Now showing items 21-40 of 11502

    • Brain microenvironment-driven resistance to immune and targeted therapies in acral melanoma

      Lee, Rebecca J; Khandelwal, Garima; Baenke, Franziska; Cannistraci, Alessio; Macleod, K.; Mundra, Piyushkumar; Ashton, Garry; Mandal, Amit; Viros, Amaya; Gremel, Gabriela; et al. (2020)
      Background: Combination treatments targeting the MEK-ERK pathway and checkpoint inhibitors have improved overall survival in melanoma. Resistance to treatment especially in the brain remains challenging, and rare disease subtypes such as acral melanoma are not typically included in trials. Here we present analyses from longitudinal sampling of a patient with metastatic acral melanoma that became resistant to successive immune and targeted therapies. Methods: We performed whole-exome sequencing and RNA sequencing on an acral melanoma that progressed on successive immune (nivolumab) and targeted (dabrafenib) therapy in the brain to identify resistance mechanisms. In addition, we performed growth inhibition assays, reverse phase protein arrays and immunoblotting on patient-derived cell lines using dabrafenib in the presence or absence of cerebrospinal fluid (CSF) in vitro. Patient-derived xenografts were also developed to analyse response to dabrafenib. Results: Immune escape following checkpoint blockade was not due to loss of tumour cell recognition by the immune system or low neoantigen burden, but was associated with distinct changes in the microenvironment. Similarly, resistance to targeted therapy was not associated with acquired mutations but upregulation of the AKT/phospho-inositide 3-kinase pathway in the presence of CSF. Conclusion: Heterogeneous tumour interactions within the brain microenvironment enable progression on immune and targeted therapies and should be targeted in salvage treatments. Keywords: acral melanoma; brain metastasis; immune therapy; targeted therapy.
    • Mechanisms of drug resistance mediated by long non-coding RNAs in non-small-cell lung cancer

      La Montagna, Manuela; Ginn, Lucy; Garofalo, Michela; Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Manchester, SK10 4TG, UK. (2020)
      Non-small-cell lung cancer (NSCLC) is the most prevalent form of lung cancer and has a poor five-year survival rate of 15%. Chemotherapy and targeted therapies have significantly improved patients' prognosis. Nevertheless, after a successful initial response, some patients relapse when cancer cells become resistant to drug treatments, representing an important clinical limitation. Therefore, investigating the mechanisms of drug resistance is of significant importance. Recently, considerable attention has been given to long non-coding RNAs (lncRNAs), a heterogeneous class of regulatory molecules that play essential roles in tumorigenesis by modulating genes and signalling pathways involved in cell growth, metastasis and drug response. In this article, we review recent research findings on the role of lncRNAs in drug resistance in NSCLC, highlighting their mechanisms of action.
    • Breast cancer management guidelines during COVID-19 pandemic

      Manoj Gowda, S.; Kabeer, K. K.; Jafferbhoy, S.; Marla, S.; Soumian, S.; Misra, Vivek; Narayanan, S.; Brunt, A. M.; Department of Breast Surgery, University Hospitals of North Midlands, Stoke-on-Trent, UK. (2020)
      The coronavirus disease (COVID-19) pandemic in 2020 has brought about complex challenges in healthcare delivery. With the new rules of lockdown and social distancing and with resources diverted to the management of COVID-19, there are difficulties in continuing usual cancer care. Patients are at risk of contracting COVID-19 with a high chance of patient to healthcare transmission and vice versa. Hospital visits, investigations and all modalities of treatment have potential complications that put patients at risk, some more than others. In this situation, there is a need to change our approach in the management of breast cancer to deliver it safely. We present modified guidelines based on the available consensus statements and evidence. Keywords: Breast cancer; Breast surgery; COVID-19; Chemotherapy; Radiotherapy.
    • Surgical and radiotherapeutic management of malignant extradural spinal cord compression

      Loblaw, A.; George, K. J.; Misra, Vivek; Sunnybrook Health Sciences Centre, Toronto, Canada. (2020)
      Malignant spinal cord compression is one of the most dreaded complications of advanced malignancy, with patients presenting with progressive paralysis, paresthesia and/or autonomic dysfunction. The choice of management should be guided by the expected prognosis and outcome, not just from a neurological function point-of-view but also from the metastatic cancer itself. The main indications for surgery are: impending cord compression, spinal instability from tumour progression, bony retropulsion, for tissue diagnosis and for pain resistant to conventional therapies. Here, surgical principles, traditional and novel techniques and complications will be reviewed. For radiotherapy, multiple randomised studies have shown that for most patients a single fraction of external radiation has the same functional outcomes compared with multi-fractionation protocols. The experience of a specialised centralised interdisciplinary team will also be discussed. Keywords: Quality of life; radiation; spinal cord compression; surgery; toxicity.
    • COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study

      Lee, L. Y. W.; Cazier, J. B.; Starkey, T.; Briggs, S. E. W.; Arnold, R.; Bisht, V.; Booth, S.; Campton, N. A.; Cheng, V. W. T.; Collins, G.; et al. (2020)
      Background: Patients with cancer are purported to have poor COVID-19 outcomes. However, cancer is a heterogeneous group of diseases, encompassing a spectrum of tumour subtypes. The aim of this study was to investigate COVID-19 risk according to tumour subtype and patient demographics in patients with cancer in the UK. Methods: We compared adult patients with cancer enrolled in the UK Coronavirus Cancer Monitoring Project (UKCCMP) cohort between March 18 and May 8, 2020, with a parallel non-COVID-19 UK cancer control population from the UK Office for National Statistics (2017 data). The primary outcome of the study was the effect of primary tumour subtype, age, and sex and on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevalence and the case-fatality rate during hospital admission. We analysed the effect of tumour subtype and patient demographics (age and sex) on prevalence and mortality from COVID-19 using univariable and multivariable models. Findings: 319 (30�6%) of 1044 patients in the UKCCMP cohort died, 295 (92�5%) of whom had a cause of death recorded as due to COVID-19. The all-cause case-fatality rate in patients with cancer after SARS-CoV-2 infection was significantly associated with increasing age, rising from 0�10 in patients aged 40-49 years to 0�48 in those aged 80 years and older. Patients with haematological malignancies (leukaemia, lymphoma, and myeloma) had a more severe COVID-19 trajectory compared with patients with solid organ tumours (odds ratio [OR] 1�57, 95% CI 1�15-2�15; p<0�0043). Compared with the rest of the UKCCMP cohort, patients with leukaemia showed a significantly increased case-fatality rate (2�25, 1�13-4�57; p=0�023). After correction for age and sex, patients with haematological malignancies who had recent chemotherapy had an increased risk of death during COVID-19-associated hospital admission (OR 2�09, 95% CI 1�09-4�08; p=0�028). Interpretation: Patients with cancer with different tumour types have differing susceptibility to SARS-CoV-2 infection and COVID-19 phenotypes. We generated individualised risk tables for patients with cancer, considering age, sex, and tumour subtype. Our results could be useful to assist physicians in informed risk-benefit discussions to explain COVID-19 risk and enable an evidenced-based approach to national social isolation policies.
    • Impact of high tumor mutational burden in solid tumors and challenges for biomarker application

      McNamara, Mairead G; Jacobs, Timothy; Lamarca, Angela; Hubner, Richard A; Valle, Juan W; Amir, E.; Division of Cancer Sciences, University of Manchester/Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom. (2020)
      Accurate identification of patients with solid tumors likely to respond to immunotherapy is crucial. Tumor mutational burden (TMB) measures the number of somatic mutations in a tumor and is an emerging prognostic and predictive biomarker for anti-programmed cell death (PD) 1/anti-PD-ligand 1 therapy and other immunotherapeutic agents. Tumor mutational burden is assessed optimally by whole exome sequencing, but next generation sequencing provides TMB estimates in a more timely and cost-effective manner. Blood-based measurement of TMB in plasma offers an alternative to the need for adequate tumor tissue for molecular testing, and has demonstrated the ability to identify patients who derive benefit from immunotherapy. Tumor mutational burden has diverse prognostic impact in different solid tumor types and also has a demonstrated role in predicting improved survival in patients receiving immunotherapy. There are challenges to TMB adoption into standard clinical practice, including variations in its definition, with the mutational number defining TMB-high appearing to vary across cancer types. The magnitude of TMB also varies across different tumor types, with the highest levels reported in melanoma and other skin cancers (where ultraviolet light is the dominant mutational process), followed by non-small cell lung cancer and other squamous carcinomas. Concerns regarding inter-laboratory and inter-platform variations in analysis methods have been raised, highlighting the need for standardization. Integration of other genomic or pathological biomarkers with TMB may increase its prognostic and predictive capabilities and validation of individual or combination models in prospective trials is warranted. Keywords: Biomarkers; Immune checkpoint blockade; Next-generation sequencing; Predictive; Prognostic; Tumor mutational burden.
    • Alternative enhancer usage and targeted polycomb marking hallmark promoter choice during t cell differentiation

      Maqbool, M. A.; Pioger, L.; El Aabidine, A. Z.; Karasu, N.; Molitor, A. M.; Dao, L. T. M.; Charbonnier, G.; van Laethem, F.; Fenouil, R.; Koch, F.; et al. (2020)
      During thymic development and upon peripheral activation, T cells undergo extensive phenotypic and functional changes coordinated by lineage-specific developmental programs. To characterize the regulatory landscape controlling T cell identity, we perform a wide epigenomic and transcriptional analysis of mouse thymocytes and naive CD4 differentiated T helper cells. Our investigations reveal a dynamic putative enhancer landscape, and we could validate many of the enhancers using the high-throughput CapStarr sequencing (CapStarr-seq) approach. We find that genes using multiple promoters display increased enhancer usage, suggesting that apparent "enhancer redundancy" might relate to isoform selection. Furthermore, we can show that two Runx3 promoters display long-range interactions with specific enhancers. Finally, our analyses suggest a novel function for the PRC2 complex in the control of alternative promoter usage. Altogether, our study has allowed for the mapping of an exhaustive set of active enhancers and provides new insights into their function and that of PRC2 in controlling promoter choice during T cell differentiation. Keywords: CapSTARR-seq; T cell enhancerome; enhancer and promoter usage; enhancer redundancy; long-distance enhancer-promoter interactions.
    • Fibrolamellar carcinoma: Challenging the challenge

      Lamarca, Angela; Frizziero, Melissa; Fulton, Alexander; McNamara, Mairead G; Filobbos, R.; Hubner, Richard A; Wardell, Steve; Valle, Juan W; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom; Division Cancer Sciences, University of Manchester; Manchester, United Kingdom. (2020)
      Fibrolamellar carcinoma (FLC) is a rare and poorly understood malignancy, which seems to be more prevalent in young patients compared with conventional hepatocellular carcinoma (HCC). Performing prospective clinical trials recruiting patients diagnosed with FLC has proven challenging with scarce data available guiding clinical management. The use of a number of chemotherapy compounds in these patients, including cisplatin, epirubicin, 5-fluorouracil (5-FU) and recombinant interferon ?-2B (IFN-?-2B), has been reported in the literature, mainly in the form of case reports. The most promising systemic therapy tested so far is the combination of 5-FU infusion and 3-weekly IFN-?-2B, based on results from a phase II clinical trial. This article provides an overview of our own experience with this treatment schedule for patients with FLC, confirming its activity and treatment-derived benefit in the real world. Current challenges being faced by healthcare professionals treating patients with advanced FLC are discussed, especially the increasingly limited access to IFN-?-2B, which could compromise the access to an active therapy in the coming future, and the difficulties in the development of new treatment options for advanced FLC. Keywords: 5-FU; 5-fluorouracil treatment; Advanced; Chemotherapy; FLC; Fibrolamellar carcinoma; IFN; Interferon; Systemic therapy.
    • Obesity: A critical risk factor in the COVID-19 pandemic

      Kwok, S.; Adam, Safwaan; Ho, J. H.; Iqbal, Z.; Turkington, P.; Razvi, S.; Le Roux, C. W.; Soran, H.; Syed, A. A.; Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, UK. (2020)
      Obesity is an emerging independent risk factor for susceptibility to and severity of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Previous viral pandemics have shown that obesity, particularly severe obesity (BMI > 40 kg/m2 ), is associated with increased risk of hospitalization, critical care admission and fatalities. In this narrative review, we examine emerging evidence of the influence of obesity on COVID-19, the challenges to clinical management from pulmonary, endocrine and immune dysfunctions in individuals with obesity and identify potential areas for further research. We recommend that people with severe obesity be deemed a vulnerable group for COVID-19; clinical trials of pharmacotherapeutics, immunotherapies and vaccination should prioritize inclusion of people with obesity.
    • Epidemiological and clinical characteristics of coronavirus disease (COVID-19) cases at a screening clinic during the early outbreak period: a single-centre study

      Khan, M.; Khan, H.; Khan, S.; Nawaz, Maimoona; Department of Pathology, Rehman Medical Institute Peshawar, Pakistan. (2020)
      Introduction. Coronavirus disease 2019 (COVID-19) is an infectious disease caused by Severe Acute Respiratory Corona Virus-2 (SARS-CoV-2). The disease was first identified in December 2019 in Wuhan, the capital of China's Hubei province, and has since spread globally, resulting in the ongoing 2019-2020 corona virus pandemic. SARS-CoV-2 is closely related to the original SARS-CoV. It is thought to have a zoonotic origin. The virus is primarily spread between people during close contact, often via small droplets produced by coughing, sneezing or talking. People may also become infected by touching a contaminated surface and then touching their face. COVID-19 patients currently remain the primary source of infection. An epidemiological survey indicated that the general population is susceptible to SARS-CoV-2. The spectrum of this disease ranges from mild to life-threatening. Fever is the most common symptom, although older people and those with comorbidities may experience fever later in the disease. Other common symptoms include cough, loss of appetite, fatigue, shortness of breath, sputum production, and muscle and joint pains. Symptoms such as nausea, vomiting and diarrhea have been observed in varying percentages. Some cases might progress promptly to acute respiratory distress syndrome (ARDS) and/or multiple organ function failure. Asymptomatic carriers and those in the incubation period may also be infectious.Aim. To determine the epidemiological and clinical characteristics of patients presenting with COVID-19 at the screening clinic of a tertiary care hospital in Peshawar, Pakistan.Methodology. In this descriptive study, we analysed data of patients presenting to a newly established Covid-19 screening clinic in Rehman Medical Institute. Anyone who reported with new onset fever and/or cough was tested for SARS-CoV-2 in the screening clinic. We documented and analysed demographic, epidemiological and clinical characteristics, which included age, sex, travel history, clinical features, comorbidities and laboratory data of patients confirmed by real-time reverse-transcription (RT)-PCR at Rehman Medical Institute, Peshawar, Pakistan from 15 March till 21 April 2020. Paired specimens of throat swabs and nasal swabs were obtained from 845 patients, ribonucleic acid (RNA) was extracted and tested for SARS-CoV-2 by the RT-PCR assay.Results. A total of 845 specimens were taken as described above. The positive rate for SARS-CoV-2 was about 14.3%. Male and older population had a significantly higher positive rate. Of the 121 patients infected with SARS-CoV-2, the mean age was 43.19 years (sd, 17.57) and the infections were more frequent among male gender accounting for 85 (70.25 %) patients. Common symptoms included fever (88 patients, 72 %), cough (72 patients, 59.5 %) and shortness of breath (69 patients, 57 %). Twenty-two (18 %) patients had recent travel history outside Pakistan in the previous 14 days, the majority of whom had returned back from Saudi Arabia.Conclusion. In this single-centre, prospective, descriptive study, fever, cough and shortness of breath were the most common symptoms. Old age (>50 years), chronic underlying comorbidities and travel history may be risk factors. Therefore, we concluded that viral nucleic acid amplification tests (NAAT) played an important role in identifying SARS-CoV-2 infection in a screening clinic, which helped with isolation and cohorting of these patients.
    • Mitochondrial spongiotic brain disease: astrocytic stress and harmful rapamycin and ketosis effect

      Ignatenko, O.; Nikkanen, J.; Kononov, Alexander; Zamboni, N.; Ince-Dunn, G.; Suomalainen, A.; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland. (2020)
      Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is a group of severe, tissue-specific diseases of childhood with unknown pathogenesis. Brain-specific MDS manifests as devastating spongiotic encephalopathy with no curative therapy. Here, we report cell type-specific stress responses and effects of rapamycin treatment and ketogenic diet (KD) in mice with spongiotic encephalopathy mimicking human MDS, as these interventions were reported to improve some mitochondrial disease signs or symptoms. These mice with astrocyte-specific knockout of Twnk gene encoding replicative mtDNA helicase Twinkle (TwKOastro) show wide-spread cell-autonomous astrocyte activation and mitochondrial integrated stress response (ISRmt) induction with major metabolic remodeling of the brain. Mice with neuronal-specific TwKO show no ISRmt Both KD and rapamycin lead to rapid deterioration and weight loss of TwKOastro and premature trial termination. Although rapamycin had no robust effects on TwKOastro brain pathology, KD exacerbated spongiosis, gliosis, and ISRmt Our evidence emphasizes that mitochondrial disease treatments and stress responses are tissue- and disease specific. Furthermore, rapamycin and KD are deleterious in MDS-linked spongiotic encephalopathy, pointing to a crucial role of diet and metabolism for mitochondrial disease progression.
    • Carboplatin dose capping affects pCR rate in HER2-positive breast cancer patients treated with neoadjuvant Docetaxel, Carboplatin, Trastuzumab, Pertuzumab (TCHP)

      Howell, Sacha J; Coe, Faye; Wang, Xin; Horsley, Laura; Ekholm, Maria; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK. (2020)
      Purpose: Estimated glomerular filtration rate (eGFR) is commonly used to calculate carboplatin doses and capping the eGFR may be used to reduce the risk of excessive dosing and toxicity. We sought to retrospectively examine the impact of our carboplatin guidelines on pathological complete response rates (pCR) and toxicity in women with HER2+ breast cancer receiving neoadjuvant docetaxel, carboplatin, trastuzumab and pertuzumab (TCHP). Methods: The delivered area under the curve (dAUC) was calculated [(actual carboplatin dose at cycle 1 � dose calculated with uncapped/unbanded eGFR) � 6] and dichotomized at the median value. The impact of this and other clinical factors on pCR rate, dose intensity (DI) and toxicity was assessed. Results: 124 eligible patients were identified of whom 63.7% (79/124) achieved pCR. The median dAUC at cycle 1 was 5.75 mg � ml/min. Those with lower dAUC were more frequently younger and overweight/obese. Patients with lower dAUC had significantly inferior pCR rates of 54.8% (34/62) vs 72.6% (45/62), respectively (p = 0.040). Similar results were seen in the ER+ subgroup; 45.2% (19/42) vs 68.3% (28/41), p = 0.037%, whereas no significant difference was seen among ER- patients; 75.0% (15/20) vs 81.0% (17/21), p = 0.72. DI and toxicity were comparable between the two dAUC groups. Conclusions: The overall pCR rate was high in patients with HER2+ breast cancer receiving the TCHP regimen; however, carboplatin dose capping resulted in inferior pCR rates, particularly in the ER+ subgroup. To ensure optimal dosing, isotopic measurement of renal function is warranted in patients who would otherwise have their eGFR and dose capped. Keywords: Administration and dosing; Breast neoplasms; Carboplatin; Neoadjuvant therapy; Treatment outcome.
    • Radio-induced cardiotoxicity: From physiopathology and risk factors to adaptation of radiotherapy treatment planning and recommended cardiac follow-up

      Kirova, Y.; Tallet, A.; Aznar, Marianne Camille; Loap, P.; Bouali, A.; Bourgier, C.; Department of radiation oncology, institut Curie, 75005 Paris, France. (2020)
      Cancer and cardiovascular disease (CVD) are the leading cause of mortality worldwide, and breast cancer (BC) the most common malignancy affecting women worldwide. Radiotherapy is an important component of BC treatment and participates in CVD occurrence. It seems, therefore, crucial to gather both radiation oncology and cardiology medical fields to improve the follow-up quality of our BC patients. This review aims at updating our knowledge regarding cardiotoxicities risk factors, and consequently, doses constraints in case of 3D-conformal and IMRT treatment planning. Then we will develop how to reduce cardiac exposure and what kind of cardiac follow-up we could recommend to our breast cancer patients.
    • ESMO consensus conference recommendations on the management of metastatic melanoma: the ESMO Guidelines Committee

      Keilholz, U.; Ascierto, P. A.; Dummer, R.; Robert, C.; Lorigan, Paul C; van Akkooi, A.; Arance, A.; Blank, C. U.; Sileni, V. C.; Donia, M.; et al. (2020)
      The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment for brain metastases. The expert panel was divided into five working groups to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of metastatic melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.
    • Guidelines for management of urgent symptoms in patients with cholangiocarcinoma and biliary stents or catheters using the modified RAND/UCLA Delphi Process

      Iyer, R. V.; Acquisto, S. G.; Bridgewater, J. A.; Choti, M. A.; Hong, T. S.; Kis, B.; Mead, P. A.; Parikh, N. D.; Roberts, L. R.; Roberts, R.; et al. (2020)
      Background: Patients with cholangiocarcinoma often have indwelling biliary stents or catheters which are prone to obstructions and/or infections; studies show that 20-40% present with fever and/or jaundice requiring urgent treatment in the outpatient setting for which there are no uniform guidelines. The goal was to develop an expert panel consensus on this topic using the modified RAND/UCLA Delphi process to rate treatment appropriateness. Methods: Thirteen expert physicians from relevant specialties, geography, and practice settings were recruited for the panel. Patient scenarios were developed and panelists rated the therapies before and after a face-to-face discussion. The appropriateness of various therapies was rated on a scale from 1-9 and classified as appropriate, inappropriate, or uncertain. Scenarios with greater than 2 (>2) ratings of 1-3 (inappropriate) and greater than 2 (>2) ratings of 7-9 (appropriate) were considered to have disagreement and were not assigned an appropriateness rating. Results: Panelists were from all US regions and the UK (8%) and had practiced for a mean 16.5 years (4-33 years). Panelists rated 480 scenarios before the meeting and re-rated 288 of the clinical scenarios after the meeting. The panelists agreed that ongoing treatment with chemotherapy did not influence decision-making and, therefore, 192 scenarios were excluded from the final list. Disagreement decreased from 37.5% before to 10.4% after the meeting. Consensus on stent/tube manipulation and inpatient antibiotic therapy was obtained and summarized in patients as "appropriate" or "maybe appropriate" based on a patient's bilirubin level at presentation. Conclusions: The Delphi process produced consensus guidelines to fill an unmet need in the urgent management of ascending cholangitis in patients with cholangiocarcinoma.
    • Evaluation of drugs for potential repurposing against COVID-19 using a tier-based scoring system

      Jarvis, M. A.; Hansen, F. A.; Rosenke, K.; Haddock, E.; Rollinson, C.; Rule, S.; Sewell, G.; Hughes, Andrew; Feldmann, H.; University of Plymouth, Plymouth, Devon, UK. (2020)
      Background: As the Coronavirus Disease 2019 (COVID-19) pandemic grows daily, we remain with no prophylactic and only minimal therapeutic interventions to prevent or ameliorate severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). Prior to SARS-CoV-2 emergence, high throughput screens utilizing clinically developed drugs identified compounds with in vitro inhibitory effect on human coronaviruses that may have potential for repurposing as treatment options for COVID-19. However, caution should be applied to repurposing of these drugs when they are taken out of context of human pharmacokinetic parameters associated with normal therapeutic use. Methods: Our aim was to provide a tier-based scoring system to interrogate this data set and match each drug with its human pharmacokinetic criteria, such as route of administration, therapeutic plasma levels and half-life, tissue distribution, and safety. Results: Our analysis excluded most previously identified drugs but identified members of 4 drug classes (antimalarial amino-quinolones, selective estrogen receptor modulators; SERMs, low potency tricyclic antipsychotics and tricyclic antidepressants) as potential drug candidates for COVID-19. Two of them, the tricyclic antipsychotics and tricyclic antidepressants were further excluded based on a high adverse event profile. Conclusions: In summary, our findings using a new pharmacokinetic-based scoring system supports efficacy testing of only a minority of candidates against SARS-CoV-2 infection.
    • Melanoma risk in patients treated with biologic therapy for common inflammatory diseases a systematic review and meta-analysis

      Esse, S.; Mason, K. J.; Green, Ad�le C; Warren, R. B.; Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, United Kingdom. (2020)
      Importance: Biologic therapies are widely prescribed immunomodulatory agents. There are concerns that compared with treatment with conventional systemic therapy, long-term biologic treatment for common immune-mediated inflammatory diseases, namely inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and psoriasis, may be associated with increased risk of melanoma. Objective: To examine whether biologic treatment of IBD, RA, or psoriasis is associated with an increased risk of melanoma compared with conventional systemic therapy. Data sources: Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for articles published from January 1, 1995, to February 7, 2019, for eligible studies. Study selection: Randomized clinical trials, cohort studies, and nested case-control studies quantifying the risk of melanoma in biologic-treated patients with IBD, RA, and psoriasis compared with patients treated with conventional systemic therapy were included. Data extraction and synthesis: Two reviewers independently extracted key study characteristics and outcomes. Study-specific risk estimates were pooled, and random- and fixed-effects model meta-analyses were conducted. Heterogeneity was assessed using the I2 statistic. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines were followed. Main outcomes and measures: The pooled relative risk (pRR) of melanoma in biologic-treated patients with IBD, RA, and psoriasis compared with biologic-naive patients treated with conventional systemic therapy. Results: Seven cohort studies comprising 34 029 biologic-treated patients and 135 370 biologic-naive patients treated with conventional systemic therapy were eligible for inclusion. Biologic treatment was positively associated with melanoma in patients with IBD (pRR, 1.20; 95% CI, 0.60-2.40), RA (pRR, 1.20; 95% CI, 0.83-1.74), or psoriasis (hazard ratio, 1.57; 95% CI, 0.61-4.09) compared with those who received conventional systemic therapy, but the differences were not statistically significant. Adjustment for other risk factors was absent from most studies. Conclusions and relevance: The findings suggest that clinically important increases in melanoma risk in patients treated with biologic therapy for common inflammatory diseases cannot be ruled out based on current evidence. However, further studies with large patient numbers that adjust for key risk factors are needed to resolve the issue of long-term safety of biologic therapy.
    • Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of severe gastrointestinal and hepatic toxicities from checkpoint inhibitors

      Dougan, M.; Blidner, A. G.; Choi, J.; Cooksley, Timothy J; Glezerman, I.; Ginex, P.; Girotra, M.; Gupta, D.; Johnson, D.; Shannon, V. R.; et al. (2020)
      Immune-related adverse events (IrAEs) affecting the gastrointestinal (GI) tract and liver are among the most frequent and most severe inflammatory toxicities from contemporary immunotherapy. Inflammation of the colon and or small intestines (entero)colitis is the single most common GI IrAE and is an important cause of delay of discontinuation of immunotherapy. The severity of these GI IrAEs can range from manageable with symptomatic treatment alone to life-threatening complications, including perforation and liver failure. The frequency and severity of GI IrAEs is dependent on the specific immunotherapy given, with cytotoxic T lymphocyte antigen (CTLA)-4 blockade more likely to induce severe GI IrAEs than blockade of either programmed cell death protein 1 (PD-1) or PD-1 ligand (PD-L1), and combination therapy showing the highest rate of GI IrAEs, particularly in the liver. To date, we have minimal prospective data on the appropriate diagnosis and management of GI IrAEs, and recommendations are based largely on retrospective data and expert opinion. Although clinical diagnoses of GI IrAEs are common, biopsy is the gold standard for diagnosis of both immunotherapy-induced enterocolitis and hepatitis and can play an important role in excluding competing, though less common, diagnoses and ensuring optimal management. GI IrAEs typically respond to high-dose corticosteroids, though a significant fraction of patients requires secondary immune suppression. For colitis, both TNF-? blockade with infliximab and integrin inhibition with vedolizumab have proved highly effective in corticosteroid-refractory cases. Detailed guidelines have been published for the management of low-grade GI IrAEs. In the setting of more severe toxicities, involvement of a GI specialist is generally recommended. The purpose of this review is to survey the available literature and provide management recommendations focused on the GI specialist.
    • Invivo binding of recombination proteins to non-dsb DNA lesions and to replication forks

      Gonz�lez-Prieto, R.; Cabello-Lobato, Maria J; Prado, F.; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands. (2021)
      Homologous recombination (HR) has been extensively studied in response to DNA double-strand breaks (DSBs). In contrast, much less is known about how HR deals with DNA lesions other than DSBs (e.g., at single-stranded DNA) and replication forks, despite the fact that these DNA structures are associated with most spontaneous recombination events. A major handicap for studying the role of HR at non-DSB DNA lesions and replication forks is the difficulty of discriminating whether a recombination protein is associated with the non-DSB lesion per se or rather with a DSB generated during their processing. Here, we describe a method to follow the in vivo binding of recombination proteins to non-DSB DNA lesions and replication forks. This approach is based on the cleavage and subsequent electrophoretic analysis of the target DNA by the recombination protein fused to the micrococcal nuclease.
    • Problems following treatment for cancer: Building a picture and pathways for Manchester Cancer (UK) 2015-2018

      Higham, Claire E; Wilby, L.; O'Rourke, C.; Makin, Wendy; Christie Hospital NHS Foundation Trust, Manchester, (2019)
      Background: Greater Manchester Cancer (GMC) is the cancer program for Greater Manchester�s (GM) devolved health and social care system. 13 tumor-specific (TPB�s) and 7 cross-cutting (inc Living With and Beyond Cancer (LWBCPB)) pathway boards were formed to support this. Aims:The LWBCPB tasked the TPB�s to describe late consequences of treatment, define current care pathways/resources and highlight service gaps. Methods: Questionnaires were sent to all TPB�s. Returned questionnaires (11/13) from 2015-18 were analysed quantitatively (Excel) and qualitatively (Nvivo). Results: Frequent cross cutting long term effects were fatigue(9/11 TPB�s), psychological distress(7/11), sexual dysfunction(6/11), memory loss(5/11), neuropathy(5/11). Management strategies were described; eg, for fatigue; specific workshops(11/11), verbal +/- written advice(7/11), referral to other HCP(6/11). Tumour specific long term effects included a mix of clinical and psychosocial issues; with all TPB�s providing information to patients; only 6/11 to Primary Care. Limited evidence was given for active screening for long term effects. Resources offered included national websites, charities, local services and support groups. For specific clinical issues eg cardiac; referral was mainly to local services; despite identification of clinicians with an interest in LWBC offering specialist services within GM. Lack of resource was the commonly cited reason for absence of care pathways. Identified gaps in current approaches to management were; lack of access to specific resources(11/11) (psychology(7/11), specialist nurse(2/11), hospice care(2/11); inequity of access to resources(7/11); need for specific pathways and referral guidance(3/11). Conclusions: Long term consequences of cancer treatments are cross-cutting. GMC PB�s are an opportunity to use these baseline data to define and implement locally appropriate LWBC pathways including optimal referral, screening and communication with primary care.