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Purpose: Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers.Experimental Design: Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m2, day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 109, 1 × 1010, and 3 × 1010 TCID50 in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 1010 TCID50 dose characterized the response rate in patients with head and neck cancer.Results: Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D.Conclusions: The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment. Clin Cancer Res; 18(7); 2080–9. ©2012 AACR.

The omicron (B.1.1.529) variant of SARS-CoV-2 is highly transmissible and escapes vaccine-induced immunity. We aimed to describe outcomes due to COVID-19 during the omicron outbreak compared with the prevaccination period and alpha (B.1.1.7) and delta (B.1.617.2) waves in patients with cancer in Europe.In this retrospective analysis of the multicentre OnCovid Registry study, we recruited patients aged 18 years or older with laboratory-confirmed diagnosis of SARS-CoV-2, who had a history of solid or haematological malignancy that was either active or in remission. Patient were recruited from 37 oncology centres from UK, Italy, Spain, France, Belgium, and Germany. Participants were followed up from COVID-19 diagnosis until death or loss to follow-up, while being treated as per standard of care. For this analysis, we excluded data from centres that did not actively enter new data after March 1, 2021 (in France, Germany, and Belgium). We compared measures of COVID-19 morbidity, which were complications from COVID-19, hospitalisation due to COVID-19, and requirement of supplemental oxygen and COVID-19-specific therapies, and COVID-19 mortality across three time periods designated as the prevaccination (Feb 27 to Nov 30, 2020), alpha-delta (Dec 1, 2020, to Dec 14, 2021), and omicron (Dec 15, 2021, to Jan 31, 2022) phases. We assessed all-cause case-fatality rates at 14 days and 28 days after diagnosis of COVID-19 overall and in unvaccinated and fully vaccinated patients and in those who received a booster dose, after adjusting for country of origin, sex, age, comorbidities, tumour type, stage, and status, and receipt of systemic anti-cancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974, and is ongoing.As of Feb 4, 2022 (database lock), the registry included 3820 patients who had been diagnosed with COVID-19 between Feb 27, 2020, and Jan 31, 2022. 3473 patients were eligible for inclusion (1640 [47·4%] were women and 1822 [52·6%] were men, with a median age of 68 years [IQR 57-77]). 2033 (58·5%) of 3473 were diagnosed during the prevaccination phase, 1075 (31·0%) during the alpha-delta phase, and 365 (10·5%) during the omicron phase. Among patients diagnosed during the omicron phase, 113 (33·3%) of 339 were fully vaccinated and 165 (48·7%) were boosted, whereas among those diagnosed during the alpha-delta phase, 152 (16·6%) of 915 were fully vaccinated and 21 (2·3%) were boosted. Compared with patients diagnosed during the prevaccination period, those who were diagnosed during the omicron phase had lower case-fatality rates at 14 days (adjusted odds ratio [OR] 0·32 [95% CI 0·19-0·61) and 28 days (0·34 [0·16-0·79]), complications due to COVID-19 (0·26 [0·17-0·46]), and hospitalisation due to COVID-19 (0·17 [0·09-0·32]), and had less requirements for COVID-19-specific therapy (0·22 [0·15-0·34]) and oxygen therapy (0·24 [0·14-0·43]) than did those diagnosed during the alpha-delta phase. Unvaccinated patients diagnosed during the omicron phase had similar crude case-fatality rates at 14 days (ten [25%] of 40 patients vs 114 [17%] of 656) and at 28 days (11 [27%] of 40 vs 184 [28%] of 656) and similar rates of hospitalisation due to COVID-19 (18 [43%] of 42 vs 266 [41%] of 652) and complications from COVID-19 (13 [31%] of 42 vs 237 [36%] of 659) as those diagnosed during the alpha-delta phase.Despite time-dependent improvements in outcomes reported in the omicron phase compared with the earlier phases of the pandemic, patients with cancer remain highly susceptible to SARS-CoV-2 if they are not vaccinated against SARS-CoV-2. Our findings support universal vaccination of patients with cancer as a protective measure against morbidity and mortality from COVID-19.National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust.

Background: The medium-term and long-term impact of COVID-19 in patients with cancer is not yet known. In this study, we aimed to describe the prevalence of COVID-19 sequelae and their impact on the survival of patients with cancer. We also aimed to describe patterns of resumption and modifications of systemic anti-cancer therapy following recovery from SARS-CoV-2 infection. Methods: OnCovid is an active European registry study enrolling consecutive patients aged 18 years or older with a history of solid or haematological malignancy and who had a diagnosis of RT-PCR confirmed SARS-CoV-2 infection. For this retrospective study, patients were enrolled from 35 institutions across Belgium, France, Germany, Italy, Spain, and the UK. Patients who were diagnosed with SARS-CoV-2 infection between Feb 27, 2020, and Feb 14, 2021, and entered into the registry at the point of data lock (March 1, 2021), were eligible for analysis. The present analysis was focused on COVID-19 survivors who underwent clinical reassessment at each participating institution. We documented prevalence of COVID-19 sequelae and described factors associated with their development and their association with post-COVID-19 survival, which was defined as the interval from post-COVID-19 reassessment to the patients’ death or last follow-up. We also evaluated resumption of systemic anti-cancer therapy in patients treated within 4 weeks of COVID-19 diagnosis. The OnCovid study is registered in ClinicalTrials.gov, NCT04393974. Findings: 2795 patients diagnosed with SARS-CoV-2 infection between Feb 27, 2020, and Feb 14, 2021, were entered into the study by the time of the data lock on March 1, 2021. After the exclusion of ineligible patients, the final study population consisted of 2634 patients. 1557 COVID-19 survivors underwent a formal clinical reassessment after a median of 22·1 months (IQR 8·4–57·8) from cancer diagnosis and 44 days (28–329) from COVID-19 diagnosis. 234 (15·0%) patients reported COVID-19 sequelae, including respiratory symptoms (116 [49·6%]) and residual fatigue (96 [41·0%]). Sequelae were more common in men (vs women; p=0·041), patients aged 65 years or older (vs other age groups; p=0·048), patients with two or more comorbidities (vs one or none; p=0·0006), and patients with a history of smoking (vs no smoking history; p=0·0004). Sequelae were associated with hospitalisation for COVID-19 (p

Sensory perception in natural environments involves the dual challenge to encode external stimuli and manage the influence of changes in body position that alter the sensory field. To examine mechanisms used to integrate sensory signals elicited by both external stimuli and motor activity, we trained rats to perform an active search task with a single vibrissa. We recorded neuronal activity in primary somatosensory cortex, along with vibrissa position and touch signals, as rats rhythmically swept their vibrissa in search of a target. A majority of neurons respond to touch and, critically, ̃20 % are transiently excited only when contact occurs at a cell- specific phase in the whisk cycle. This response arises from a nonlinear interaction, consistent with gating by shunting synaptic inhibition, between vibrissa touch and a motion-derived signal that dynamically labels each neuron with a preferred phase. The observed response is likely to underlie estimation of object position in a head-centered reference frame as rodents search for vibrisso-tactile targets. More generally, our results delineate a computation that is likely to occur in all active sensorimotor systems

Background. Systemic inflammation is a pathogenic mechanism shared by infection and cancer. Mortality from Covid-19 is strongly linked to systemic cytokine excess. We investigated systemic inflammation as a driver of Covid-19 severity in patients with Covid-19 and cancer. Methods. Between 27/02 and 23/06/2020, OnCovid retrospectively accrued 1,318 consecutive European cancer patients with Covid-19. Patients with myeloma, leukemia, or insufficient data were excluded. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), prognostic nutritional index (PNI), modified Glasgow prognostic score (mGPS), and prognostic index (PI) were evaluated for their prognostic potential, with the NLR, PLR, and PNI risk stratifications dichotomized around median values, and the pre-established risk categorizations from literature utilized for the mGPS and PI. Results. 1,071 eligible patients were randomly assorted into a training set (TS, n=529) and validation set (VS, n=542) matched for age (67.9±13.3 TS, 68.5±13.5 VS), presence of >1 comorbidity (52.1% TS, 49.8% VS), development of >1 Covid-19 complication (27% TS, 25.9% VS), and active malignancy at Covid-19 diagnosis (66.7% TS, 61.6% VS). Among all 1,071 patients, deceased patients tended to categorize into poor risk groups for the NLR, PNI, mGPS, and PI (P6 (44.6% vs 28%, P6 30 days 95%CI 1-63, PNI Conclusion. Systemic inflammation drives mortality from Covid-19. Hypoalbuminemia and lymphocytopenia as measured by the PNI are the most accurate predictors of outcome and enable repurposing of the PNI as the OnCovid Inflammatory Score (OIS) as a readily available biomarker of severity. Citation Format: Gino M. Dettorre, Saoirse Dolly, Angela Loizidou, John Chester, Amanda Jackson, Uma Mukherjee, Alberto Zambelli, Juan Aguilar-Company, Mark Bower, Christopher C. Sng, Ramon Salazar, Alexia Bertuzzi, Joan Brunet, Ricard Mesia, Ailsa Sita-Lumsden, Elia Seguí, Federica Biello, Daniele Generali, Salvatore Grisanti, Pavetha Seeva, Gianpiero Rizzo, Michela Libertini, Antonio Maconi, Charlotte Moss, Josep Tabernero, Beth Russell, Nadia Harbeck, Bruno Vincenzi, Rossella Bertulli, Diego Ottaviani, Raquel Liñan, Andrea Marrari, M. Carmen Carmona-García, Neha Chopra, Carlo Tondini, Oriol Mirallas, Valeria Tovazzi, Vittoria Fotia, Claudia Andrea Cruz, Nadia Saoudi-Gonzalez, Eudald Felip, Ariadna Roqué, Alvin J. Lee, Thomas Newsom-Davis, Andrea Patriarca, Lorenza Rimassa, Armando Santoro, Alessandra Gennari, Nikolaos Diamantis, David J. Pinato. The acute phase response identifies cancer patients with adverse outcomes from SARS-CoV-2 infection as quantified by the OnCovid Inflammatory Score [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 701.

This study was supported by Cancer Research UK, AstraZeneca and Pfizer UK. Introduction: Phase I of the Cancer Research UK Stratified Medicine Programme (SMP1) was designed to roll out molecular pathology testing nationwide at the point of cancer diagnosis, as well as facilitate an infrastructure where surplus cancer tissue could be used for research. It offered a non-trial setting to examine common UK cancer genetics in a real-world context. Methods: A total of 26 sites in England, Wales and Scotland, recruited samples from 7814 patients for genetic examination between 2011 and 2013. Tumour types involved were breast, colorectal, lung, prostate, ovarian cancer and malignant melanoma. Centralised molecular testing of surplus material from resections or biopsies of primary/metastatic tissue was performed, with samples examined for 3-5 genetic alterations deemed to be of key interest in site-specific cancers by the National Cancer Research Institute Clinical Study groups. Results: 10 754 patients (98% of those approached) consented to participate, from which 7814 tumour samples were genetically analysed. In total, 53% had at least one genetic aberration detected. From 1885 patients with lung cancer, KRAS mutation was noted to be highly prevalent in adenocarcinoma (37%). In breast cancer (1873 patients), there was a striking contrast in TP53 mutation incidence between patients with ductal cancer (27.3%) and lobular cancer (3.4%). Vast inter-tumour heterogeneity of colorectal cancer (1550 patients) was observed, including myriad double and triple combinations of genetic aberrations. Significant losses of important clinical information included smoking status in lung cancer and loss of distinction between low-grade and high-grade serous ovarian cancers. Conclusion: Nationwide molecular pathology testing in a non-trial setting is feasible. The experience with SMP1 has been used to inform ongoing CRUK flagship programmes such as the CRUK National Lung MATRIX trial and TRACERx. Publisher PDF

Objectives To explore how the concept of randomization is described by clinicians and understood by patients in randomized controlled trials (RCTs) and how it contributes to patient understanding and recruitment. Study Design and Setting Qualitative analysis of 73 audio recordings of recruitment consultations from five, multicenter, UK-based RCTs with identified or anticipated recruitment difficulties. Results One in 10 appointments did not include any mention of randomization. Most included a description of the method or process of allocation. Descriptions often made reference to gambling-related metaphors or similes, or referred to allocation by a computer. Where reference was made to a computer, some patients assumed that they would receive the treatment that was “best for them”. Descriptions of the rationale for randomization were rarely present and often only came about as a consequence of patients questioning the reason for a random allocation. Conclusions The methods and processes of randomization were usually described by recruiters, but often without clarity, which could lead to patient misunderstanding. The rationale for randomization was rarely mentioned. Recruiters should avoid problematic gambling metaphors and illusions of agency in their explanations and instead focus on clearer descriptions of the rationale and method of randomization to ensure patients are better informed about randomization and RCT participation., Highlights • Practices commonly used to describe randomisation in RCT recruitment could confuse patients. • Patients found it difficult to comprehend gambling-related metaphors of randomisation. • Computer-agency descriptions led to patients believing they would receive the best treatment.

Reciprocal interactions between cancers and the surrounding microenvironment have an important role in tumour evolution. In this study, our data suggested that through thrombospondin 1 (TSP1), tumour-associated microvessel provides a dormant niche to sustain inactive status of breast invasive ductal carcinoma (IDC) cells. TSP1 levels in the tumour stroma were negatively correlated with vascular indoleamine 2,3-dioxygenase 1 (IDO1) in IDC tissues. IDO1 is an intracellular enzyme initiating the first and rate-limited step of tryptophan breakdown. Lower stromal TSP1 levels and positive tumour vascular IDO1 staining seems to associate with poor survive of patients with IDC. IDC cells induced a significantly increase in IDO1 expression in endothelial cells (ECs). IFNγ exerts a similar effect on ECs. We hypothesized a tryptophan starvation theory that since tryptophan is essential for the synthesis of TSP1, IDO1 induce a decrease in tryptophan availability and a reduction in TSP1 synthesis in ECs, leading to overcoming the dormancy state of IDC cells and exacerbating conditions such as tumour invasion and metastasis. These findings identify a non-canonical role of IFNγ/IDO1/TSP1 axis in microvascular niche-dominated dormancy of breast invasive ductal carcinoma with a solid foundation for further investigation of therapeutic and prognostic relevance.

This study investigated the development of time concepts, comparing children of Afro-American and Anglo-American ethnic groups with each other and with results obtained by Piaget. A sample of 120 children aged seven, nine, and eleven years from one school were individually administered four time conservation tests (two on simultaneity and two on order of events). No significant relationships were found between seven, nine and eleven-year-old Afro-American and Anglo-American children in their performance on these four tests. With the exception of one group, all age levels were considered to be nonconservers by the Piaget 75 percent criterion, but conservation appeared to increase with age. (Author/MM)

Transitional cell carcinoma (TCC) of the bladder is the commonest malignancy affecting the urothelium. Muscle-invasive TCC is a life-threatening, but potentially curable, cancer which presents significant challenges for the uro-oncological multidisciplinary team. Treatment options for localized muscle-invasive bladder cancer are evolving. There is solid trial-based evidence for the use of neoadjuvant systemic therapy, prior to radical treatment, with curative intent; the use of adjuvant chemotherapy is less well established. Systemic therapy treatment decisions are complicated by disease-related complications and co-morbidities, especially impaired renal function. This chapter explores a typical bladder cancer patient journey, from presentation with a new diagnosis of muscle-invasive disease to the failure of first-line palliative chemotherapy. The chapter illustrates potential problems that can arise in routine clinical practice, suggests some solutions to commonly encountered difficulties, and reviews the evidence base for the range of treatment approaches.

High-level systemic delivery of viral vectors to tumors has proved problematic as a result of immune neutralization, nonspecific adhesion, and clearance of circulating viral particles. Some cell types localize to tumors in response to particular biological properties associated with tumor growth. Their use to deliver viral vectors to tumors would allow precious viral stocks to be protected until they can be released at high local concentrations. Here, we describe a mechanism by which retroviral vector production by T cells can be regulated by a tumor-specific trigger through engagement of a chimeric immune receptor (CIR) with its target antigen. The virus that is released from the T cells can also be transcriptionally targeted. Finally, we show that it is possible to use vector-loaded, antigen-triggered human T cells as therapeutic, tumor-specific vector delivery cells in models of both local intratumoral and systemic delivery to both lung and liver metastases. This strategy incorporates multiple levels of targeting into the delivery system at the stages of surface targeting, viral production, and gene expression.

We aimed to use cell-based carriers to direct vector production to target sites for systemic therapy. We used T cells engineered to express a chimeric T cell receptor that can specifically recognize target cells expressing the tumor-associated carcinoembryonic antigen (CEA). These T cells were modified to produce a retrovirus under tight pharmacological control using the rapamycin-inducible transcriptional regulatory system. The retroviral vectors produced were transcriptionally targeted to CEA-expressing target cells. We found that vector production and transgene expression from these T cells in vitro was dependent on pharmacological induction and expression of CEA in target cells, respectively. Mice bearing metastatic tumors that received cell carriers delivering the HSVtk gene demonstrated a significant increase in survival, but only in response to pharmacological induction of vector production. Interestingly, the therapeutic effect required the presence of the tumor-specific chimeric receptor on T cells. Further studies demonstrated that systemic delivery of tumor-specific T cells to mice bearing metastatic tumors caused recruitment of nonspecific T cells to the tumor site. We hypothesize that this enhanced targeting to tumor sites is responsible for the efficiency of T cell-mediated retroviral gene transfer and that this principle can be used to enhance systemic therapies using immune-cell carriers.

The present work is concerned with descriptions of acoustic wave behaviour in the presence of rigid boundaries. The unifying theme of this work is the application of Green’s function techniques to a selection of duct and cavity problems in acoustics. Although the central theme of this thesis is theoretical, experiments are also performed to test the validity of the theory. The thesis covers two basic areas: the diffraction of sound in cylindrical pipes fitted with flanges and orifice plates; and the inverse acoustics of rigid rectangular cavities. The diffraction of sound from flanged cylindrical waveguides is a classical problem in acoustics. Chapter 2 deals with the initial work on this subject. In this chapter, non—dissipative, inviscid, linear wave theory is compared with experiment and some of the mathematical formulations of this problem by previous authors are unified. A central problem with the ‘classical’ theory is the prediction of velocity singularities at sharp edges. In Chapter 3, the diffraction of sound is considered in a cylindrical duct with a thin orifice plate blockage, in the presence of a mean flow. Viscosity in the fluid produces vorticity, the strength of which may be determined by the requirement that the fluid velocity at the orifice rim be finite. Theoretical analysis is performed based on this principle. Numerical calculations are made for various physical parameters and an experiment is performed to test the predictions of the theory. Chapter 4 deals with inverse wave problems in a rigid rectangular, two dimensional cavity. The primary emphasis of this chapter is on reconstructing a spatially incoherent random source within a rigid rectangular cavity by pressure measurements on the cavity walls. The related problem of reconstructing a deterministic point source under these conditions is also addressed. Two other formalisms are derived. Again, they are both set in a rigid rectangular cavity. The first of these is a method for iteratively reconstructing a source profile. The second formalism concerns the problem of reconstructing a rigid scatterer under the restriction of the first Born approximation.

The services of vascular specialists are in demand to treat common vascular emergencies—patients with acute ischaemia of the limbs and leaking aortic aneurysms.1 2 3 4 The management of these problems has become increasingly complex, often involving a team approach with specialists in interventional vascular radiology.1 General surgeons who do not perform elective arterial surgery have become concerned about dealing with difficult vascular emergencies because clinical governance will no longer support surgeons practising outside their normal sphere of work. The public expects treatment by specialists, and in vascular emergencies this is justified by outcome data.1 2 3 4 Unfortunately, there are not enough vascular surgeons to provide formal emergency rotas in most hospitals, and the number required would far exceed those needed to do the elective vascular work. Many vascular surgeons have provided informal emergency cover at the expense of their family lives—some have made themselves available “one in two” or …