• A biomarker-guided first-in-human trial of subcutaneous ALM201 in patients with solid tumours.

      El-Helali, A; Plummer, R; Jayson, Gordon C; Coyle, V.; Rogers, C; D'arcangelo, M; Graham, D; Drew, Y; Clamp, Andrew R; McCann, J; et al. (2016-10-01)
    • A Phase IIa study of tisotumab vedotin (HuMax (R)-TF-ADC) in patients with relapsed, recurrent and/or metastatic cervical cancer: updated safety and efficacy.

      Concin, N; Vergote, I; Dean, Emma J; Lassen, U; De Bono, J; Drew, Y; Machiels, J; Nielsen, D; Arkenau, T; Forster, M; et al. (2017)
    • A video demonstrating minimally invasive cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: video vignette.

      Bullen, T; Fulford, Paul E; Wilson, Malcolm S; Aziz, Omer; Renehan, Andrew G; O'Dwyer, Sarah T; Selvasekar, Chelliah; Department of colorectal surgery, University Hospital North Midlands NHS Trust, Newcastle Rd, Stoke on Trent, (2016-09-20)
      We submit a video of the highlights of three cases of laparoscopic cytoreductive surgery and heated intra-peritoneal chemotherapy. These cases point to some of the challenges of laparoscopic cytoreductive surgery and logical variations such as natural orifice specimen extraction, performed in the third case. This article is protected by copyright. All rights reserved.
    • A20 deletion is associated with copy number gain at the TNFA/B/C locus and occurs preferentially in translocation-negative MALT lymphoma of the ocular adnexa and salivary glands.

      Chanudet, E; Ye, Hongtao; Ferry, J; Bacon, C M; Adam, P; Müller-Hermelink, H K; Radford, John A; Pileri, S A; Ichimura, K; Collins, V P; et al. (2009-02)
      The genetic basis of MALT lymphoma is largely unknown. Characteristic chromosomal translocations are frequently associated with gastric and pulmonary cases, but are rare at other sites. We compared the genetic profiles of 33 ocular adnexal and 25 pulmonary MALT lymphomas by 1 Mb array-comparative genomic hybridization (CGH) and revealed recurrent 6q23 losses and 6p21.2-6p22.1 gains exclusive to ocular cases. High-resolution chromosome 6 tile-path array-CGH identified NF-kappaB inhibitor A20 as the target of 6q23.3 deletion and TNFA/B/C locus as a putative target of 6p21.2-22.1 gain. Interphase fluorescence in situ hybridization showed that A20 deletion occurred in MALT lymphoma of the ocular adnexa (8/42=19%), salivary gland (2/24=8%), thyroid (1/9=11%) and liver (1/2), but not in the lung (26), stomach (45) and skin (13). Homozygous deletion was observed in three cases. A20 deletion and TNFA/B/C gain were significantly associated (p<0.001) and exclusively found in cases without characteristic translocation. In ocular cases, A20 deletion was associated with concurrent involvement of different adnexal tissues or extraocular sites at diagnosis (p=0.007), a higher proportion of relapse (67% versus 37%) and a shorter relapse-free survival (p=0.033). A20 deletion and gain at TNFA/B/C locus may thus play an important role in the development of translocation-negative MALT lymphoma.
    • ABC of breast diseases. Psychological aspects.

      Maguire, Peter; CRC Psychological Medicine Group, Christie Hospital, Manchester, M20 4BX, UK. (1994-12-17)
    • ABC of colorectal diseases: Anal cancer.

      Jones, D J; James, Roger D; Department of Surgery, Hope Hospital, Salford. (1992-07-18)
    • Abdominal and gluteofemoral size and risk of liver cancer: the liver cancer pooling project

      Florio, AA; Campbell, PT; Zhang, X; Zeleniuch-Jacquotte, A; Wactawski-Wende, J; Smith-Warner, SA; Sinha, R; Simon, TG; Sesso, HD; Schairer, C; et al. (2019)
      Obesity is known to be associated with primary liver cancer (PLC), but the separate effects of excess abdominal and gluteofemoral size are unclear. Thus, we examined the association between waist and hip circumference with risk of PLC overall and by histologic type - hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The Liver Cancer Pooling Project is a consortium of prospective cohort studies that includes data from 1,167,244 individuals (PLC n=2,208, HCC n=1,154, ICC n=335). Multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Waist circumference, per 5 cm increase, was associated with an 11% increased PLC risk (HR=1.11, 95%CI: 1.09-1.14), including when adjusted for hip circumference (HR=1.12, 95%CI: 1.08-1.17) and also when restricted to individuals in a normal body mass index (BMI) range (18.5-<25 kg/m2 ; HR=1.14, 95%CI: 1.07-1.21). Hip circumference, per 5 cm increase, was associated with a 9% increased PLC risk (HR=1.09, 95%CI: 1.06-1.12), but no association remained after adjustment for waist circumference (HR=0.99, 95%CI: 0.94-1.03). HCC and ICC results were similar. These findings suggest that excess abdominal size is associated with an increased risk of liver cancer, even among individuals considered to have a normal BMI. However, excess gluteofemoral size alone confers no increased risk. Our findings extend prior analyses, which found an association between excess adiposity and risk of liver cancer, by disentangling the separate effects of excess abdominal and gluteofemoral size through utilization of both waist and hip circumference measurements. This article is protected by copyright. All rights reserved.
    • Abdominal computed tomography in teratoma of the testis: its accuracy in stage I disease and an assessment of the distribution of retroperitoneal lymph-node metastases in other stages of the disease.

      Bradey, N; Johnson, Richard J; Read, G (1987-05)
      One hundred and one patients with Stage I teratoma of the testis have had an abdomino-pelvic computed tomography (CT) scan. These patients have been followed up for a minimum of 18 months and only eight patients have relapsed in the abdomen alone. The abdomino-pelvic CT scan has a negative predictive value of 92%. In those shown by CT to have retroperitoneal lymphadenopathy, the distribution of disease correlates closely with that reported in the literature following retroperitoneal lymphadenectomy. The CT scan provides information about the amount of tumour present and this influences treatment. Computed tomography is the imaging modality of choice for staging patients with teratoma of the testis and invasive techniques do not appear to be justified.
    • Abdominal irradiation in childhood; the potential for pregnancy.

      Critchley, H O; Wallace, W Hamish B; Shalet, Stephen M; Mamtora, H; Higginson, J; Anderson, D C; Department of Obstetrics and Gynaecology, St. Mary's Hospital, Manchester, UK. (1992-05)
      OBJECTIVE: To investigate the impact of premature ovarian failure due to whole abdominal radiotherapy (DXT) in childhood on uterine physical characteristics and blood flow and measuring the uterine response to exogenous sex steroid replacement. DESIGN: A comparative observational study SUBJECTS: 10 women with premature ovarian failure due to treatment with whole abdominal irradiation in childhood. A comparison group of 22 women with premature ovarian failure who had not received whole abdominal DXT. MAIN OUTCOME MEASURES: Uterine length and uterine blood flow measurement plus serial assessment of endometrial thickness during a cycle of exogenous sex steroid replacement. RESULTS: Uterine length was significantly less (P less than 0.01) in women who had been exposed to whole abdominal DXT in childhood (mean 4.1 cm, 2SE 0.8) compared with a mean of 7.3 cm (2SE 0.6) in the comparison group. The three women in the DXT group who were studied serially had no increase in endometrial thickness in response to physiological sex steroid replacement therapy and most of the 10 irradiated women had no detectable uterine blood flow with Doppler ultrasound. CONCLUSIONS: Uterine musculature and blood flow are irreversibly affected by high dose irradiation in childhood. Non-invasive assessment of this nature may predict potential for pregnancy following ovum donation and embryo transfer.
    • Abdomino-pelvic computed tomography in the management of ovarian carcinoma.

      Johnson, Richard J; Blackledge, George; Eddleston, Brian; Crowther, Derek; Department of Diagnostic Radiology, Christie Hospital, Manchester, (1983-02)
      121 CT scans were obtained in 75 women with ovarian cancer, including 108 scans of the abdomen and pelvis and 13 of the pelvis alone. 70 patients had epithelial carcinoma. In 48 cases, pelvic CT was performed within 3 weeks after surgery, confirming the operative findings in all but 6. In the abdomen, CT identified intrahepatic deposits and minimal ascites not seen at surgery; however, small peritoneal deposits not usually shown by CT were readily found at surgery. CT was superior to clinical examination, detecting unsuspected disease and delineating areas of known disease more accurately. It was also helpful in assessing suitability for repeat laparotomy. In 7 cases, CT demonstrated an operable lesion which had been thought to be inoperable. In 65 cases (59%), CT contributed additional information which was helpful in management, proving it to be an important noninvasive investigation in patients with ovarian carcinoma.
    • Abdominopelvic CT scan findings after surgery for ovarian cancer.

      Razzaq, R; Carrington, Bernadette M; Hulse, Paul; Kitchener, Henry C; Department of Diagnostic Radiology, Christie Hospital NHS Trust, Manchester, UK. (1998-11)
      AIMS: To evaluate abdomino-pelvic changes in patients who had total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) for stage I ovarian cancer. METHOD: The postoperative computed tomographic (CT) scans of 23 patients who had undergone TAH and BSO for stage I ovarian tumours between 3 and 14 weeks previously were assessed, providing there had been no treatment with chemotherapy or radiotherapy and that each patient had normal tumour marker (CA125) levels after surgery. After the CT scan patients were followed up and had no clinical or biochemical (CA125) evidence of relapse for a median of 27 months (range 11 to 78 months). The following sites were assessed by two observers: the vaginal vault, round ligaments, bladder, rectum, perirectal fat, pelvic sidewalls, omentum, surgical scar and abdominal wall. Any abnormality was recorded, with re-evaluation on follow-up CT scans in ten patients (between three and 17 months). RESULTS: The following abnormalities were seen: (1) Thickened round ligaments (n=12) with bulbous masses at the surgically transected ends (n=7). This was bilateral in eight patients. (2) Vaginal vault thickening (n=11) either uniform (n=6) or bulbous bilaterally (n=2) or unilaterally (n=3). (3) Subtle omental bed stranding or nodularity (n=11). (4) Peritoneal thickening underlying the scar (n=4). (5) Asymmetrical rectus abdominis muscles (n=3) adjacent to the surgical scar or thickened scar tissue in the anterior abdominal wall (n=4). No significant bladder, rectal, perirectal or nodal abnormalities were found. CONCLUSION: Pseudotumours at the transected ends of the round ligaments, or uniformly swollen round ligaments, may be identified in patients who have had TAH and BSO, as may vaginal vault thickening. Other changes which may be observed in the abdomen and pelvis are peritoneal thickening adjacent to the scar and omental bed stranding.
    • Abemaciclib combined with endocrine therapy for the adjuvant treatment of hr+, her2-, node-positive, high-risk, early breast cancer (monarche)

      Johnston, S. R. D.; Harbeck, N.; Hegg, R.; Toi, M.; Martin, M.; Shao, Z. M.; Zhang, Q. Y.; Martinez Rodriguez, J. L.; Campone, M.; Hamilton, E.; et al. (2020)
      Purpose: Many patients with HR+, HER2early breast cancer (EBC) will not experience recurrence or have distant recurrence with currently available standard therapies. However, up to 30% of patients with high-risk clinical and/or pathologic features may experience distant recurrence, many in the first few years. Superior treatment options are needed to prevent early recurrence and development of metastases for this group of patients. Abemaciclib is an oral, continuously dosed, CDK4/6 inhibitor approved for HR+, HER2advanced breast cancer (ABC). Efficacy and safety of abemaciclib in ABC supported evaluation in the adjuvant setting. Methods: This open-label, phase III study included patients with HR+, HER2-, high-risk EBC, who had surgery and, as indicated, radiotherapy and/or adjuvant/neoadjuvant chemotherapy. Patients with four or more positive nodes, or one to three nodes and either tumor size ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%, were eligible and randomly assigned (1:1) to standard-of-care adjuvant endocrine therapy (ET) with or without abemaciclib (150 mg twice daily for 2 years). The primary end point was invasive disease-free survival (IDFS), and secondary end points included distant relapse-free survival, overall survival, and safety. Results: At a preplanned efficacy interim analysis, among 5,637 randomly assigned patients, 323 IDFS events were observed in the intent-to-treat population. Abemaciclib plus ET demonstrated superior IDFS versus ET alone (P = .01; hazard ratio, 0.75; 95% CI, 0.60 to 0.93), with 2-year IDFS rates of 92.2% versus 88.7%, respectively. Safety data were consistent with the known safety profile of abemaciclib. Conclusion: Abemaciclib when combined with ET is the first CDK4/6 inhibitor to demonstrate a significant improvement in IDFS in patients with HR+, HER2node-positive EBC at high risk of early recurrence.
    • Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial

      Tolaney, S. M.; Wardley, Andrew M; Zambelli, S.; Hilton, J. F.; Troso-Sandoval, T. A.; Ricci, F.; Im, S. A.; Kim, S. B.; Johnston, S. R. D.; Chan, A.; et al. (2020)
      Background: Patients with HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. The monarcHER trial aimed to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant with standard-of-care chemotherapy of physician's choice plus trastuzumab in women with advanced breast cancer. Methods: This phase 2, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries. Eligible patients were women aged 18 years or older, who had hormone receptor-positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to the abemaciclib, trastuzumab, and fulvestrant (group A), abemaciclib and trastuzumab (group B), or standard-of-care chemotherapy and trastuzumab (group C). Oral abemaciclib 150 mg 12 hourly was administered on days 1-21 of a 21-day cycle, intravenous trastuzumab 8 mg/kg on cycle 1 day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle, and intramuscular fulvestrant 500 mg on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Randomisation was by a computer-generated random sequence by means of an interactive web-response system and stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, first testing group A versus group C and, if this result was significant, then group B versus group C. Safety was assessed in all patients who had received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT02675231) and is ongoing for long-term survival follow-up. Findings: Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 eligible patients were enrolled and randomly assigned to groups A (n=79), B (n=79), and C (n=79). Median follow-up was 19·0 months (IQR 14·7-25·1). The study met its primary endpoint, showing a significant difference at the prespecified two-sided ? of 0·2 in median progression-free survival between group A (8·3 months, 95% CI 5·9-12·6) and group C (5·7 months, 5·4-7·0; HR 0·67 [95% CI 0·45-1·00]; p=0·051). No difference was observed between median progression-free survival in group B (5·7 months, 95% CI 4·2-7·2) and group C (HR 0·94 [0·64-1·38]; p=0·77). The most common grade 3-4 treatment-emergent adverse event in groups A, B, and C was neutropenia (21 [27%] of 78 patients, 17 [22%] of 77, and 19 [26%] of 72). The most common serious adverse events were: in group A, pyrexia (three [4%]), diarrhoea (two [3%]), urinary tract infection (two [3%]), and acute kidney injury (two [3%]); in group B, diarrhoea (two [3%]) and pneumonitis (two [3%]); and in group C, neutropenia (four [6%]) and pleural effusion (two [3%]). Two deaths were attributed to treatment: one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C. Interpretation: The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer.
    • Aberrant CDKN1A transcriptional response associates with abnormal sensitivity to radiation treatment.

      Badie, Christophe; Dziwura, S; Raffy, C; Tsigani, Theodora; Alsbeih, G; Moody, J; Finnon, Paul; Levine, Edward; Scott, David A; Bouffler, Simon; et al. (2008-06-03)
      Normal tissue reactions to radiation therapy vary in severity among patients and cannot be accurately predicted, limiting treatment doses. The existence of heritable radiosensitivity syndromes suggests that normal tissue reaction severity is determined, at least in part, by genetic factors and these may be revealed by differences in gene expression. To test this hypothesis, peripheral blood lymphocyte cultures from 22 breast cancer patients with either minimal (11) or very severe acute skin reactions (11) have been used to analyse gene expression. Basal and post-irradiation expression of four radiation-responsive genes (CDKN1A, GADD45A, CCNB1, and BBC3) was determined by quantitative real-time PCR in T-cell cultures established from the two patient groups before radiotherapy. Relative expression levels of BBC3, CCNB1, and GADD45A 2 h following 2 Gy X-rays did not discriminate between groups. However, post-irradiation expression response was significantly reduced for CDKN1A (P<0.002) in severe reactors compared to normal. Prediction of reaction severity of approximately 91% of individuals sampled was achieved using this end point. Analysis of TP53 Arg72Pro and CDKN1A Ser31Arg single nucleotide polymorphisms did not show any significant association with reaction sensitivity. Although these results require confirmation and extension, this study demonstrates the possibility of predicting the severity of acute skin radiation toxicity in simple tests.
    • Aberrant DNA hypermethylation signature in acute myeloid leukemia directed by EVI1.

      Lugthart, S; Figueroa, M; Bindels, E; Skrabanek, L; Valk, P J M; Li, Y; Meyer, Stefan; Erpelinck-Verschueren, C; Greally, J; Löwenberg, B; et al. (2011-01-06)
      DNA methylation patterns are frequently dysregulated in cancer, although little is known of the mechanisms through which specific gene sets become aberrantly methylated. The ecotropic viral integration site 1 (EVI1) locus encodes a DNA binding zinc-finger transcription factor that is aberrantly expressed in a subset of acute myeloid leukemia (AML) patients with poor outcome. We find that the promoter DNA methylation signature of EVI1 AML blast cells differs from those of normal CD34(+) bone marrow cells and other AMLs. This signature contained 294 differentially methylated genes, of which 238 (81%) were coordinately hypermethylated. An unbiased motif analysis revealed an overrepresentation of EVI1 binding sites among these aberrantly hypermethylated loci. EVI1 was capable of binding to these promoters in 2 different EVI1-expressing cell lines, whereas no binding was observed in an EVI1-negative cell line. Furthermore, EVI1 was observed to interact with DNA methyl transferases 3A and 3B. Among the EVI1 AML cases, 2 subgroups were recognized, of which 1 contained AMLs with many more methylated genes, which was associated with significantly higher levels of EVI1 than in the cases of the other subgroup. Our data point to a role for EVI1 in directing aberrant promoter DNA methylation patterning in EVI1 AMLs.