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Purpose: To determine the safety and feasibility of combining intratumoral reovirus and radiotherapy in patients with advanced cancer and to assess viral biodistribution, reoviral replication in tumors, and antiviral immune responses.Experimental Design: Patients with measurable disease amenable to palliative radiotherapy were enrolled. In the first stage, patients received radiotherapy (20 Gy in five fractions) plus two intratumoral injections of RT3D at doses between 1 × 108 and 1 × 1010 TCID50. In the second stage, the radiotherapy dose was increased (36 Gy in 12 fractions) and patients received two, four, or six doses of RT3D at 1 × 1010 TCID50. End points were safety, viral replication, immunogenicity, and antitumoral activity.Results: Twenty-three patients with various solid tumors were treated. Dose-limiting toxicity was not seen. The most common toxicities were grade 2 (or lower) pyrexia, influenza-like symptoms, vomiting, asymptomatic lymphopenia, and neutropenia. There was no exacerbation of the acute radiation reaction. Reverse transcription-PCR (RT-PCR) studies of blood, urine, stool, and sputum were negative for viral shedding. In the low-dose (20 Gy in five fractions) radiation group, two of seven evaluable patients had a partial response and five had stable disease. In the high-dose (36 Gy in 12 fractions) radiation group, five of seven evaluable patients had partial response and two stable disease.Conclusions: The combination of intratumoral RT3D and radiotherapy was well tolerated. The favorable toxicity profile and lack of vector shedding means that this combination should be evaluated in newly diagnosed patients receiving radiotherapy with curative intent. Clin Cancer Res; 16(11); 3067–77. ©2010 AACR.

Supplementary Data from Two-Stage Phase I Dose-Escalation Study of Intratumoral Reovirus Type 3 Dearing and Palliative Radiotherapy in Patients with Advanced Cancers

Aims Botulinum Toxin A (BTA) is widely used in complex abdominal wall reconstruction (CAWR). It temporarily paralyses the oblique muscles allowing medialisation of the rectus sheath and decreases tension on the closure. This analysis presents the use of BTA in management of the ‘open abdomen’ (OA). Methods Retrospective series of patients with OA where BTA was used in conjunction with AbtheraTM negative pressure wound therapy (NPWT) and polypropylene mesh-mediated traction (MMT) to attempt fascial closure. BTA was performed by Anaesthetists with experience of BTA use in CAWR using Dysport® 600 IU. Results We include 5 patients since 2020. Median age at index operation was 55 years (range 39–81); four were male. Index operations were intra-abdominal catastrophe where fascia closure impossible (n=2), dehiscence after Vertical Rectus Abdominis Myocutaneous (VRAM) flap for pelvic malignancy (n=2) and colectomy for obstructing colorectal cancer complicated by rectus sheath necrotising fasciitis (n=1). There were no immediate complications from BTA infiltration. All patients achieved primary fascial closure with a median of five re-looks (range 3–7). There were no full-thickness dehiscences after final closure. One patient died within 1 month from unrelated cause. One patient had no clinically palpable incisional hernia at six months and a further two had no incisional hernia at six and 12 months, respectively, on cancer surveillance CT. Conclusion BTA in the setting of the OA in conjunction with NPWT and MMT appears safe and effective in achieving fascial closure, and can potentially reduce the risk of incisional hernia. Further studies are welcomed.

Aim Surgical site infections (SSIs) are associated with increased morbidity, hospital stay and cost. The literature reports that 25% of patients who undergo colorectal surgical procedures develop a SSI. Due to the enhanced recovery programme, patients are being discharged earlier with some SSIs presenting in primary care, making accurate recording of SSIs difficult. The aim of this study was to accurately record the 30-day SSI rate after surgery performed by colorectal surgeons nationally within Wales. Method During March 2019, a national prospective snapshot study of all patients undergoing elective or emergency colorectal and general surgical procedures under the care of a colorectal consultant at 12 Welsh hospitals was completed. There was a multimodal 30-day follow-up using electronic records, clinic visits and/or telephone calls. Diagnosis of SSI was based on Centers for Disease Control and Prevention diagnostic criteria. Results Within Wales, of the 545 patients included, 13% developed a SSI within 30 days, with SSI rates of 14.3% for elective surgery and 11.7% for emergency surgery. Of these SSIs, 49.3% were diagnosed in primary care, with 28.2% of patients being managed exclusively in the community. There were two peaks of diagnosis at days 5-7 and days 22-28. SSI rates between laparoscopic (8.6%) and open (16.2%) surgeries were significantly different (p = 0.028), and there was also a significantly different rate of SSI between procedure groups (p = 0.001), with high SSI rates for colon (22%) and rectal (18.9%) surgery compared with general surgical procedures. Conclusion This first all-Wales prospective study demonstrated an overall SSI rate of 13%. By incorporating accurate primary care follow-up it was found that 49.3% of these SSIs were diagnosed in primary care.

Older adults undergoing emergency abdominal surgery have significantly poorer outcomes than younger adults. For those who survive, the level of care required on discharge from hospital is unknown and such information could guide decision-making. The ELF (Emergency Laparotomy and Frailty) study aimed to determine whether preoperative frailty in older adults was associated with increased dependence at the time of discharge.The ELF study was a UK-wide multicentre prospective cohort study of older patients (65 years or more) undergoing emergency laparotomy during March and June 2017. The objective was to establish whether preoperative frailty was associated with increased care level at discharge compared with preoperative care level. The analysis used a multilevel logistic regression adjusted for preadmission frailty, patient age, sex and care level.A total of 934 patients were included from 49 hospitals. Mean(s.d.) age was 76·2(6·8) years, with 57·6 per cent women; 20·2 per cent were frail. Some 37·4 per cent of older adults had an increased care level at discharge. Increasing frailty was associated with increased discharge care level, with greater predictive power than age. The adjusted odds ratio for an increase in care level was 4·48 (95 per cent c.i. 2·03 to 9·91) for apparently vulnerable patients (Clinical Frailty Score (CFS) 4), 5·94 (2·54 to 13·90) for those mildly frail (CFS 5) and 7·88 (2·97 to 20·79) for those moderately or severely frail (CFS 6 or 7), compared with patients who were fit.Over 37 per cent of older adults undergoing emergency laparotomy required increased care at discharge. Frailty scoring was a significant predictor, and should be integrated into all acute surgical units to aid shared decision-making and discharge planning.Los adultos mayores sometidos a cirugía abdominal de urgencia tienen resultados significativamente peores que los adultos jóvenes. Para aquellos pacientes que sobreviven, el nivel de atención que requieren tras el alta hospitalaria se desconoce y esta información podría servir de guía en la toma de decisiones. El estudio ELF (Emergency Laparotomy and Frailty) tenía como objetivo determinar si la fragilidad preoperatoria en adultos mayores se asociaba con un aumento de la dependencia en el momento del alta. MÉTODOS: El estudio ELF era un estudio multicéntrico extenso efectuado en el Reino Unido (n = 49) que incluyó una cohorte prospectiva de 934 pacientes mayores ( 65 años) sometidos a laparotomía de urgencia durante marzo-junio de 2017. El objetivo fue establecer si la fragilidad preoperatoria aumentaba el nivel de asistencia en el momento del alta en comparación con el nivel de asistencia preoperatorio. Para el análisis se utilizó una regresión logística multinivel ajustada a características previas al ingreso: fragilidad, edad del paciente, género, y nivel de asistencia.La edad media de los pacientes fue 76,2 años (DE = 6,83), con un 57% de mujeres, un 20,2% de pacientes frágiles y un 37,4% de adultos mayores que presentaron un aumento en el nivel de asistencia en el momento del alta. Un aumento de la fragilidad se asoció con un incremento en el nivel de asistencia en el momento del alta (y mayor poder predictivo que la edad). La razón de oportunidades (odds ratio, OR) ajustada por el aumento del nivel de asistencia fue 4,48 (i.c. del 95% 2,03-9,91) para pacientes aparentemente vulnerables (Clinical Frailty Scale, CFS 4); 5,94 (i.c. del 95% 2,54-13,90) para aquellos ligeramente frágiles (CFS 5); y 7,88 (i.c. del 95% 2,97-20,79) para aquellos con fragilidad moderada o grave (CFS 6 and 7) en comparación con pacientes en buenas condiciones. CONCLUSIÓN: Este es el primer estudio que documenta que más del 37% de adultos mayores sometidos a laparotomía de urgencia precisaron un aumento en el nivel de asistencia en el momento del alta. La evaluación de la fragilidad debería integrarse en todas las unidades quirúrgicas de agudos para ayudar a compartir la toma de decisiones y los planes de tratamiento.

Aims: Retrospectively audit the outcome of frail older patients referred to a regional medical oncology service in New Zealand and assess the 8 item G8 frailty score. Methods: For all patients 75 years and older assigned a first assessment at the medical oncology service over 12 months, data on diagnosis and health status was collected, and the G8 score determined. Results: 305 of the 350 given an appointment attended, 52% were male, 53% had metastatic disease, 29% had colorectal cancer. If aged 84+ years, 50% deteriorated or died within 6 months. Age, cancer diagnosis, stage, and higher neutrophil/lymphocyte ratio were associated with poor outcome at 6 months; use of chemotherapy, endocrine therapy, radiation and surgery with better outcome. Data allowed use of 6 items from the G8 score; with 55% classified frail or vulnerable on G6 score. At 6 months 62.7% deemed frail had deteriorated or died, compared with 22.9% of those not frail. Conclusion: In patients with a new cancer diagnosis aged 75 years and older, outcome at 6 months was associated with age, cancer type, stage, treatment and G6 score. The G6 frailty score used age, weight and height (BMI), loss of appetite, decreased mobility, self-declared health status and medication use, and should be tested prospectively.

Background Worst-case, typical, and best-case scenarios for survival, based on simple multiples of an individual's expected survival time (EST), estimated by their oncologist, are a useful way of formulating and explaining prognosis. We aimed to determine the accuracy and prognostic significance of oncologists’ estimates of EST, and the accuracy of the resulting scenarios for survival time, in advanced gastric cancer. Materials and Methods Sixty-six oncologists estimated the EST at baseline for each of the 152 participants they enrolled in the INTEGRATE trial. We hypothesized that oncologists’ estimates of EST would be unbiased (∼50% would be longer or shorter than the observed survival time [OST]); imprecise ( Results Oncologists’ estimates of EST were unbiased (45% were shorter than the OST, 55% were longer); imprecise (29% were within 0.67–1.33 times observed); moderately discriminative (Harrell's C-statistic 0.62, p = .001); and an independently significant predictor of OS (hazard ratio, 0.89; 95% confidence interval, 0.83–0.95; p = .001) in a Cox model including performance status, number of metastatic sites, neutrophil-to-lymphocyte ratio ≥3, treatment group, age, and health-related quality of life (EORTC-QLQC30 physical function score). Scenarios for survival time derived from oncologists’ estimates were remarkably accurate: 9% of patients died within a quarter of their EST, 57% lived within half to double their EST, and 12% lived three times their EST or longer. Conclusion Oncologists’ estimates of EST were unbiased, imprecise, moderately discriminative, and independently significant predictors of OS. Simple multiples of the EST accurately estimated worst-case, typical, and best-case scenarios for survival time in advanced gastric cancer. Implications for Practice Results of this study demonstrate that oncologists’ estimates of expected survival time for their patients with advanced gastric cancer were unbiased, imprecise, moderately discriminative, and independently significant predictors of overall survival. Simple multiples of the expected survival time accurately estimated worst-case, typical, and best-case scenarios for survival time in advanced gastric cancer.

Background Social media has changed the way surgeons communicate worldwide, particularly in dissemination of trial results. However, it is unclear if social media could be used in recruitment to surgical trials. This study aimed to investigate the influence of Twitter in promoting surgical recruitment in The Emergency Laparotomy and Frailty (ELF) Study. Methods The ELF Study was a UK-based, prospective, observational cohort that aimed to assess the influence of frailty on 90-day mortality in older adults undergoing emergency surgery. A power calculation required 500 patients to be recruited to detect a 10% change in mortality associated with frailty. A 12-week recruitment period was selected, calculated from information submitted by participating hospitals and the numbers of emergency surgeries performed in adults aged > 65 years. A Twitter handle was designed (@ELFStudy) with eye-catching logos to encourage enrolment and inform the public and clinicians involved in the study. Twitter Analytics and Twitonomy (Digonomy Pty Ltd) were used to analyse user engagement in relation to patient recruitment. Results After 90 days of data collection, 49 sites from Scotland, England and Wales recruited 952 consecutive patients undergoing emergency laparotomy, with data logged into a database created on REDCap. Target recruitment (n = 500) was achieved by week 11. A total of 591 tweets were published by @ELFStudy since its conception, making 218,136 impressions at time of writing. The number of impressions (number of times users see a particular tweet) prior to March 20th 2017 (study commencement date) was 23,335 (343.2 per tweet), compared to the recruitment period with 114,314 impressions (256.3 per tweet), ending June 20th 2017. Each additional tweet was associated with an increase in recruitment of 1.66 (95%CI 1.36 to 1.97; p Conclusion The ELF Study over-recruited by nearly 100%, reaching over 200,000 people across the U.K. Branding enhanced tweet aesthetics and helped increase tweet engagement to stimulate discussion and healthy competition amongst clinicians to aid trial recruitment. Other studies may draw from the social media experiences of the ELF Study to optimise collaboration amongst researchers. Trial registration This study is registered online at www.clinicaltrials.gov (registration number NCT02952430) and has been approved by the National Health Service Research Ethics Committee.

A felt guide roll fractured in-service on a paper manufacturing machine, damaging the belt as well as multiple dryer rolls, nearby felt guide rolls, and the frame of the machine. The investigation included visual and stereoscopic examination, chemical and microstructural analysis, microhardness and tensile testing, stress calculations, and vibration measurements. Based on the results, the roll fracture was attributed to high-cycle fatigue associated with a plug weld over one of the five threaded fasteners added to secure a balance weight inside the roll. The balance weight was installed to compensate for variations in wall thickness (i.e., weight distribution) of the pipe product used to make the roll. According to the investigation, resonance and vibration, which were initially considered, did not cause the failure.

A paper manufacturing machine experienced an in-service fracture of one of the machine’s felt guide rolls. An engineering analysis of the fractured roll was conducted to determine the cause. Consideration was given to resonant vibration of the roll with respect to operation of the machine at or near the natural frequency of the roll. However, analysis demonstrated that vibration was not an issue. Rather, the roll fracture was attributed to a high cycle fatigue fracture mechanism associated with a plug weld at a threaded fastener used to attach a large balance weight to the inside of the roll. The balance weight was, in turn, installed to compensate for variation in the wall thickness of a pipe product used to make the roll. The cause of the roll fracture was defective manufacture.

Colorectal cancer is common with half of all patients developing metastases to the liver. The aim of this study was to document the survival for patients undergoing liver resection for colorectal cancer metastases.A review of all patients undergoing hepatic resection for colorectal liver metastases at a New Zealand tertiary level public hospital over a 9-year period was performed.Primary survival outcomes assessed were overall survival (OS) and disease-free survival (DFS). Of the 116 patients followed-up with a median (range) of 53 (10-116) months, the OS at 5 years was 53%. Median survival was 6.5 years. At end of follow-up, 57% of patients were alive and 49% were alive without recurrence. The overall rate of recurrence was 39%.This study confirms that excellent long term survival can be achieved with hepatic resection for colorectal liver metastases.

Purpose: To determine the safety and feasibility of combining intratumoral reovirus and radiotherapy in patients with advanced cancer and to assess viral biodistribution, reoviral replication in tumors, and antiviral immune responses. Experimental Design: Patients with measurable disease amenable to palliative radiotherapy were enrolled. In the first stage, patients received radiotherapy (20 Gy in five fractions) plus two intratumoral injections of RT3D at doses between 1 × 108 and 1 × 1010 TCID50. In the second stage, the radiotherapy dose was increased (36 Gy in 12 fractions) and patients received two, four, or six doses of RT3D at 1 × 1010 TCID50. End points were safety, viral replication, immunogenicity, and antitumoral activity. Results: Twenty-three patients with various solid tumors were treated. Dose-limiting toxicity was not seen. The most common toxicities were grade 2 (or lower) pyrexia, influenza-like symptoms, vomiting, asymptomatic lymphopenia, and neutropenia. There was no exacerbation of the acute radiation reaction. Reverse transcription-PCR (RT-PCR) studies of blood, urine, stool, and sputum were negative for viral shedding. In the low-dose (20 Gy in five fractions) radiation group, two of seven evaluable patients had a partial response and five had stable disease. In the high-dose (36 Gy in 12 fractions) radiation group, five of seven evaluable patients had partial response and two stable disease. Conclusions: The combination of intratumoral RT3D and radiotherapy was well tolerated. The favorable toxicity profile and lack of vector shedding means that this combination should be evaluated in newly diagnosed patients receiving radiotherapy with curative intent. Clin Cancer Res; 16(11); 3067–77. ©2010 AACR.

At physiological temperature In water, the relaxed state of the protein, elastin, and model elastomeric sequential polypeptides derived from this biological elastomer is the result of an inverse temperature transition. At lower temperatures, say at 20°C. the hydrophobic side chams of the elastomers are hydrated with a low-entropy net of water. On raising the temperature, the more ordered waters of hydrophobic hydration are converted to less ordered bulk water as the polypeptide chains fold increasing intra- and intermolecular hydrophobic contacts. Following Flory and colleagues, thermoelasticity studies suggests that these polypeptide elastomers are dominantly entropic elastomers above the temperature of the inverse temperature transition. A central question becomes the source of the entropic elastomeric force. On stretching, hydrophobic side chains become exposed to water, resulting in an exothermic reaction of hydrophobic hydration. The issue addressed by the present report is whether this decrease in solvent entropy on stretching might make a major contribution to the entropic elastomeric restoring force. It has previously been argued that the free energy of solvation can be made very small by a 30% ethylene glycol (EG):70% water solvent mixture. This is demonstrated here using the repeating pentapeptide sequence of elastin (Val '-Pro2-Gly'-Va14-Gly '). or poly( VPGVG) and its 7-irradiation cross-linked elastomeric matrix. Differential scanning calorimetry of the inverse temperature transition of poly( VPGVG) shows the endothermic heat of the transition to become very small in EG/HZO when compared with H20 alone, which also indicates a very small entropy change for the transition on exposure of the hydrophobic side chains to the EG/H20 solvent mixture. A similar result is found for the crosslinked elastomeric matrix. Significantly, however, in spite of the lower heats for hydrophobic solvation. the elastic modulus and the entropic elastomeric forces generated are greater in EG/H2O. Thus, even though the heat of the transition and the entropy change on solvation are markedly reduced, the entropic elastomeric force is increased. Accordingly, it is argued that the entropy change due to hydrophobic sidechain solvation on extension is considered not to be a primary source of the entropic elastomeric force.

High molecular weight polytetrapeptide of elastin, (L.Val1-L.Pro2-Gly3-Gly4)n, was synthesized using activation of the (GGVP) permutation for polymerization. The temperature-dependence of aggregation was characterized as a function of concentration and the circular dichroism spectra were obtained in the 20 degrees to 70 degrees C temperature range. The latter showed an inverse temperature transition centered near 50 degrees C in which polypeptide order increased on raising the temperature. A concentration of 0.6 g of polytetrapeptide in 1 g of water was gamma irradiation cross-linked (20 Mrad) to form an elastomeric matrix. A study of the temperature-dependence of elastomeric force demonstrated a transition toward increased force on raising the temperature with a midpoint of the transition near 50 degrees C. Thus, there is a correlation between increase in intramolecular order and elastomeric force development. These results are compared to previous results on the polypentapeptide of elastin, (VPGVG)n and on an analog, (IPGVG)n, to demonstrate that the temperature of the transition is proportional to the hydrophobicity of the repeating unit. The point is noted that the elastomeric force development correlates better with intramolecular ordering than with intermolecular processes.

The classical method for designing against high-cycle fatigue fracture is based primarily on statistical models derived from laboratory experimental data. This paper considers a number of actual fatigue failures where the analyses of the failures, in part, made use of classical high-cycle fatigue resistance design methodology as an analytical tool. This paper uses failure analyses to demonstrate that the long-taught classical methodology is useful and accurate as both a design and an analysis tool. The usefulness and accuracy of the method is verified in that it is shown to have predicted actual failures, given known materials, manufacturing histories, and service operating conditions. Example analyses include: a fatigue-cracked roll from a paper-making machine, a fractured anvil on a steam powered forge, and a fractured shaft on a helical ribbon dryer.

Acid—base titrations at 37°C determined the p K a values in water and saline of twelve synthesized polypentapeptides poly( f K (GVGIP), f v (GKGIP), where f v + f K = 1 with f K ranging from 1 to 0.06 and where K is the lysine (NH + 3 /NH 2 ) residue. In water the p K a was 9.60 near f K = 0.9 decreasing to 9.20 at f K = 1 and to 8.18 at f K = 0.06. At 37°C in the NH 2 state, the polymers form a viscoelastic phase of 50% water by volume where for f K = 0 previous dielectric permittivity data place the dielectric constant near 65. For f K K a could not be explained by the usual electrostatic self-energy argument of decreased dielectric constant as Lys (K) is replaced by Val (V). Instead, an apolar—polar repulsive free energy of hydration is discussed which provides a basis for hydrophobic-induced p K a shifts.

Polypeptides of the composition poly[ƒv (GVGVP), ƒx(GXGVP)] exhibit inverse temperature transitions wherein there is an increase in order due to hydrophobic folding and assembly on raising the temperature. In cross-linked matrices, the transition is observed as a thermally-driven contraction capable of performing mechanical work, that is, as thermomechanical transduction. The temperature, Tt, at which the inverse temperature transition occurs, is dependent on pressure when X is an aromatic, Phe(F), residue. For cross-linked matrices of poly[0.79(GVGVP), 0.21(GFGVP)], it is reported here that the temperature at which thermomechanical transduction occurs increases on increasing the pressure, and that release of pressure results in contraction with the lifting of a weight. Thus baromechanical transduction in a model protein system is demonstrated.

Early clinical trials of reovirus administered via the intratumoral or intravenous routes in patients with advanced cancers established the safety profile and MTD of these agents. Reovirus is an orphan virus and is the cause of a well-documented subclinical syndrome. Preclinical evidence of the novel mechanisms of anticancer activity of reovirus provided the rationale for advancing this agent into clinical trials. Preclinical studies have also defined the specificity of the antitumor activity of reovirus, and also its efficacy in combination with cytotoxic chemotherapies and immunosuppressants. Early clinical trials of combinations of the injectable oncolytic reovirus therapy Reolysin (Oncolytics Biotech Inc) plus cytotoxic chemotherapies are ongoing, as are phase II trials of Reolysin as a single agent for the treatment of specific tumor types.