• YAP/Hippo Pathway and Cancer Immunity: It Takes Two to Tango

      Matthaios, D.; Tolia, M.; Mauri, D.; Kamposioras, K.; Karamouzis, M.; Department of Medical Oncology, Rhodes General Hospital, 85100 Rhodes, Greece (2021)
      Hippo pathway with its main molecule YAP is a crucial pathway for development, tissue homeostasis, wound healing, tissue regeneration, and cancer. In this review, we discuss the multiple effects of the YAP/Hippo pathway in the immune system and cancer. We analyzed a series of effects: extracellular vesicles enhanced immunity through inhibition of LATS1/2, ways of modulation of the tumor microenvironment, YAP- and TAZ-mediated upregulation of PDL1, high expression of YAP and PDL1 in EGFR-TKI-resistant cells, enhanced YAP activity in inflammation, and the effect of the Hippo pathway on T cells, B cells, Tregs, macrophages, and myeloid-derived suppressor cells (MDSCs). These pleiotropic effects render the YAP and Hippo pathway a key pathway for exploitation in the future, in order to enhance our immunotherapy treatment strategies in oncology.
    • YoDA BRCA: views and experiences around genetic testing for young women with breast cancer: developing a decision aid

      Grimmett, C; Brooks, C; Recio-Saucedo, A; Cutress, R; Copson, E; Evans, G; Gerty, S; Armstrong, Anne C; Turner, L; Mason, S; et al. (2016)
    • Young adulthood body mass index, adult weight gain and breast cancer risk: the PROCAS Study (United Kingdom)

      Renehan, Andrew G; Pegington, Mary; Harvie, MH; Sperrin, M; Astley, SM; Brentnall, AR; Howell, Anthony; Cusick, J; Evans, D Gareth R; Manchester Cancer Research Centre and NIHR Manchester Biomedical Research Centre, Manchester, UK (2020)
    • Young age at first pregnancy does protect against early onset breast cancer in BRCA1 and BRCA2 mutation carriers.

      Evans, D; Harkness, E; Howell, Sacha J; Woodward, E; Howell, Anthony; Lalloo, F; Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre (MAHSC), Institute of Human Development, St Mary's Hospital, University of Manchester, Manchester (2017-11-07)
      Previous research assessing the impact of pregnancy and age at first pregnancy on breast cancer risk in BRCA1 and BRCA2 mutation carriers has produced conflicting results, with some studies showing an increased risk following early first pregnancy in contrast to the reduced risk in the general population of women. The present study addresses these inconsistencies.
    • Yttrium-90 radioembolization in intrahepatic cholangiocarcinoma: a multicenter retrospective analysis

      Buettner, S.; Braat, A.; Margonis, G. A.; Brown, D. B.; Taylor, K. B.; Borgmann, A. J.; Kappadath, S. C.; Mahvash, A.; JNM, I. J.; Weiss, M. J.; et al. (2020)
      PURPOSE: To report outcomes of yttrium-90 ((90)Y) radioembolization in patients with unresectable intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS: Retrospective review was performed of 115 patients at 6 tertiary care centers; 92 were treated with resin microspheres (80%), 22 were treated with glass microspheres (19%), and 1 was treated with both. Postintervention outcomes were compared between groups with chi(2) tests. Survival after diagnosis and after treatment was assessed by Kaplan-Meier method. RESULTS: Grade 3 laboratory toxicity was observed in 4 patients (4%); no difference in toxicity profile between resin and glass microspheres was observed (P = .350). Clinical toxicity per Society of Interventional Radiology criteria was noted in 29 patients (25%). Partial response per Response Evaluation Criteria In Solid Tumors 1.1 was noted in 25% of patients who underwent embolization with glass microspheres and 3% of patients who were treated with resin microspheres (P = .008). Median overall survival (OS) from first diagnosis was 29 months (95% confidence interval [CI], 21-37 mo) for all patients, and 1-, 3-, and 5-year OS rates were 85%, 31%, and 8%, respectively. Median OS after treatment was 11 months (95% CI, 8-13 mo), and 1- and 3-year OS rates were 44% and 4%, respectively. These estimates were not significantly different between resin and glass microspheres (P = .730 and P = .475, respectively). Five patients were able to undergo curative-intent resection after (90)Y radioembolization (4%). CONCLUSIONS: This study provides observational data of treatment outcomes after (90)Y radioembolization in patients with unresectable ICC.
    • Yttrium-90 transarterial radioembolization for chemotherapy-refractory intrahepatic cholangiocarcinoma: a prospective, observational study

      White, J; Carolan-Rees, G; Dale, M; Patrick, H; See, T; Bell, Jon; Manas, D; Crellin, A; Slevin, Nicholas J; Sharma, R; et al. (2019)
      PURPOSE: To evaluate the safety and efficacy of yttrium-90 transarterial radioembolization (TARE) for the treatment of unresectable, chemotherapy-refractory intrahepatic cholangiocarcinoma (ICC). METHODS: A prospective, observational study was carried out in 10 centers between 2013 and 2017. TARE plus standard care was delivered to patients with unresectable, chemotherapy-refractory or chemotherapy-intolerant ICC. Primary outcome was overall survivaL Secondary outcomes included safety, progression-free survival (PFS), and liver-specific progression-free survival (LPFS). RESULTS: Sixty-one patients were treated with TARE Patients were 53% male; median age was 64 years; 91% had performance status 0/1; 92% had received prior chemotherapy; and 59% had no extrahepatic disease. Median follow-up was 13.9 months (95% confidence interval [CI], 9.6-18.1). Overall survival was 8.7 months (95% CI, 5.3-12.1), and 37% of patients survived to 12 monthS PFS was 2.8 months (95% CI, 2.6-3.1), and LPFS was 3.1 months (95% CI, 1.3-4.8). One severe complication (abdominal pain) occurred at the time of the TARE procedure. Thirty patients experienced a total of 49 adverse events, of which 8% were grade >/=3; most common were grade 1-2 fatigue and abdominal pain. A total of 77 abnormal laboratory value events were recorded, of which 4% were grade >/=3. CONCLUSIONS: Patients with advanced ICC have limited therapeutic options and a poor prognosis. This prospective study examined the survival of patients with unresectable, chemotherapy-refractory primary ICC treated with TARE in real-world practice. The results demonstrate that this treatment merits further investigation in this patient cohort in a larger study, including collection of patient-reported outcomes.
    • YY1 expression predicts favourable outcome in follicular lymphoma.

      Naidoo, Khimara; Clay, V; Hoyland, J A; Swindell, Ric; Linton, Kim M; Illidge, Timothy M; Radford, John A; Byers, RJ; School of Cancer and Enabling Sciences, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, UK. (2011-02)
      Follicular lymphoma is the second most common type of non-Hodgkin's lymphoma worldwide. The majority of patients diagnosed as having follicular lymphoma have an indolent form of the disease, but a subset of patients have aggressive disease with a shorter survival interval. Optimal treatment stratification requires a distinction between these two groups, though there are presently few prognostic biomarkers available. The transcription factor YY1 has been shown to play an important role in cancer biology. The authors have previously reported a correlation of Yin Yang 1 (YY1) mRNA levels with survival in FL. This study aimed to validate these findings at the protein level.
    • ZD1839 (IRESSA): a selective EGFR-TK inhibitor.

      Ranson, Malcolm R; Mansoor, Was; Jayson, Gordon C; Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester, UK. malcolm.ranson@amn.ac.uk (2002-04)
      The recent development of highly selective, target-based cancer therapeutics, such as ZD1839 has resulted from a greater understanding of tumor biology. Amongst the most promising of new target-based agents are inhibitors of the epidermal growth factor receptor. ZD 1839 is a potent, selective epidermal growth factor receptor tyrosine kinase inhibitor that has demonstrated promising results in early clinical trials.
    • ZD1839 (Iressa): for more than just non-small cell lung cancer.

      Ranson, Malcolm R; Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, United Kingdom. malcolm.ranson@man.ac.uk (2002)
      ZD1839 (Iressa) is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor that blocks signal transduction pathways involved in cell proliferation. Preclinical studies demonstrated that ZD1839 is a promising agent for the treatment of a wide range of tumors and has additive-to-synergistic effects when combined with radiation or chemotherapy in various cell lines and xenografts. Phase I clinical trials have reported that ZD1839 has acceptable tolerability and antitumor activity. In addition to non-small cell lung cancer, phase II/III studies are currently investigating ZD1839 as monotherapy or in combination therapy against prostate, breast, head and neck, gastric, and colorectal tumors.
    • ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial.

      Ranson, Malcolm R; Hammond, Lisa A; Ferry, David R; Kris, Mark; Tullo, Andrew; Murray, Philip I; Miller, Vince; Averbuch, Steven D; Ochs, Judith; Morris, Charles; et al. (2002-05-01)
      PURPOSE: To investigate the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 in patients with solid malignant tumors. PATIENTS AND METHODS: This was an open, phase I, escalating multiple-dose tolerability and pharmacokinetic trial. ZD1839 was administered once daily for 14 consecutive days followed by 14 days off treatment. Dose escalation started at 50 mg/d and continued to 925 mg or until consistent dose-limiting toxicity (DLT) was observed. RESULTS: Sixty-four patients were entered at eight dose levels. The most frequent dose-related grade 1 and 2 adverse events were an acne-like (or folliculitis) rash, nausea, and diarrhea. Three of nine patients treated at 700 mg/d developed DLT (reversible grade 3 diarrhea); grade 3 and 4 events were uncommon. Exposure to ZD1839 was dose proportional, and the mean terminal half-life was 48 hours (range, 37 to 65). Four of 16 patients with non-small-cell lung cancer (NSCLC) had objective partial responses observed from ZD1839 300 to 700 mg/d. Overall, 16 patients remained on study for > or = 3 months, with seven of these patients (five with NSCLC, including three of the patients with partial response) remaining on study for > or = 6 months. CONCLUSION: ZD1839 was well tolerated, with DLT observed at a dose well above that at which antitumor activity was seen. Pharmacokinetic analysis confirmed that ZD1839 was suitable for administration as a once-daily oral tablet formulation. Phase II monotherapy and phase III combination trials in NSCLC are being conducted to investigate further the efficacy, tolerability, and optimal daily dose of ZD1839.
    • Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: a randomised, crossover study of community vs hospital bisphosphonate administration.

      Wardley, Andrew M; Davidson, N; Barrett-Lee, P J; Hong, A; Mansi, J; Dodwell, David J; Murphy, R; Mason, T; Cameron, David; Christie Hospital NHS Trust, 550 Wilmslow Road, Manchester M20 4BX, UK. Andrew.Wardley@christie-tr.nwest.nhs.uk (2005-05-23)
      Patients with bone metastases from breast cancer often experience substantial skeletal complications -- including debilitating bone pain -- which negatively affect quality of life. Zoledronic acid (4 mg) has been demonstrated to reduce significantly the risk of skeletal complications in these patients and is administered via a short, 15-min infusion every 3 weeks, allowing the possibility for home administration. This study compared the efficacy and safety of zoledronic acid administered in the community setting vs the hospital setting in breast cancer patients with > or =1 bone metastasis receiving hormonal therapy. After a lead-in phase of three infusions of 4 mg zoledronic acid in the hospital setting, 101 patients were randomized to receive three open-label infusions in the community or hospital setting, followed by three infusions in the opposite venue (a total of nine infusions). The Brief Pain Inventory (BPI) and the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30) were used to assess potential benefits of zoledronic acid therapy. At study end, analysis of the BPI showed significant reductions in worst pain (P=0.008) and average pain in the last 7 days (P=0.039), and interference with general activity (P=0.012). In each case, there were significantly greater improvements in pain scores after treatment in the community setting compared with the hospital crossover setting for worst pain (P=0.021), average pain (P=0.003), and interference with general activity (P=0.001). Overall global health status showed a significant median improvement of 8.3% (P=0.013) at study end. Physical, emotional, and social functioning also showed significant overall improvement (P=0.013, 0.005, and 0.043, respectively). Furthermore, physical, role, and social functioning showed significantly greater improvements after treatment in the community setting compared with the hospital crossover setting (P=0.018, 0.001, and 0.026, respectively). There was no difference between hospital and community administration in renal or other toxicity, with zoledronic acid being well tolerated in both treatment settings. These data confirm the safety and quality-of-life benefits of zoledronic acid in breast cancer patients with bone metastases, particularly when administered in the community setting.