit L.; Rooney K.; Roques T.; Srinivasan D.; Tyler J.; Hall E.

Citation:
Lancet Oncology. 24(8):868-880, August 2023

Abstract:
BACKGROUND: Most newly diagnosed oropharyngeal and hypopharyngeal cancers are treated with chemoradiotherapy with curative intent but at the consequence of adverse effects on quality of life. We aimed to investigate if dysphagia-optimised intensity-modulated radiotherapy (DO-IMRT) reduced radiation dose to the dysphagia and aspiration related structures and improved swallowing function compared with standard IMRT. METHOD(S): DARS was a parallel-group, phase 3, multicentre, randomised, controlled trial done in 22 radiotherapy centres in Ireland and the UK. Participants were aged 18 years and older, had T1-4, N0-3, M0 oropharyngeal or hypopharyngeal cancer, a WHO performance status of 0 or 1, and no pre-existing swallowing dysfunction. Participants were centrally randomly assigned (1:1) using a minimisation algorithm (balancing factors: centre, chemotherapy use, tumour type, American Joint Committee on Cancer tumour stage) to receive DO-IMRT or standard IMRT. Participants and speech language therapists were masked to treatment allocation. Radiotherapy was given in 30 fractions over 6 weeks. Dose was 65 Gy to primary and nodal tumour and 54 Gy to remaining pharyngeal subsite and nodal areas at risk of microscopic disease. For DO-IMRT, the volume of the superior and middle pharyngeal constrictor muscle or inferior pharyngeal constrictor muscle lying outside the high-dose target volume had a mandatory 50 Gy mean dose constraint. The primary endpoint was MD Anderson Dysphagia Inventory (MDADI) composite score 12 months after radiotherapy, analysed in the modified intention-to-treat population that included only patients who completed a 12-month assessment; safety was assessed in all randomly assigned patients who received at least one fraction of radiotherapy. The study is registered with the ISRCTN registry, ISRCTN25458988, and is complete. FINDINGS: From June 24, 2016, to April 27, 2018, 118 patients were registered, 112 of whom were randomly assigned (56 to each treatment group). 22 (20%) participants were female and 90 (80%) were male; median age was 57 years (IQR 52-62). Median follow-up was 39.5 months (IQR 37.8-50.0). Patients in the DO-IMRT group had significantly higher MDADI composite scores at 12 months than patients in the standard IMRT group (mean score 77.7 [SD 16.1] vs 70.6 [17.3]; mean difference 7.2 [95% CI 0.4-13.9]; p=0.037). 25 serious adverse events (16 serious adverse events assessed as unrelated to study treatment [nine in the DO-IMRT group and seven in the standard IMRT group] and nine serious adverse reactions [two vs seven]) were reported in 23 patients. The most common grade 3-4 late adverse events were hearing impairment (nine [16%] of 55 in the DO-IMRT group vs seven [13%] of 55 in the standard IMRT group), dry mouth (three [5%] vs eight [15%]), and dysphagia (three [5%] vs eight [15%]). There were no treatment-related deaths. INTERPRETATION: Our findings suggest that DO-IMRT improves patient-reported swallowing function compared with standard IMRT. DO-IMRT should be considered a new standard of care for patients receiving radiotherapy for pharyngeal cancers. FUNDING: Cancer Research UK.

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Management And Assessment Of Indeterminate (U3) Thyroid Nodules: A 5-Year Multisite Retrospective Study (2023)

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Type of publication:
Journal article

Author(s):
*Patel R.; *Conybeare A.; *Panesar H.; *Badrol S.; *Sood S.

Citation:
Journal of Ayub Medical College, Abbottabad : JAMC. 35(2) (pp 216-219), April 2023.

Abstract:
BACKGROUND: The U grading of Ultrasound scan (USS) is used to assess the likelihood of malignancy in a thyroid nodule and help determine those that warrant an FNAC confirmation. All those of a U3-5 warrant an FNAC for confirmation and typing. This study aims to review the follow-up practice and the likelihood of picking up a malignancy on subsequent USS and FNAC, for those determined as an indeterminate U3 nodule. METHOD(S): We retrospective reviewed the trust database (Portal) for patients who had a U3 nodule reported on USS identified, and clinical, operative and outcomes data were analysed. RESULT(S): 258 scans were identified over a 5-year period. The average age was 59 (range 15- 95) years old at first USS with a female to the male sex ratio of 4:1. The average number of USS that each patient prior to final diagnosis had averaged at 2.8 (range 1-12). Of those with an initial Thy status, 64 (33%) were benign (Thy2) and a further 49 (25%) were non diagnostics (Thy1). Over time, only 7 nodules were upgraded to a potential malignancy. Of those who underwent surgery, a final histological diagnosis was obtained in 41 cases. Only Thy1, 2 and 3f produced benign final histology results. CONCLUSION(S): For those indeterminate (U3) nodules of Th1-3f, electing for a watch and wait management strategy is reasonable for up to 2.5 years and 4 follow-up scans at an interval of 6-12 months should be implemented. A Thy2 result on a U3 nodule should not be taken as completely reassuring, a high index of suspicion of malignancy must be maintained.

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An overview of bone cement: Perioperative considerations, complications, outcomes and future implications. (2023)

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Type of publication:
Journal article

Author(s):
*Patel, Ravi; Mcconaghie, Greg; Webb, Jeremy; Laing, Georgina; *Roach, Richard; Banerjee, Robin.

Citation:
Journal of Perioperative Practice. 2023 May 26. [epub ahead of print]

Abstract:
Polymethyl methacrylate is commonly known as bone cement and is widely used for implant fixation in various orthopaedic arthroplasty and trauma surgery. The first bone cement use in orthopaedics is widely accredited to the famous English surgeon, John Charnley, who in 1958, used it for total hip arthroplasty. Since then, there have been many developments in cementing techniques in arthroplasty surgery. This overview aims to cover the perioperative considerations of bone cement, including cementing techniques, current outcomes and complications such as bone cement implantation syndrome. The overview will additionally consider future developments involving bone cement in orthopaedic arthroplasty.

Rheumatoid nodule presenting as an indeterminate soft tissue mass in the sole of the foot (2023)

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Type of publication:
Journal article

Author(s):
*Patel R.; Nand R.; Sunderamoorthy D.

Citation:
Journal of Surgical Case Reports. 2023(5) (no pagination), May 2023.

Abstract:
A 64-year-old lady with a background of rheumatoid arthritis presented to the foot and ankle clinic with lump underneath the sole of her foot causing significant discomfort. Examination revealed she had a swelling of the first and the second metatarsophalangeal joints. Magnetic resonance imaging revealed abnormal soft tissue thickening between the second and the third metatarsal and a single large encapsulating indeterminate soft tissue mass with a peripheral inflammatory rim. The appearance was suggestive of a malignant sarcoma rather than a rheumatoid nodule or rheumatoid tenosynovitis. The patient was referred to the regional sarcoma unit where the scans were reviewed, and a sarcoma was ruled out. The patient then underwent excision of the indeterminate soft tissue mass. Histology revealed granulomatous infiltration suggestive of a rheumatoid nodule. This has not been described previously in the literature.

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Focused transoesophageal TOE (fTOE): A new accreditation pathway (2023)

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Type of publication:
Journal article

Author(s):
Rubino A.; Peck M.; *Miller A.; Edmiston T.; Klein A.A.; Orme R.; Sankar V.; Fletcher N.; O'Keeffe N.; Skinner H.

Citation:
Journal of the Intensive Care Society. Date of Publication: 2023. [epub ahead of print]

Abstract:
The concept of a focused ultrasound study to identify sources of haemodynamic instability has revolutionized patient care. Point-of-care ultrasound (POCUS) using transthoracic scanning protocols, such as FUSIC Heart, has empowered non-cardiologists to rapidly identify and treat the major causes of haemodynamic instability. There are, however, circumstances when a transoesphageal, rather than transthoracic approach, may be preferrable. Due to the close anatomical proximity between the oesophagus, stomach and heart, a transoesphageal echocardiogram (TOE) can potentially overcome many of the limitations encountered in patients with poor transthoracic ultrasound windows. These are typically patients with severe obesity, chest wall injuries, inability to lie in the left lateral decubitus position and those receiving high levels of positive airway pressure. In 2022, to provide all acute care practitioners with the opportunity to acquire competency in focused TOE, the Intensive Care Society (ICS) and Association of Anaesthetists (AA) launched a new accreditation pathway, known as Focused Transoesophageal Echo (fTOE). The aim of fTOE is to provide the practitioner with the necessary information to identify the aetiology of haemodynamic instability. Focused TOE can be taught in a shorter period of time than comprehensive and teaching programmes are achievable with support from cardiothoracic anaesthetists, intensivists and cardiologists. Registration for fTOE accreditation requires registration via the ICS website. Learning material include theoretical modules, clinical cases and multiple-choice questions. Fifty fTOE examinations are required for the logbook, and these must cover a range of pathology, including ventricular dysfunction, pericardial effusion, tamponade, pleural effusion and low preload. The final practical assessment may be undertaken when the supervisors deem the candidate's knowledge and skills consistent with that required for independent practice. After the practitioner has been accredited in fTOE, they must maintain knowledge and competence through relevant continuing medical education. Accreditation in fTOE represents a joint venture between the ICS and AA and is endorsed by Association of Cardiothoracic Anaesthesia and Critical care (ACTACC). The process is led by TOE experts, and represents a valuable expansion in the armamentarium of acute care practitioners to assess haemodynamically unstable patients.

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Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol (2023)

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Type of publication:
Journal article

Author(s):
Attard, Gerhardt; Murphy, Laura; Clarke, Noel W; Sachdeva, Ashwin; Jones, Craig; Hoyle, Alex; Cross, William; Jones, Robert J; Parker, Christopher C; Gillessen, Silke; Cook, Adrian; Brawley, Chris; Gilson, Clare; Rush, Hannah; Abdel-Aty, Hoda; Amos, Claire L; Murphy, Claire; Chowdhury, Simon; Malik, Zafar; Russell, J Martin; Parkar, Nazia; Pugh, Cheryl; Diaz-Montana, Carlos; Pezaro, Carmel; Grant, Warren; Saxby, Helen; Pedley, Ian; O'Sullivan, Joe M; Birtle, Alison; Gale, Joanna; *Srihari, Narayanan; Thomas, Carys; Tanguay, Jacob; Wagstaff, John; Das, Prantik; Gray, Emma; Alzouebi, Mymoona; Parikh, Omi; Robinson, Angus; Montazeri, Amir H; Wylie, James; Zarkar, Anjali; Cathomas, Richard; Brown, Michael D; Jain, Yatin; Dearnaley, David P; Mason, Malcolm D; Gilbert, Duncan; Langley, Ruth E; Millman, Robin; Matheson, David; Sydes, Matthew R; Brown, Louise C; Parmar, Mahesh K B; James, Nicholas D.

Citation:
Lancet Oncology. 24(5):443-456, 2023 May.

Abstract:
BACKGROUND: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. METHODS: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0-2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). FINDINGS: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86-107) in the abiraterone trial and 72 months (61-74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76.6 months (95% CI 67.8-86.9) in the abiraterone group versus 45.7 months (41.6-52.0) in the standard of care group (hazard ratio [HR] 0.62 [95% CI 0.53-0.73]; p<0.0001). In the abiraterone and enzalutamide trial, median overall survival was 73.1 months (61.9-81.3) in the abiraterone and enzalutamide group versus 51.8 months (45.3-59.0) in the standard of care group (HR 0.65 [0.55-0.77]; p<0.0001). We found no difference in the treatment effect between these two trials (interaction HR 1.05 [0.83-1.32]; pinteraction=0.71) or between-trial heterogeneity (I2 p=0.70). In the first 5 years of treatment, grade 3-5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial). INTERPRETATION: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years.

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MYC/BCL6 Double Hit Lymphoma Negative For (3;8) BCL6:MYC Fusion is Associated With Inferior Survival, in Contrast with T(3;8) Positive Pseudo-Double Hit Lymphoma (2023)

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Type of publication:
Conference abstract

Author(s):
Maybury, B. D.; James, L.; Chadderton, N.; Dowds, J.; Venkatadasari, I.; Riley, J.; Qureshi, I.; Talbot, G.; Giles, H. V.; Phillips, N. J.; Gonzalez, M. Vega; Rakesh, P.; Haslam, A.; Davies, D.; Moosai, S.; Lane, S. A.; *Shenouda, A.; Cherian, G. V.; Kaudlay, P. K.;Starczynski, J.; et al

Citation:
Hematological Oncology, June 2023 Supplement 1; 41: 205-207.

Abstract:

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The SSS revolution in fungal diagnostics: speed, simplicity and sensitivity (2023)

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Type of publication:
Journal article

Author(s):
*Baker, Jacob; Denning, David W.

Citation:
British Medical Bulletin. 147(1):62-78, 2023 Sep 12.

Abstract:
INTRODUCTION: Fungal disease has historically presented a diagnostic challenge due to its often non-specific clinical presentations, relative infrequency and reliance on insensitive and time-intensive fungal culture. SOURCES OF DATA: We present the recent developments in fungal diagnostics in the fields of serological and molecular diagnosis for the most clinically relevant pathogens; developments that have the potential to revolutionize fungal diagnosis through improvements in speed, simplicity and sensitivity. We have drawn on a body of evidence including recent studies and reviews demonstrating the effectiveness of antigen and antibody detection and polymerase chain reaction (PCR) in patients with and without concurrent human immunodeficiency virus infection. AREAS OF AGREEMENT: This includes recently developed fungal lateral flow assays, which have a low cost and operator skill requirement that give them great applicability to low-resource settings. Antigen detection for Cryptococcus, Histoplasma and Aspergillus spp. are much more sensitive than culture. PCR for Candida spp., Aspergillus spp., Mucorales and Pneumocystis jirovecii is more sensitive than culture and usually faster. AREAS OF CONTROVERSY: Effort must be made to utilize recent developments in fungal diagnostics in clinical settings outside of specialist centres and integrate their use into standard medical practice. Given the clinical similarities of the conditions and frequent co-infection, further study is required into the use of serological and molecular fungal tests, particularly in patients being treated for tuberculosis. GROWING POINTS: Further study is needed to clarify the utility of these tests in low-resource settings confounded by a high prevalence of tuberculosis. AREAS TIMELY FOR DEVELOPING RESEARCH: The diagnostic utility of these tests may require revision of laboratory work flows, care pathways and clinical and lab coordination, especially for any facility caring for the immunosuppressed, critically ill or those with chronic chest conditions, in whom fungal disease is common and underappreciated.

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