• Habitat imaging of tumors enables high confidence sub-regional assessment of response to therapy

      Tar, P. D.; Thacker, N. A.; Babur, M.; Lipowska-Bhalla, G.; Cheung, S.; Little, R. A.; Williams, K. J.; O'Connor, James P B; Division of Cancer Sciences, University of Manchester, Manchester M13 9PT, UK (2022)
      Imaging biomarkers are used in therapy development to identify and quantify therapeutic response. In oncology, use of MRI, PET and other imaging methods can be complicated by spatially complex and heterogeneous tumor micro-environments, non-Gaussian data and small sample sizes. Linear Poisson Modelling (LPM) enables analysis of complex data that is quantitative and can operate in small data domains. We performed experiments in 5 mouse models to evaluate the ability of LPM to identify responding tumor habitats across a range of radiation and targeted drug therapies. We tested if LPM could identify differential biological response rates. We calculated the theoretical sample size constraints for applying LPM to new data. We then performed a co-clinical trial using small data to test if LPM could detect multiple therapeutics with both improved power and reduced animal numbers compared to conventional t-test approaches. Our data showed that LPM greatly increased the amount of information extracted from diffusion-weighted imaging, compared to cohort t-tests. LPM distinguished biological response rates between Calu6 tumors treated with 3 different therapies and between Calu6 tumors and 4 other xenograft models treated with radiotherapy. A simulated co-clinical trial using real data detected high precision per-tumor treatment effects in as few as 3 mice per cohort, with p-values as low as 1 in 10,000. These findings provide a route to simultaneously improve the information derived from preclinical imaging while reducing and refining the use of animals in cancer research.
    • Hadron accelerators for radiotherapy.

      Owen, H; Mackay, Ranald I; Peach, K; Smith, S; University of Manchester/Cockcroft Institute, Manchester, UK. (2014)
    • Haematological malignancy and nosocomial transmission are associated with an increased risk of death from COVID-19: results of a multi-center UK cohort

      Bhogal, T.; Khan, U. T.; Lee, Rebecca J; Stockdale, A.; Hesford, C.; Potti-Dhananjaya, V.; Jathanna, A.; Rahman, S.; Tivey, Ann; Shotton, Rohan; et al. (2021)
      The COVID-19 pandemic has been a disruptive event for cancer patients, especially those with haematological malignancies (HM). They may experience a more severe clinical course due to impaired immune responses. This multi-center retrospective UK audit identified cancer patients who had SARS-CoV-2 infection between 1 March and 10 June 2020 and collected data pertaining to cancer history, COVID-19 presentation and outcomes. In total, 179 patients were identified with a median age of 72 (IQR 61, 81) and follow-up of 44 days (IQR 42, 45). Forty-one percent were female and the overall mortality was 37%. Twenty-nine percent had HM and of these, those treated with chemotherapy in the preceding 28 days to COVID-19 diagnosis had worse outcome compared with solid malignancy (SM): 62% versus 19% died [HR 8.33 (95% CI, 2.56-25), p < 0.001]. Definite or probable nosocomial SARS-CoV-2 transmission accounted for 16% of cases and was associated with increased risk of death (HR 2.47, 95% CI 1.43-4.29, p = 0.001). Patients with haematological malignancies and those who acquire nosocomial transmission are at increased risk of death. Therefore, there is an urgent need to reassess shielding advice, reinforce stringent infection control, and ensure regular patient and staff testing to prevent nosocomial transmission.
    • Haemoglobin and hematinic status before and after bariatric surgery over 4 years of follow-up

      Shipton, M. J.; Johal, N. J.; Dutta, N.; Slater, C.; Iqbal, Z.; Ahmed, B.; Ammori, B. J.; Senapati, S.; Akhtar, K.; Summers, L. K. M.; et al. (2020)
      Purpose: Bariatric surgery is associated with deficiencies of vitamins and minerals, and patients are routinely advised supplements postoperatively. We studied prevalence of vitamin B12, folate and iron deficiencies and anaemia before and after bariatric surgery over 4 years of follow-up. Materials and methods: We performed a retrospective cohort analysis of 353 people with obesity, including 257 (72.8%) women, who underwent gastric bypass (252, 71.4%) or sleeve gastrectomy (101, 28.6%) at our National Health Service bariatric centre in Northwest England. Results: At baseline, mean (standard error) age was 46.0 (0.6) years, body mass index 53.1 (0.4) kg/m2, serum vitamin B12 400.2 (16.4) pg/L, folate 7.7 (0.2) μg/L, iron 12.0 (0.3) μmol/L, ferritin 118.3 (8.4) μg/L and haemoglobin 137.9 (0.8) g/L. Frequency of low vitamin B12 levels reduced from 7.5% preoperatively to 2.3% at 48 months (P < 0.038). Mean folate levels increased from baseline to 48 months by 5.3 μg/L (P < 0.001) but frequency of low folate levels increased from 4.7% preoperatively to 10.3% (P < 0.048). Ferritin levels increased from baseline to 48 months by 51.3 μg/L (P < 0.009). Frequency of low ferritin levels was greater in women (39.1%) than in men (8.9%) at baseline (P < 0.001) and throughout the study period. Haemoglobin was low in 4.6% of all patients at baseline with no significant change over the study period. Conclusion: There were notable rates of haematinic insufficiencies in bariatric surgical candidates preoperatively. Our study lends further support to regular supplementation with vitamin B12, folic acid, and iron in people undergoing bariatric surgery.
    • Haemoglobin and prognosis in childhood acute lymphoblastic leukaemia.

      Hann, I M; Scarffe, J Howard; Palmer, Michael K; Evans, D I; Jones, P H; Department of Haematology and Department of Oncology, Royal Manchester Children's Hospital (1981-09)
      Two hundred and nine children presenting consecutively with acute lymphoblastic leukaemia to a regional paediatric oncology unit were investigated to determine the prognostic significance of various factors at diagnosis. There was a strong positive correlation between the pretreatment haemoglobin level and the percentage of bone marrow blast cells in S phase of the cell cycle as assessed by flow cytometry. Patients with T- and B-cell leukaemia had significantly higher haemoglobin levels than non-B non-T patients. In patients with total white cell counts less than 20 X 10(9)/l, aged less than 13 years, and no mediastinal mass, there was no association of haemoglobin with length of first remission. However, among those with white blood counts greater than 20 +/- 10(9)/l there was a strong positive trend towards shorter remission with higher haemoglobin levels. Children with high white blood counts at diagnosis and low haemoglobin levels may have a better prognosis than predicted by the white blood count alone.
    • Haemopoietic cell kinetics in humans treated with rGM-CSF.

      Lord, Brian I; Gurney, H; Chang, James; Thatcher, Nick; Crowther, Derek; Dexter, T Michael; Cancer Research Campaign Department of Experimental Haematology, Paterson Institute for Cancer Research, Manchester, UK. (1992-01-02)
      We have investigated the kinetics of myeloid cell proliferation in the marrow of patients with small-cell lung cancer and treated with 10 daily subcutaneous injections of granulocyte/macrophage colony-stimulating factor (GM-CSF). Bone marrow, obtained before and during treatment with the growth factor, was labelled in vitro with tritiated thymidine (3H-TdR). A 3rd bone-marrow sample was obtained 1 hr following an intravenous injection of 3H-TdR. Subsequent daily blood samples were also collected, and 3H-TdR labelling was assessed on these and the marrow preparations by autoradiography. GM-CSF treatment increased the peripheral granulocytic cells nearly 5-fold, but this included significant eosinophilia, so that the neutrophilic granulocytes increased only 3.3-fold. These cells were released from the marrow over a normal time scale, but their peripheral half-life was about 6 times longer than normal and they were probably functionally defective. Furthermore, significant numbers of immature cells were released from the marrow. Neutrophil production stimulated by GM-CSF was thus overestimated by measurement of the apparent peripheral granulocytosis. Increased labelling indices and grain counts in the proliferating granulocytic cells of the marrow indicate shortened cell-cycle times, and the excess granulocyte production appears to be the result of extra amplification divisions in the proliferative compartments.
    • Haemopoietic growth factor and dose intensity in high-grade and intermediate-grade lymphoma.

      Pettengell, Ruth; Crowther, Derek; CRC Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, United Kingdom. (1994)
      Here we review the evidence that cytotoxic dose intensity is an important determinant of outcome in high- and intermediate-grade non-Hodgkin's lymphoma. The results of retrospective analyses and prospective studies support this proposition but confirmatory studies are required. We discuss the role of haemopoietic growth factors and mobilized peripheral blood progenitor cells to increase dose intensity. Studies using these modalities will enable the importance of dose intensity to be tested.
    • Haemopoietic progenitor and myeloid cell kinetics in humans treated with interleukin-3 and granulocyte/macrophage colony-stimulating factor in combination.

      Lord, Brian I; Testa, Nydia G; Bretti, Sergio; Chang, James; Demuynck, Hilde; Coutinho, Lucia H; De Campos, E S; Fitzsimmons, Lesley; Scarffe, J Howard; Department of Experimental Haematology, PICR, Manchester, UK. (1994-11-15)
      Patients with advanced adenocarcinoma of the colon, rectum or pancreas were entered into trials for evaluation of treatment with sequential doses of IL-3 and GM-CSF. They received 0.25 to 5 micrograms IL-3/kg/d for up to 7 days, followed by 1 microgram GM-CSF/kg/day for a maximum of 10 further days. We assessed the kinetics of bone-marrow cell proliferation and of blood production using tritiated thymidine labelling in vitro and in vivo. Megakaryocytic-CFC were unaffected but proliferation rates of GM-CFC and BFU-E were increased. Progenitor cells were mobilized (12-fold over baseline) into the peripheral blood. The proliferative activity of maturing cells in the marrow was increased (cell-cycle times were reduced by at least 30%). This translated into amplified blood cell production (WCC approximately 30 x 10(9)/l), a 2.2-fold increase in platelet counts and significant eosinophilia. Newly generated neutrophils appeared in the circulation at the normal time and their peripheral half-life was also normal. The calculated 3.2-fold amplification in neutrophil production required nearly 2 extra divisions in the marrow, shared between the progenitors and the proliferating granulocytic cells. The results were compared with those of a previous trial using GM-CSF only, although at a 10-fold higher dose level. Comparable levels of peripheral neutrophils were obtained in both trials but significant ineffective granulopoiesis developed in the earlier study. This was overcome in the present study, the priming dose of IL-3 apparently giving the latitude to utilize lower doses of GM-CSF with less risk of complications.
    • Haemopoietic stem cell inhibition: potential for dose intensification.

      Marshall, E; CRC Department of Medical Oncology, Christie CRC Research Centre, Christie Hospital NHS Trust, Manchester, UK. (1995-09)
    • Haemostatic property of cyanoacrylate in pedicled flaps.

      Ranson, John Michael; Amin, Kavit; Schechter, Eyal M M; Kosutic, Damir; Department of Plastic Surgery, The Christie NHS Foundation Trust, Wilmslow Road, M20 4BX, Manchester (2016-03-07)
      We present a technique that can, in principle, be applied to any pedicled flap that is routinely used for reconstructions of the forehead. In our experience, cyanoacrylate glue applied to the pedicle before the flap is inserted decreases postoperative bleeding and wound exudate.
    • Haemostatic radiotherapy for bleeding cancers of the upper gastrointestinal tract

      Hughes, Christopher; Radhakrishna, Ganesh; Department of Clinical Oncology, the Christie NHS Foundation Trust, Manchester M20 4BX (2019)
    • HALT: targeted therapy with or without dose-intensified radiotherapy in oligo-progressive disease in oncogene addicted lung tumours

      McDonald, F.; Guckenberger, M.; Popat, S.; Faivre-Finn, Corinne; Andratschke, N.; Riddell, A.; Hanna, G.; Franks, K.; Harrow, S.; Miles, E.; et al. (2020)
      Introduction: Following initial response to TKI, advanced NSCLC patients with actionable mutations will ultimately develop treatment resistance. In a proportion of patients (15–40%), limited progression (≤3 lesions) is initially observed, termed oligoprogressive disease (OPD). Optimal management of these patients is uncertain, with subsequent systemic therapy options limited in the UK. The potential benefit offered by SBRT to ablate OPD sites prior to change in systemic therapy is an important question to address. HALT is designed to assess whether SBRT treatment to OPD sites can increase the time patients derive clinical benefit from TKI therapy until further disease progression Methods: HALT is a randomised, multi-centre, phase II/III trial with seamless transition to phase III incorporated. International participation is established via a UK-led (ICR, NCRI Lung CSG, RTTQA) intergroup collaboration with European coordinating groups (EORTC and SAKK). Eligible patients (Stage IV NSCLC, actionable mutation, initial TKI response prior to OPD) are randomised 2:1 to SBRT and continued TKI or continued TKI alone. Follow-up aligned with routine care at 3 monthly intervals until change in systemic therapy is clinically indicated, with imaging and toxicity assessment at each visit. Results: HALT opened for recruitment November 2017; 19 centres (14 UK; 5 non-UK) are open to date (30/09/2019) with 43 patients registered and 26 randomised. A virtual MDT comprising trial clinicians and radiologists convenes remotely to confirm eligibility (OPD; SBRT suitability). Of 43 patients registered vMDT review has been performed for 37 (6 screen fails prior to vMDT review); 26 patients randomised and 11 confirmed ineligible via vMDT. Conclusion: The vMDT remains an important novel aspect of the trial, ensuring robust patient selection ahead of randomisation. As the first randomised trial assessing the benefit of SBRT in this patient population, HALT will provide valuable treatment efficacy and safety information, informing the design of an international phase III trial.
    • HALT: targeted therapy with or without dose-intensified radiotherapy in oligo-progressive disease in oncogene addicted lung tumours

      McDonald, F.; Guckenberger, M.; Popat, S.; Faivre-Finn, Corinne; Andratschke, N.; Riddell, A.; Hanna, G.; Prakash, V.; Nair, A.; Diez, P.; et al. (2021)
      Background: Following initial response to TKI, advanced NSCLC patients with actionable mutations ultimately develop treatment resistance. In a proportion of patients (15-40%), initial, limited pro gression (≤3 lesions) is observed, termed oligoprogressive disease (OPD). SBRT offers hypofractionated, targeted radiotherapy treatment hypothesised to prolong clinical benefit from TKI prior to widespread disease development. The potential benefit offered by SBRT to ablate OPD sites prior to change in systemic therapy is an important question to address, particularly during the current pandemic, where reducing clinic visits is particularly advantageous. Method: HALT is a randomised, multi-centre, phase II/III international trial with seamless transition to phase III incorporated. Eligible patients (stage IV NSCLC, actionable mutation, TKI response prior to OPD) are randomised 2:1 to SBRT/continued TKI or continued TKI alone. Eligibility is confirmed by a virtual MDT comprising trial clinicians and radiologists (OPD, SBRT suitability). Follow-up assessments aligned with routine care at 3-monthly intervals until change in systemic therapy is clinically indicated, imaging and toxicity assessment at each visit. Current status: Recruitment commenced November 2017; 27 centres (16 UK; 11 non-UK) open to date (09/03/2021), 94 patients registered and 50 randomised. Because of the COVID-19 pandemic, recruitment was temporarily paused on 20/03/2020 and restarted in accordance with national guidelines on 16/06/2020. Of 94 patients registered, vMDT review performed for 74 patients (18 screen fails prior to vMDT); 50 randomised, 22 confirmed ineligible via vMDT (inc. >3 lesions, lesion >5cm, intracranial disease identified). Conclusion: The vMDT remains an important, novel aspect of the trial, ensuring robust patient selection ahead of randomisation. As the first randomised trial assessing SBRT benefit in this patient population, HALT will provide valuable treatment efficacy and safety information, informing subsequent trial design and contribute to the development of international guidelines for the identification and clinical management of oligoprogression in mutation positive lung cancer.
    • Hand function after high dose rate brachytherapy for squamous cell carcinoma of the skin of the hand.

      Somanchi, B V; Stanton, Anthony; Webb, M; Loncaster, Juliette A; Allan, Ernest; Muir, L T S W; Department of Hand Surgery, Salford Royal Hospital, Salford M6 8HD, UK. brindavihari2001@yahoo.com (2008-11)
      AIMS: Current recommendations for the treatment of squamous cell carcinoma of the hand are almost unanimously in favour of ablative surgery. However, many of the patients are frail and elderly, and surgical techniques frequently involve skin grafts or amputation of digits. A non-invasive method of treatment is, therefore, often preferred. Radiotherapy using a brachytherapy technique is a well-established option. This study investigated whether patients found the treatment acceptable and assessed the outcome of treatment in terms of local control, cosmesis and hand function. MATERIALS AND METHODS: Twenty-five patients who underwent mould brachytherapy using a microselectron high dose rate radiotherapy device were available for assessment. We assessed the functional status of the hand and fingers by means of the Disability of Arm, Shoulder and Hand and Michigan Hand Outcomes questionnaires. We examined the hand to assess the severity of post-radiation stigmata. We enquired as to patient acceptability of treatment and outcome. RESULTS: Of 25 patients who agreed to participate, the fingers were affected in 15 and the dorsum of the hand in 10. The mean age at the time of radiotherapy was 69 years (range 50-87). There were no significant differences in parameters, such as range of motion of fingers and wrist, hand/finger grip strength, between the treated and opposite sides. Sensation, including two-point discrimination, was not significantly different from the untreated hand. Seventeen patients had minor skin changes. No patient found the treatment painful or unacceptable. Twenty patients were very satisfied and five patients were moderately satisfied with the cosmetic result. CONCLUSIONS: We conclude that high dose rate brachytherapy is a safe and simple alternative to surgical treatment for squamous cell carcinoma of the hand, as it is not only successful in eradicating tumour, but also preserves hand function.
    • Handling the withdrawn patient--a flow diagram.

      Maguire, Peter; Faulkner, A; Regnard, C; CRC Psychological Medicine Group, Christie Hospital, Manchester, UK. (1993)
      The withdrawn patient challenges effective communication. Some patients are naturally introverted or quiet, but for others the withdrawal represents a change with many possible causes. This flow diagram describes the approach to a withdrawn patient and outlines management.
    • Haploidentical transplantation and posttransplant cyclophosphamide for treating aplastic anemia patients: a report from the EBMT Severe Aplastic Anemia Working Party

      Prata, PH; Eikema, DJ; Afansyev, B; Bosman, P; Smiers, F; Diez-Martin, JL; Arrais-Rodrigues, C; Koc, Y; Poire, X; Sirvent, A; et al. (2019)
      In the absence of an HLA-matched donor, the best treatment for acquired aplastic anemia patients refractory to immunosuppression is unclear. We collected and analyzed data from all acquired aplastic anemia patients who underwent a haploidentical transplantation with posttransplant cyclophosphamide in Europe from 2011 to 2017 (n?=?33). The cumulative incidence of neutrophil engraftment was 67% (CI95%: 51-83%) at D +28 and was unaffected by age group, stem cell source, ATG use, or Baltimore conditioning regimen. The cumulative incidence of grades II-III acute GvHD was 23% at D +100, and limited chronic GvHD was 10% (0-20) at 2 years, without cases of grade IV acute or extensive chronic GvHD. Two-year overall survival was 78% (64-93), and 2-year graft-versus-host disease-free survival was 63% (46-81). In univariate analysis, the 2-year OS was higher among patients who received the Baltimore conditioning regimen (93% (81-100) versus 64% (41-87), p?=?0.03), whereas age group, stem cell source, and ATG use had no effect. Our results using unmanipulated haploidentical transplantation and posttransplant cyclophosphamide for treating refractory AA patients are encouraging, but warrant confirmation in a prospective study with a larger number of patients and longer follow-up.
    • Haploidentical transplantation using high dose post-transplant cyclophosphamide for patients with aplastic anemia : the European Group for Blood and Marrow Transplantation experience

      Prata, H; Afanasyev, B; Eikema, J; Smiers, F; Knol, C; Diez-Martin, JL; Rocha, G; Koc, Y; Poire, X; Fegueux, N; et al. (2018)
    • The harmonisation of growth hormone measurements: taking the next steps.

      Wieringa, Gilbert E; Sturgeon, C; Trainer, Peter J (2014-02-06)
      For over 20 years differences in results of growth hormone (GH) measurement have been recognised as being significant enough to lead to misdiagnosis and inappropriate management of patients with GH-related disorders. Whilst issues of method standardisation, variable antibody specificity, use of different reporting units with different conversion factors, and interference from GH binding protein have been acknowledged as contributing to the discrepancies, inconsistent approaches to method harmonisation have hampered opportunities to enhance the evidence base for GH measurements. Amongst the first steps to be taken, international collaboratives recommended the universal adoption of the International Standard 98/547 and the reporting of results in mass units. Whilst inter-method variability may have improved over the last 10years, clinically significant differences remain. A more recently recognised issue contributing to the discrepancies may be the differences in the matrix materials used by kit manufacturers to assign values to their calibrants. The establishment of an international harmonisation oversight group is recommended: its key roles to include identification of a commutable matrix reference material, assessing the clinical significance of assay interferents, the evaluation of liquid chromatography-mass spectrometry as a reference measurement procedure and the provision of acceptance criteria for the clinical application of GH methods.
    • Harmonizing growth hormone measurements: learning lessons for the future.

      Wieringa, Gilbert E; Trainer, Peter J; Department of Biochemistry, Christie Hospital National Health Service Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom. (2007-08)
    • Hartmann's procedure versus intersphincteric abdominoperineal excision (HiP Study): a multicentre prospective cohort study

      Fowler, H.; Clifford, R.; Sutton, Paul; Watson, A.; Fearnhead, N.; Bach, S.; Moran, B.; Rose, A.; Jackson, R.; Vimalachandran, D.; et al.
      Aim: In patients with low rectal cancer it is occasionally necessary to avoid a low coloanal anastomosis due to patient frailty or poor function. In such situations there are two alternative approaches: Hartmann's procedure (HP) or intersphincteric abdominoperineal excision (IAPE). There are few data to guide surgeons as to which of these two procedures is the safest. The aim of this study was to determine the surgical complication rates associated with each procedure. Method: This was a multicentre, nonrandomized prospective cohort study of patients undergoing either HP or IAPE. The primary objective was to determine surgical complication rates. Secondary objectives included length of stay, time to adjuvant therapy and quality of life at 90 days. Results: One hundred and seventy nine patients were recruited between April 2016 and June 2019; approximately two thirds of patients underwent HP and one third IAPE. The overall complication rate was high in both groups (54% for the HP group and 52% for the IAPE group). Surgery-specific complication rates were also high, but not significantly different: 43% for HP and 48% for IAPE. The pelvic abscess rate in HP was 11% and was significantly higher in patients with a palpable staple line (15% vs 2%). There was a higher incidence of serious medical complications following IAPE (16% vs 5%), along with a reduction in 90-day quality of life scores. Conclusion: This is the largest prospective study to compare HP and IAPE in patients undergoing rectal cancer surgery where primary anastomosis is not deemed appropriate. With similar complication rates, these data support the ongoing use of either HP or IAPE in this patient group.