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1دورية أكاديمية
المؤلفون: Rasco, Drew W, Medina, Theresa, Corrie, Pippa, Pavlick, Anna C, Middleton, Mark R, Lorigan, Paul, Hebert, Chris, Plummer, Ruth, Larkin, James, Agarwala, Sanjiv S, Daud, Adil I, Qiu, Jiaheng, Bozon, Viviana, Kneissl, Michelle, Barry, Elly, Olszanski, Anthony J
المصدر: Cancer chemotherapy and pharmacology. 92(1)
مصطلحات موضوعية: Humans, Neoplasms, Melanoma, Skin Neoplasms, Neoplasms, Second Primary, Proto-Oncogene Proteins B-raf, Mitogen-Activated Protein Kinase Kinases, Protein Kinase Inhibitors, Maximum Tolerated Dose, Adult, BRAF, Pan-RAF inhibitor, Phase 1, Tovorafenib, Clinical Trials and Supportive Activities, Clinical Research, Cancer, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Pharmacology and Pharmaceutical Sciences, Oncology & Carcinogenesis
الوصف: PurposeGenomic alterations of BRAF and NRAS are oncogenic drivers in malignant melanoma and other solid tumors. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib.MethodsThis two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics.ResultsTovorafenib was administered to 149 patients (Q2D n = 110, QW n = 39). The RP2D of tovorafenib was defined as 200 mg Q2D or 600 mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade ≥ 3 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in systemic circulation in the dose range of 400-800 mg.ConclusionsThe safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in BRAF-mutated melanoma was promising and justifies continued clinical development across multiple settings.ClinicaltrialsGov identifierNCT01425008.
وصف الملف: application/pdf
الوصول الحر: https://escholarship.org/uc/item/6jq463hgTest
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2دورية أكاديمية
المؤلفون: Thompson, Nicola A, Stewart, Grant D, Welsh, Sarah J, Doherty, Gary J, Robinson, Matthew J, Neville, B Anne, Vervier, Kevin, Harris, Simon R, Adams, David J, Dalchau, Katy, Bruce, David, Demiris, Nikolaos, Lawley, Trevor D, Corrie, Pippa G
المصدر: nlmid: 100967800 ; essn: 1471-2407
مصطلحات موضوعية: Biomarker, Efficacy, Immune checkpoint inhibitor, Immunotherapy, Melanoma, Microbiome, Non-small cell lung cancer, Renal cancer, Toxicity, Antibodies, Viral, Antigens, Carcinoma, Non-Small-Cell Lung, Disease Progression, Feces, Gastrointestinal Microbiome, Humans, Immune Checkpoint Inhibitors, Kidney Neoplasms, Lung Neoplasms, Microbial Consortia, Neoplasms, Progression-Free Survival, Prospective Studies, SARS-CoV-2, Skin Neoplasms
الوصف: BACKGROUND: The gut microbiome is implicated as a marker of response to immune checkpoint inhibitors (ICI) based on preclinical mouse models and preliminary observations in limited patient series. Furthermore, early studies suggest faecal microbial transfer may have therapeutic potential, converting ICI non-responders into responders. So far, identification of specific responsible bacterial taxa has been inconsistent, which limits future application. The MITRE study will explore and validate a microbiome signature in a larger scale prospective study across several different cancer types. METHODS: Melanoma, renal cancer and non-small cell lung cancer patients who are planned to receive standard immune checkpoint inhibitors are being recruited to the MITRE study. Longitudinal stool samples are collected prior to treatment, then at 6 weeks, 3, 6 and 12 months during treatment, or at disease progression/recurrence (whichever is sooner), as well as after a severe (≥grade 3 CTCAE v5.0) immune-related adverse event. Additionally, whole blood, plasma, buffy coat, RNA and peripheral blood mononuclear cells (PBMCs) is collected at similar time points and will be used for exploratory analyses. Archival tumour tissue, tumour biopsies at progression/relapse, as well as any biopsies from body organs collected after a severe toxicity are collected. The primary outcome measure is the ability of the microbiome signature to predict 1 year progression-free survival (PFS) in patients with advanced disease. Secondary outcomes include microbiome correlations with toxicity and other efficacy end-points. Biosamples will be used to explore immunological and genomic correlates. A sub-study will evaluate both COVID-19 antigen and antibody associations with the microbiome. DISCUSSION: There is an urgent need to identify biomarkers that are predictive of treatment response, resistance and toxicity to immunotherapy. The data generated from this study will both help inform patient selection for these drugs and provide information that may ...
وصف الملف: application/pdf
الإتاحة: https://doi.org/10.17863/CAM.81887Test
https://www.repository.cam.ac.uk/handle/1810/334470Test -
3دورية أكاديمية
المؤلفون: Mendes Serrao, Eva, Joslin, Emily, McMorran, Victoria, Hough, Caroline, Palmer, Cheryl, McDonald, Sarah, Cargill, Emma, Shaw, Ashley S, O'Carrigan, Brent, Parkinson, Christine A, Corrie, Pippa G, Sadler, Timothy J
المصدر: essn: 1470-7330 ; nlmid: 101172931
مصطلحات موضوعية: Aneurysmal, Melanoma, Metastatic, Radiology, Small bowel, Abdomen, Humans, Intestine, Small, Quality of Life, Skin Neoplasms
الوصف: BACKGROUND: Melanoma is the most aggressive form of skin cancer, with a tendency to metastasise to any organ of the human body. While the most common body organs affected include liver, lungs, brain and soft tissues, spread to the gastrointestinal tract is not uncommon. In the bowel, it can present with a multitude of imaging appearances, more rarely as an aneurysmal dilatation. This appearance is classically associated with lymphoma, but it has more rarely been associated with other forms of malignancy. CASE PRESENTATION: We report a case series of three patients with aneurysmal dilatation in the small bowel (SB) confirmed to be due to metastatic melanoma (MM). All patients had non-specific symptoms; most times being attributed initially to causes other than melanoma. On CT the identified aneurysmal SB dilatations were diagnosed as presumed lymphoma in all cases. In two cases, the aneurysmal dilatation was the first presentation of metastatic disease and in two of the cases more than one site of the gastrointestinal tract was concomitantly involved. All patients underwent surgical resection with histological confirmation of MM. CONCLUSIONS: Recognition of unusual SB presentation of MM, such as aneurysmal SB dilatation, is important to expedite diagnosis, provide appropriate treatment, and consequently improve quality of life and likely survival of these patients. As the most common cancer to metastasise to the SB and as a known imaging mimicker, MM should remain in any radiologist's differential diagnosis for SB lesions with aneurysmal dilatation. ; Acknowledgements The authors acknowledge support from National Institute of Health Research Cambridge Biomedical Research Centre, Cancer Research UK (Cambridge Imaging Centre grant number C197/A16465), the Engineering and Physical Sciences Research Council Imaging Centre in Cambridge and Manchester and the Cambridge Experimental Cancer Medicine Centre. Funding source and conflicts of interest E.M.S is funded by NIHR Clinical Lectureship (Reference number: NIHR ...
وصف الملف: application/pdf
الإتاحة: https://doi.org/10.17863/CAM.86590Test
https://www.repository.cam.ac.uk/handle/1810/339180Test -
4دورية أكاديمية
المؤلفون: Rabbie, Roy, Ansari-Pour, Naser, Cast, Oliver, Lau, Doreen, Scott, Francis, Welsh, Sarah J, Parkinson, Christine, Khoja, Leila, Moore, Luiza, Tullett, Mark, Wong, Kim, Ferreira, Ingrid, Gómez, Julia M Martínez, Levesque, Mitchell, Gallagher, Ferdia A, Jiménez-Sánchez, Alejandro, Riva, Laura, Miller, Martin L, Allinson, Kieren, Campbell, Peter J, Corrie, Pippa, Wedge, David C, Adams, David J
مصطلحات موضوعية: Aged, Biopsy, Clonal Evolution, DNA Mutational Analysis, Genetic Heterogeneity, Humans, Male, Melanoma, Prospective Studies, Skin, Skin Neoplasms, Whole Genome Sequencing
الوصف: Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages. UV-induced mutations dominate the trunk, whereas APOBEC-associated mutations are found in the branches of the evolutionary tree. Multi-sample analyses from a further seven patients confirmed that lineage diversification was pervasive, representing an important mode of melanoma dissemination. Our analyses demonstrate that joint analysis of cancer cell fraction estimates across multiple metastases can uncover previously unrecognised levels of tumour heterogeneity and highlight the limitations of inferring heterogeneity from a single biopsy.
وصف الملف: Electronic; application/pdf
الإتاحة: https://doi.org/10.17863/CAM.57832Test
https://www.repository.cam.ac.uk/handle/1810/310743Test -
5دورية أكاديمية
المؤلفون: Jones, James, Lucey, Rebecca, Corrie, Pippa
مصطلحات موضوعية: BRAF, dabrafenib, encorafenib, immunotherapy, melanoma, Humans, Proto-Oncogene Proteins B-raf, Retrospective Studies, Molecular Targeted Therapy, Neoplasms, Second Primary, Mutation, Skin Neoplasms, Antineoplastic Combined Chemotherapy Protocols
الوصف: BRAF-mutant melanoma patients can theoretically access both immunotherapy and BRAF-targeted therapy as treatment for metastatic disease. BRAF-targeted therapy is increasingly used 1st line for poorer prognostic patients, so we wanted to assess realistic expectations of these patients accessing 2nd-line immunotherapy. We conducted a retrospective review of clinical outcomes in 25 patients treated over the last 3 years with 1st-line BRAF-targeted therapy in a real-world clinical setting at a UK-based tertiary centre. Compared with the registration trials, our patients receiving 1st-line BRAF-targeted therapy had poorer performance status, higher disease burden, shorter median progression-free survival (5.05 months, 95% CI: 3.96-8.88) and shorter median overall survival (11.5 months, 95% CI: 6.24 - not reached). Overall response rate was similar, at 64%. On disease progression, median survival was 2.34 months (95% CI: 1.62 - not reached). Only five patients went on to receive 2nd-line immunotherapy. Metastatic melanoma patients treated with 1st-line BRAF-targeted therapy now have different demographics compared with those recruited to registration trials conducted over the last 10 years. In a modern-day, real-world setting, these patients should be counselled that only 1 in 5 are likely to receive 2nd-line immunotherapy and their survival times are expected to be short.
وصف الملف: text/xml; application/pdf
الإتاحة: https://doi.org/10.17863/CAM.88793Test
https://www.repository.cam.ac.uk/handle/1810/341367Test -
6دورية أكاديمية
المؤلفون: Walter, Fiona M, Abel, Gary A, Lyratzopoulos, Georgios, Melia, Jane, Greenberg, David, Brewster, David H, Butler, Helen, Corrie, Pippa G, Campbell, Christine
مصطلحات موضوعية: Melanoma, Seasonal variation, Skin cancer, Adult, Aged, England, Female, Humans, Incidence, Male, Middle Aged, Neoplasm Invasiveness, Scotland, Seasons, Skin Neoplasms
الوصف: BACKGROUND: Worldwide, the incidence of cutaneous melanoma has been reported to be highest in the summer and lowest in the winter. Northern Irish data suggested seasonal variation for women only, especially those with thinner melanomas, sited on limbs. We interrogated two larger UK cancer registries for temporal differences in melanoma diagnosis and associated patient characteristics. METHODS: Melanomas diagnosed from 2006 to 2010 in the Eastern England and Scottish cancer registries (n=11,611) were analysed by month of diagnosis, patient demographics and melanoma characteristics, using descriptive and multivariate modelling methods. RESULTS: More patients with melanoma were diagnosed in the summer months (June 9.9%, July 9.7%, August 9.8%) than the winter months (December 7.2%, January 7.2%, February 7.1%) and this pattern was consistent in both regions. There was evidence that the seasonal patterns varied by sex (p=0.015), melanoma thickness (p=0.002), body site (p=0.006), and type (superficial spreading melanomas p=0.005). The seasonal variation was greatest for diagnosis of melanomas occurring on the limbs. CONCLUSION: This study has confirmed seasonal variation in melanoma diagnosis in Eastern England and Scotland across almost all population demographics and melanoma characteristics studied, with higher numbers diagnosed in the summer months, particularly on the limbs. Seasonal patterns in skin awareness and related help-seeking are likely to be implicated. Targeted patient interventions to increase sun awareness and encourage year-long skin inspection are warranted. ; The paper was materially supported by the National Institute for Health Research (NIHR-CS-012-030), supporting FMW through a Clinician Scientist award. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. During this project, GL was supported by a post-doctoral fellowship by the National Institute for Health Research ...
وصف الملف: application/pdf
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7دورية أكاديمية
المؤلفون: Dalle, Stéphane, Mortier, Laurent, Corrie, Pippa, Lotem, Michal, Board, Ruth, Arance, Ana María, Meiss, Frank, Terheyden, Patrick, Gutzmer, Ralf, Buysse, Brian, Oh, Kelly, Brokaw, Jane, Le, T Kim, Mathias, Susan D, Scotto, Julie, Lord-Bessen, Jennifer, Moshyk, Andriy, Kotapati, Srividya, Middleton, Mark R
مصطلحات موضوعية: Advanced melanoma, Ipilimumab, Overall survival, Quality of life, Real-world, Subsequent therapy, Adult, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Chemoradiotherapy, Female, Follow-Up Studies, Humans, Immune Checkpoint Inhibitors, Male, Melanoma, Middle Aged, Prospective Studies, Radiosurgery, Skin Neoplasms, Survival Analysis, Treatment Outcome, Young Adult
الوصف: Funder: This work was supported by Bristol Myers Squibb (no grant number is applicable). ; BACKGROUND: Ipilimumab has shown long-term overall survival (OS) in patients with advanced melanoma in clinical trials, but robust real-world evidence is lacking. We present long-term outcomes from the IMAGE study (NCT01511913) in patients receiving ipilimumab and/or non-ipilimumab (any approved treatment other than ipilimumab) systemic therapies. METHODS: IMAGE was a multinational, prospective, observational study assessing adult patients with advanced melanoma treated with ipilimumab or non-ipilimumab systemic therapies between June 2012 and March 2015 with ≥3 years of follow-up. Adjusted OS curves based on multivariate Cox regression models included covariate effects. Safety and patient-reported outcomes were assessed. RESULTS: Among 1356 patients, 1094 (81%) received ipilimumab and 262 (19%) received non-ipilimumab index therapy (systemic therapy [chemotherapy, anti-programmed death 1 antibodies, or BRAF ± MEK inhibitors], radiotherapy, and radiosurgery). In the overall population, median age was 64 years, 60% were male, 78% were from Europe, and 78% had received previous treatment for advanced melanoma. In the ipilimumab-treated cohort, 780 (71%) patients did not receive subsequent therapy (IPI-noOther) and 314 (29%) received subsequent non-ipilimumab therapy (IPI-Other) on study. In the non-ipilimumab-treated cohort, 205 (78%) patients remained on or received other subsequent non-ipilimumab therapy (Other-Other) and 57 (22%) received subsequent ipilimumab therapy (Other-IPI) on study. Among 1151 patients who received ipilimumab at any time during the study (IPI-noOther, IPI-Other, and Other-IPI), 296 (26%) reported CTCAE grade ≥ 3 treatment-related adverse events, most occurring in year 1. Ipilimumab-treated and non-ipilimumab-treated patients who switched therapy (IPI-Other and Other-IPI) had longer OS than those who did not switch (IPI-noOther and Other-Other). Patients with prior therapy who did not switch therapy ...
وصف الملف: text/xml; application/pdf; application/zip
الإتاحة: https://doi.org/10.17863/CAM.70643Test
https://www.repository.cam.ac.uk/handle/1810/323189Test -
8دورية أكاديمية
المؤلفون: Rabbie, Roy, Ferguson, Peter, Wong, Kim, Couturier, Dominique-Laurent, Moran, Una, Turner, Clinton, Emanuel, Patrick, Haas, Kerstin, Saunus, Jodi M, Davidson, Morgan R, Lakhani, Sunil R, Shivalingam, Brindha, Long, Georgina V, Parkinson, Christine, Osman, Iman, Scolyer, Richard A, Corrie, Pippa, Adams, David J
مصطلحات موضوعية: Brain Neoplasms, DNA Mutational Analysis, Humans, Melanoma, Mutation, Proto-Oncogene Proteins p21(ras), Recurrence, Skin Neoplasms, Cutaneous Malignant
الوصف: Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440Test ; Brain metastases are a major cause of melanoma-related mortality and morbidity. We undertook whole-exome sequencing of 50 tumours from patients undergoing surgical resection of brain metastases presenting as the first site of visceral disease spread and validated our findings in an independent dataset of 18 patients. Brain metastases had a similar driver mutational landscape to cutaneous melanomas in TCGA. However, KRAS was the most significantly enriched driver gene, with 4/50 (8%) of brain metastases harbouring non-synonymous mutations. Hotspot KRAS mutations were mutually exclusive from BRAFV600, NRAS and HRAS mutations and were associated with a reduced overall survival from the resection of brain metastases (HR 10.01, p = 0.001). Mutations in KRAS were clonal and concordant with extracranial disease, suggesting that these mutations are likely present within the primary. Our analyses suggest that KRAS mutations could help identify patients with primary melanoma at higher risk of brain metastases who may benefit from more intensive, protracted surveillance.
وصف الملف: text/xml; application/pdf; application/zip
الإتاحة: https://doi.org/10.17863/CAM.76536Test
https://www.repository.cam.ac.uk/handle/1810/329090Test -
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المؤلفون: Walter, Fiona M., Pannebakker, Merel M., Barclay, Matthew E., Mills, Katie, Saunders, Catherine L., Murchie, Peter, Corrie, Pippa, Hall, Per, Burrows, Nigel, Emery, Jon D.
المصدر: JAMA Network Open
مصطلحات موضوعية: Adult, Male, Skin Neoplasms, integumentary system, Research, Dermatology, Middle Aged, Mobile Applications, Risk Assessment, Time-to-Treatment, Online Only, Young Adult, Humans, Self-Examination, Female, Smartphone, Melanoma, Original Investigation
الوصف: Key Points Question Does a smartphone application that prompts monthly skin self-monitoring result in individuals with increased risk of melanoma having more timely or more frequent family practice consultations for skin changes? Findings In this phase 2 randomized clinical trial of 238 participants, there were no significant differences in skin consultation rates, measures of skin self-monitoring, or psychological harm. Meaning Because there was no evidence that a smartphone application increased skin self-examination or health care consulting rates among a family practice population at increased risk of melanoma, its implementation is not yet recommended.
This phase 2 randomized clinical trial studies the effect of a commercially available skin self-monitoring smartphone application among individuals with increased risk of melanoma on their decision to seek help for changing skin lesions.
Importance Melanoma is among the most lethal skin cancers; it has become the fifth most common cancer in the United Kingdom, and incidence rates are rising. Population approaches to reducing incidence have focused on mass media campaigns to promote earlier presentation and potentially improve melanoma outcomes; however, interventions using smartphone applications targeting those with the greatest risk could promote earlier presentation to health care professionals for individuals with new or changing skin lesions. Objective To study the effect of a commercially available skin self-monitoring (SSM) smartphone application among individuals with increased risk of melanoma on their decision to seek help for changing skin lesions. Design, Setting, and Participants This phase 2 randomized clinical trial was conducted in 12 family practices in Eastern England between 2016 and 2017. A total of 238 participants, aged 18 to 75 years and with an increased risk of melanoma, were identified using a real-time melanoma risk assessment tool in family practice waiting rooms. Analysis was intention to treat. Participants were observed for 12 months, and data analysis was conducted from January to August 2018. Intervention The intervention and control groups received a consultation with standard written advice on sun protection and skin cancer detection. The intervention group had an SSM application loaded on their smartphone and received instructions for use and monthly self-monitoring reminders. Main Outcomes and Measures The coprimary outcomes were skin consultation rates with family practice physicians and patient intervals, measured as the time between noticing a skin change and consulting with a family practice clinician. Follow-up questionnaires were sent at 6 and 12 months, and consultation rates were extracted from family practice records. Secondary outcomes included skin self-examination benefits and barriers, self-efficacy for consulting without delay, perceived melanoma risk, sun protection habits, and potential harms. Results A total of 238 patients were randomized (median [interquartile range] age, 55 [43-65] years, 131 [55.0%] women, 227 [95.4%] white British; 119 [50.0%] randomized to the intervention group). Overall, 51 participants (21.4%) had consultations regarding skin changes during the 12 months of follow-up, and 157 participants (66.0%) responded to at least 1 follow-up questionnaire. There were no significant differences in skin consultation rates (adjusted risk ratio, 0.96; 95% CI, 0.56 to 1.66; P = .89), measures of SSM (adjusted mean difference, 0.08; 95% CI, −0.83 to 1.00; P = .86), or psychological harm (eg, Melanoma Worry Scale: adjusted mean difference, −0.12; 95% CI, −0.56 to 0.31; P = .58). Conclusions and Relevance In this study, recruitment, retention, and initial delivery of the intervention were feasible, and this research provided no evidence of harm from the SSM smartphone application. However, no evidence of benefit on skin self-examination or health care consulting was found, and there is no reason at this stage to recommend its implementation in this population at increased risk of melanoma. Trial Registration isrctn.org Identifier: ISRCTN16061621الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid________::256e1e26f944eca79867583bd2008c89Test
http://europepmc.org/articles/PMC7137684Test -
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المؤلفون: Danson, Sarah, Hook, Jane, Marshall, Helen, Smith, Alexandra, Bell, Sue, Rodwell, Simon, Corrie, Pippa
مصطلحات موضوعية: Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, Duration of Therapy, Humans, Ipilimumab, Melanoma, Nivolumab, Programmed Cell Death 1 Receptor, Skin Neoplasms
الوصف: Anti-PD-1 antibodies offer potentially life-saving treatment for some cancer patients, but their chronic administration generates high and ever-increasing costs. Despite licensing for long-term use, optimal treatment duration is unknown. We challenge the need for long-term treatment duration, using evidence from melanoma research, both published and in process.
وصف الملف: text/xml; application/pdf
الإتاحة: https://doi.org/10.17863/CAM.57452Test
https://www.repository.cam.ac.uk/handle/1810/310358Test
