Intratumoral delivery of tavokinogene telseplasmid yields systemic immune responses in metastatic melanoma patients.

BACKGROUND: Interleukin 12 (IL-12) is a pivotal regulator of innate and adaptive immunity. We conducted a prospective open-label, phase II clinical trial of electroporated plasmid IL-12 in advanced melanoma patients (NCT01502293). PATIENTS AND METHODS: Patients with stage III/IV melanoma were treated intratumorally with plasmid encoding IL-12 (tavokinogene telseplasmid; tavo), 0.5 mg/ml followed by electroporation (six pulses, 1500 V/cm) on days 1, 5, and 8 every 90 days in the main study and additional patients were treated in two alternative schedule exploration cohorts. Correlative analyses for programmed death-ligand 1 (PD-L1), flow cytometry to assess changes in immune cell subsets, and analysis of immune-related gene expression were carried out on pre- and post-treatment samples from study patients, as well as from additional patients treated during exploration of additional dosing schedules beyond the pre-specified protocol dosing schedule. Response was measured by study-specific criteria to maximize detection of latent and potentially transient immune responses in patients with multiple skin lesions and toxicities were graded by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). RESULTS: The objective overall response rate was 35.7% in the main study (29.8% in all cohorts), with a complete response rate of 17.9% (10.6% in all cohorts). The median progression-free survival in the main study was 3.7 months while the median overall survival was not reached at a median follow up of 29.7 months. A total of 46% of patients in all cohorts with uninjected lesions experienced regression of at least one of these lesions and 25% had a net regression of all untreated lesions. Transcriptomic and immunohistochemistry analysis showed that immune activation and co-stimulatory transcripts were up-regulated but there was also increased adaptive immune resistance. CONCLUSIONS: Intratumoral Tavo was well tolerated and led to systemic immune responses in advanced melanoma patients. While tumor regression and increased immune infiltration were observed in treated as well as untreated/distal lesions, adaptive immune resistance limited the response.

Impact of systemic lupus erythematosus on burden of illness and work productivity in the United States.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by clinical manifestations that can cause diminished activity and productivity. The objectives of this study were to: (a) longitudinally evaluate patient-reported SLE disease activity, and (b) measure work productivity, missed work hours, and associated lost income among employed patients with SLE. Three cohorts (employed subjects with SLE (n = 281), nonemployed subjects with SLE (n = 265), and a control group of employed individuals without SLE (n = 300)) completed a baseline survey. Employed subjects with SLE completed follow-up surveys every two weeks during a six-month period. Measured outcomes included perceived health, disease manifestations and severity, the Lupus Impact Tracker, the Modified Systemic Lupus Activity Questionnaire, and Work Productivity and Activity Impairment Questionnaire. Higher self-reported SLE disease severity was directly associated with experiencing more frequent and more severe symptoms as well as higher levels of lost work time and lost work productivity. Though patient self-assessment may differ from physician's clinical assessment, it is important to incorporate the patient perspective in clinical decision-making to optimally manage SLE patients. Given the evidence associating SLE with work disability and job loss, it may be beneficial for professionals addressing worksite modifications or compensatory strategies to be included as members of SLE medical teams.

Adverse event burden, resource use, and costs associated with immunosuppressant medications for the treatment of systemic lupus erythematosus: a systematic literature review.

This paper assessed the burden of adverse events (AEs) associated with azathioprine (AZA), cyclophosphamide (CYC), mycophenolate mofetil (MMF), methotrexate (MTX), and cyclosporine (CsA) in patients with systemic lupus erythematosus (SLE). Thirty-eight publications were included. Incidence of AEs ranged from 42.8% to 97.3%. Common AEs included infections (2.4-77%), gastrointestinal AEs (3.2-66.7%), and amenorrhea and/or ovarian complications (0-71%). More hematological cytopenias were associated with AZA (14 episodes) than MMF (2 episodes). CYC was associated with more infections than MMF (40-77% versus 12.5-32%, resp.) or AZA (17-77% versus 11-29%, resp.). Rates of hospitalized infections were similar between MMF and AZA patients, but higher for those taking CYC. There were more gynecological toxicities with CYC than MMF (32-36% versus 3.6-6%, resp.) or AZA (32-71% versus 8-18%, resp.). Discontinuation rates due to AEs were 0-44.4% across these medications. In summary, the incidence of AEs associated with SLE immunosuppressants was consistently high as reported in the literature; discontinuations due to these AEs were similar across treatments. Studies on the economic impact of these AEs were sparse and warrant further study. This paper highlights the need for more treatment options with better safety profiles.

The hospital burden of disease associated with bone metastases and skeletal-related events in patients with breast cancer, lung cancer, or prostate cancer in Spain.

Metastatic bone disease (MBD) is the most common cause of cancer pain and of serious skeletal-related events (SREs) reducing quality of life. Management of MBD involves a multimodal approach aimed at delaying the first SRE and reducing subsequent SREs. The objective of the study was to characterise the hospital burden of disease associated with MBD and SREs following breast, lung and prostate cancer in Spain. Patients admitted into a participating hospital, between 1 January 2003 and 31 December 2003, with one of the required cancers were identified and selected for inclusion into the study. The index admission to hospital, incidence of patients admitted and hospital length of stay were analysed. There were 28,162 patients identified with breast, lung and prostate cancer. The 3 year incidence rates of hospital admission due to MBD were 95 per 1000 for breast cancer, 156 per 1000 for lung cancer and 163 per 1000 for prostate cancer. For patients admitted following an SRE, the incidence rates were 211 per 1000 for breast cancer, 260 per 1000 for lung cancer and 150 per 1000 for prostate cancer. This study has shown that cancer patients consume progressively more hospital resources as MBD and subsequent SREs develop.

Should etomidate be the induction agent of choice for rapid sequence intubation in the emergency department?

The ideal induction agent for emergency airway management should be rapidly acting, permit optimum intubating conditions, and be devoid of significant side effects. This review was performed to ascertain whether etomidate should be the induction agent of choice for rapid sequence intubation (RSI) in the emergency department, specifically examining its pharmacology, haemodynamic profile, and adrenocortical effects. A search of Medline (1966-2002), Embase (1980-2002), the Cochrane controlled trials register, and CINAHL was performed. In addition, the major emergency medicine and anaesthesia journals were hand searched for relevant material. Altogether 144 papers were identified of which 16 were relevant. Most studies were observational studies or retrospective reviews with only one double blind randomised controlled trial and one un-blinded randomised controlled trial. Appraisal of the available evidence suggests that etomidate is an effective induction agent for emergency department RSI; it has a rapid onset of anaesthesia and results in haemodynamic stability, even in hypovolaemic patients or those with limited cardiac reserve. Important questions regarding the medium to long term effects on adrenocortical function (even after a single dose) remain unanswered.

Paediatric intubation in Scottish emergency departments.

BACKGROUND: Intubation of children in the emergency department setting is uncommon. This prospective observational study examines the practice of paediatric intubation in Scottish adult/paediatric urban emergency departments. METHODS: A prospective observational study of every intubation attempt was performed in seven urban Scottish emergency departments in 1999 and 2000. Children were defined as those patients who were less than 13 years of age on the day of presentation. Prehospital intubations were only included if they were performed by a mobile medical team doctor from one of the seven hospitals. RESULTS: A total of 1713 patients were identified, 44 of whom (2.6%) were children. The median age was 4 years (range 0-12 years), and 57% (25 of 44) of intubations were performed on patients with traumatic injuries. Emergency physicians attempted intubation in 27% (12 of 44) of cases, anaesthetists in 73% (32 of 44); 18% (eight of 44) of patients were intubated in nontraumatic cardiac arrest, 68% (30 of 44) underwent rapid sequence intubation (RSI), one (2%) had inhalational anaesthesia and 13 (30%) were intubated without drugs. Eighty per cent (35 of 44) of patients were intubated at the first attempt; eight patients required two attempts, and one required three attempts. Three children were intubated prehospital by mobile medical teams. Emergency physicians intubated more patients with 'physiological compromise' (100% vs 91%). CONCLUSIONS: Paediatric intubation in the emergency department is uncommon. Collaboration and appropriate training for doctors in emergency medicine, anaesthesia and paediatrics is essential.

The components of excess mortality after hip fracture.

A high excess mortality is well described after hip fracture. Deaths are in part related to comorbidity and in part due directly or indirectly to the hip fracture event itself (causally related deaths). The aim of this study was to examine the quantum and pattern of mortality following hip fracture. We studied 160,000 hip fractures in men and women aged 50 years or more, in 28.8 million person-years from the patient register of Sweden, using Poisson models applied to hip fracture patients and the general population. At all ages the risk of death was markedly increased compared with population values immediately after the event. Mortality subsequently decreased over a period of 6 months, but thereafter remained higher than that of the general population. The latter function was assumed to account for deaths related to comorbidity and the residuum assumed to be due to the hip fracture. Causally related deaths comprised 17-32% of all deaths associated with hip fracture (depending on age) and accounted for more than 1.5% of all deaths in the population aged 50 years or more. Hip fracture was a more common cause for mortality than pancreatic or stomach cancer. Thus, interventions that decreased hip fracture rate by, say, 50% would avoid 0.75% or more of all deaths.

Rapid sequence intubation in Scottish urban emergency departments.

OBJECTIVE: Airway care is the cornerstone of resuscitation. In UK emergency department practice, this care is provided by anaesthetists and emergency physicians. The aim of this study was to determine current practice for rapid sequence intubation (RSI) in a sample of emergency departments in Scotland. METHODS: Two year, multicentre, prospective observational study of endotracheal intubation in the emergency departments of seven Scottish urban teaching hospitals. RESULTS: 1631 patients underwent an intubation attempt in the emergency department and 735 patients satisfied the criteria for RSI. Emergency physicians intubated 377 patients and anaesthetists intubated 355 patients. There was no difference in median age between the groups but there was a significantly greater proportion of men (73.2% versus 65.3%, p=0.024) and trauma patients (48.5% versus 37.4%, p=0.003) in the anaesthetic group. Anaesthetists had a higher initial success rate (91.8% versus 83.8%, p=0.001) and achieved more good (Cormack-Lehane Grade I and II) views at laryngoscopy (94.0% versus 89.3%, p=0.039). There was a non-significant trend to more complications in the group of patients intubated by emergency physicians (8.7% versus 12.7%, p=0.104). Emergency physicians intubated a higher proportion of patients with physiological compromise (91.8% versus 86.1%, p=0.027) and a higher proportion of patients within 15 minutes of arrival (32.6% versus 11.3%, p<0.0001). CONCLUSION: Anaesthetists achieve more good views at laryngoscopy with higher initial success rates during RSI. Emergency physicians perform RSI on a higher proportion of critically ill patients and a higher proportion of patients within 15 minutes of arrival. Complications may be fewer in the anaesthetists' group, but this could be related to differences in patient populations. Training issues for RSI and emergency airway care are discussed. Complication rates for both groups are in keeping with previous studies.

Intervention thresholds for osteoporosis.

The aim of this study was to determine the threshold of fracture probability at which interventions become cost-effective. We modeled the effects of a treatment costing $500/year, given for 5 years, that decreased the risk of all osteoporotic fractures by 35%, followed by a waning of effect for 5 years. Sensitivity analyses included a range of effectiveness (10%-50%) and a range of intervention costs (200-500 dollars/year). Data on costs and risks were from Sweden. Costs included direct costs and costs in added years of life, but excluded indirect costs due to morbidity. A threshold for cost-effectiveness of 60,000 dollars per quality-adjusted life-year (QALY) gained was used. Costs of added years were excluded in a sensitivity analysis for which a threshold value of 30,000 dollars per QALY was used. In the base case, intervention was cost-effective when treatment was targeted to women at average risk at age of >or=65 years. Irrespective of the efficacy modeled (10%-50%) or of cost of intervention (200-500 dollars/year) segments of the population at average risk could be targeted cost-effectively: The lower the intervention cost and the higher the effectiveness, the lower the age at which intervention was cost-effective. With the base case (500 dollars/year; 35% efficacy) treatment in women was cost-effective with a 10 year hip fracture probability that ranged from 1.4% at the age of 50 years to 4.4% at the age of 65 years. The exclusion of osteoporotic fractures other than hip fracture would increase the threshold to a 9%-11% 10 year probability because of the substantial morbidity from fractures other than hip fracture, particularly at younger ages. We conclude that the inclusion of all osteoporotic fractures has a marked effect on intervention thresholds, that these vary with age, and that available treatments can be cost-effectively targeted to individuals at moderately increased risk.

Comparison of oral and intravenous morphine following acute injury in children.

The objective of this research was to examine the speed of onset and effectiveness of pain relief between oral and intravenous morphine in acutely injured children. An observational study of children aged 3 to 13 years with closed forearm fractures was performed in three accident and emergency departments. The study gathered information on age, gender, body weight, time of arrival, dose, route and time of morphine administration. Pain assessment using a Faces Scale was documented on arrival and repeated at 10, 30 and 60 minutes after morphine was given. Forty-seven children were studied. Of these, 25 were given intravenous morphine, 22 were given oral morphine. There was no statistically significant difference in age, body weight or time until morphine was administered. The change in median pain scores was analysed using the Mann-Whitney U test. This showed that there was a statistically significant reduction in pain score in the intravenous group compared with the oral group between arrival and 10 minutes after giving morphine and between arrival and 60 minutes after giving morphine. Intravenous morphine appears to give more rapid onset and more prolonged pain relief than oral morphine for children with acute injuries. We recommend that in accident and emergency departments where staff are experienced in paediatric cannulation, morphine should be given via the intravenous route in acutely injured children. However we do not advocate inexperienced staff attempting multiple venepunctures in a child resulting in increased anxiety.

Squamous cell carcinoma of the anus: a twenty-five year retrospective.

Squamous cell carcinoma of the anus (SCCA), an aggressive and often fatal malignancy, has traditionally been treated with surgery. In recent years, however, nonoperative therapy has emerged as an alternative to operation. Twenty five years of experience with SCCA at this institution were reviewed to examine the presentation and outcome of a population treated primarily with surgery. Forty two patients, including 26 women and 16 men, had a mean age of 56 years. SCCA was usually heralded by a mass, bleeding, or pain and was associated with chronic perianal disease in 25.8%. Symptoms were present for an average of 11 months. Among the patients in this review, 92.3 per cent underwent radical surgery, while 11.9 per cent had radiation as their primary therapy following palliative surgery or local excisions for biopsy. Actuarial 5-year-survival for the entire group was 45.5 percent; all patients with nodal or disseminated disease at diagnosis have died. Patients with perianal lesions fared no better than those with anal tumors, probably due to the unusually large perianal tumors in this series. To diagnose SCCA at its earliest stage, a high index of suspicion must be maintained when dealing with anal and perianal lesions, especially if the abnormality is chronic. When compared with reported advances in combined therapy, it is likely that in most cases surgery alone no longer offers optimal treatment for SCCA.

Marker X syndrome in an oriental family with probable transmission by a normal male.

We report an oriental family with sex-linked mental retardation, macroorchidism, and a marker or fragile site on the X chromosome--mar(X)(q28). The three affected males resemble clinically most previously reported affected Caucasians. The marker was present in four female 40-70 years old, including one with normal intelligence. Transmission of the disorder appears to have taken place through a clinically normal male to his grandson.

General revenue sharing funds for the health care of mothers and children.

In a study of the use of General Revenue Sharing (GRS) funds by the states and by cities of 100,000 and over in the United States for fiscal years 1973 and 1974, we found that few states and large cities allocated or requested GRS funds for Maternal and Child Health (MCH), Crippled Children (CC), and related services. One third of the states and cities reported suggestions for use of GRS funds for MCH, CC, and related services.

Patterns of infant and early childhood mortality in the California Project of a collaborative Inter-American Study.

The California Project of the Inter-American Investigation of Mortality in Childhood was carried out in San Francisco and three surrounding counties in 1969 and 1970. The study found infant death rates of 18.5 per 1,000 live births in San Francisco and 17.2 per 1,000 live births in the three counties. Mortality in the neonatal period (the first 28 days of life) accounted for two-thirds of these deaths. Low birth-weitht played a key role in neonatal mortality, one that was particularly marked during the first day of life. Overall, the study found that 77.7 per cent of the neonatal fatalities and 85.6 percent of those dying in the first day of life weighed 2,500 grams or less at birth. Mortality was also very high among infants of mothers under 20 and over 34 years of age., the risks being especially great in the case of young mothers. Moreover, the vast majority of babies that were born to young mothers and died the first day had very low birth-weights. It is therefore concluded that young mothers ran a relatively high risk of having low birth weight babies prone to dying in the first day of life. This demonstrates a clear need for special measures capable of reducing the health risk faced by both young mothers and their children. Besides providing a more detailed explanation of these points, the authors recommend various specific measures that should be taken and present data obtained by the California Project on other aspects of mortality among infants and preschool children 1-4 years of age