Low-dose ipilimumab plus nivolumab combined with IL-2 and hyperthermia in cancer patients with advanced disease: exploratory findings of a case series of 131 stage IV cancers - a retrospective study of a single institution.

The 3-year overall survival (OS) rate of patients with previously treated or untreated stage III or IV melanoma has by now reached 63% using ipilimumab and nivolumab therapy. However, immune-related adverse events (irAEs) of grade 3 or 4 occurred in 59% of patients leading to discontinuation of therapy in 24.5% of patients and one death. Therapy with checkpoint inhibitors could be safer and more effective in combination with hyperthermia and fever inducing therapies. We conducted a retrospective analysis to test the safety and efficacy of a new combination immune therapy in 131 unselected stage IV solid cancer patients with 23 different histological types of cancer who exhausted all conventional treatments. Treatment consisted of locoregional- and whole-body hyperthermia, individually dose adapted interleukin 2 (IL-2) combined with low-dose ipilimumab (0.3 mg/kg) plus nivolumab (0.5 mg/kg). The objective response rate (ORR) was 31.3%, progression-free survival (PFS) was 10 months, survival probabilities at 6 months was 86.7% (95% CI, 81.0-92.8%), at 9 months was 73.5% (95% CI, 66.2-81.7%), at 12 months was 66.5% (95% CI, 58.6-75.4%), while at 24 months survival was 36.6% (95% CI:28.2%; 47.3%). irAEs of World Health Organization (WHO) Toxicity Scale grade 1, 2, 3, and 4 were observed in 23.66%, 16.03%, 6.11%, and 2.29% of patients, respectively. Our results suggest that the irAEs profile of the combined treatment is safer than that of the established protocols without compromising efficacy.

Bone microstructure and volumetric bone mineral density in patients with hyperuricemia with and without psoriasis.

We analyzed volumetric bone mineral density (vBMD) and bone microstructure using HR-pQCT in subjects with normouricemia (NU) and subjects with hyperuricemia (HU) with and without psoriasis (PSO). HU was associated with higher cortical vBMD and thickness. Differences in average and trabecular vBMD were found between patients with PSO + HU and NU. INTRODUCTION: Hyperuricemia (HU) and gout are co-conditions of psoriasis and psoriatic arthritis. Current data suggest a positive association between HU and areal bone mineral density (BMD) and a negative influence of psoriasis on local bone, even in the absence of arthritis. However, the influence of the combination of HU and psoriasis on bone is still unclear. The aim of this study was to assess the impact of HU with and without psoriasis on bone microstructure and volumetric BMD (vBMD). METHODS: Healthy individuals with uric acid levels within the normal range (NU), with hyperuricemia (HU), patients with hyperuricemia and psoriasis (PSO + HU), and patients with uric acid within the normal range and psoriasis (PSO + NU) were included in our study. Psoriasis patients had no current or past symptoms of arthritis. Average, trabecular, and cortical vBMD (mgHA/cm3); trabecular number (Tb.N, 1/mm) and thickness (Tb.Th, mm); inhomogeneity of the network (1/N.SD, mm); and cortical thickness (Ct.Th., mm) were carried out at the ultradistal radius using high-resolution peripheral quantitative computed tomography. In addition, bone turnover markers such as DKK-1, sclerostin, and P1NP were analyzed. RESULTS: In total, 130 individuals were included (44 NU participants (34% female), 50 HU (24%), 16 PSO + HU (6%), 20 PSO + NU (60%)). Subjects were aged: NU 54.5 (42.8, 62.1), HU 57.5 (18.6, 65.1), PSO + HU 52.0 (42.3, 57.8), and PSO + NU 42.5 (34.8, 56.8), respectively. After adjusting for age, sex, BMI, and diabetes, patients in the HU group revealed significantly higher values of cortical vBMD (p < 0.001) as well as cortical thickness (p = 0.04) compared to the NU group. PSO + NU showed no differences to NU, but PSO + HU demonstrated both lower average (p = 0.03) and trabecular vBMD (p = 0.02). P1NP was associated with average, cortical, and trabecular vBMD as well as cortical thickness while sclerostin levels were related to trabecular vBMD. CONCLUSION: Hyperuricemia in otherwise healthy subjects was associated with a better cortical vBMD and higher cortical thickness. However, patients with both psoriasis and hyperuricemia revealed a lower vBMD.

Preceding and subsequent high- and low-trauma fracture patterns-a 13-year epidemiological study in females and males in Austria.

This study investigated the implication of a preceding high-trauma fracture on subsequent high- and low-trauma fractures at different skeletal sites in postmenopausal women and similarly aged men at an age range of 54 to 70 years. A preceding high-trauma fracture increases the risk of future low-trauma non-vertebral fractures including hip. INTRODUCTION: Little is known about the impact of the skeletal fracture site in conjunction with the severity of a past fracture (high- or low-trauma preceding fracture) and its effect on future fracture risk. METHODS: Patients with de novo high- and low-trauma fractures admitted to seven large trauma centers across Austria between 2000 and 2012 were stratified into sex and different age groups. Kaplan-Meier estimates, Cox proportional hazards regression models (HR), and likelihood calculations estimated effects of age, sex, and the anatomic region on the probability of a subsequent fracture in the same patient. RESULTS: Included in the study were 433,499 female and male patients at an age range of 0 to 100 years with 575,772 de novo high- and low-trauma fractures. In the age range of 54-70 years, subsequent fractures were observed in 16% of females and 12.1% of males. A preceding high-trauma fracture was associated with 12.9% of subsequent fractures, thereof 6.5% of high- and 6.4% of low-trauma in origin, usually at the hip, humerus, or pelvis. The highest effect sizes were observed for femur, humerus, and thorax fractures with hazard ratios (HR) of 1.26, 1.18, and 1.14. After splitting into high-trauma preceding and subsequent low-trauma fractures, the femoral neck (HR = 1.59), the female sex (HR = 2.02), and age (HR = 1.03) were discriminators for increased future fracture risk. CONCLUSIONS: Preceding high-trauma fractures increase the risk of future low-trauma non-vertebral fractures including hip. For each patient with a fracture, regardless of the severity of the trauma, osteoporosis should be taken into clinical consideration.

Influence of a multiple emulsion, liposomes and a microemulsion gel on sebum, skin hydration and TEWL.

OBJECTIVE: In this study, the influence of three cosmetically relevant, priorly characterized vehicles on skin hydration, sebum content and transepidermal water loss was investigated. The chosen vehicles included a liposomal pre-formulation, a multiple W/O/W emulsion and a microemulsion gel. The in vivo effects of these vehicles were demonstrated and compared among them. METHODS: The stability of the prepared vehicles was determined visually, microscopically, rheologically by pH measurements and particle size. Interactions with skin were assessed by non-invasive biophysical techniques using the Corneometer(®), Aqua Flux(®) and Sebumeter, measuring skin hydration, TEWL and skin sebum content, respectively. RESULTS: All vehicles remained stable over an observation period of 6 weeks. The multiple emulsion increased sebum content and skin hydration. In case of the liposomes, each monitored parameter remained almost constant. In contrast, the microemulsion gel lowered skin hydration and increased TEWL values, but even 1 week after termination of the treatment TEWL decreased almost close to control levels. CONCLUSION: All produced vehicles were proven to remain physically stable over the duration of this study. The used multiple emulsion showed very skin-friendly properties by increasing sebum and skin hydration. Likewise, the liposomal pre-formulation exhibited no negative effects. On the contrary, the investigated microemulsion gel seemed to have skin dehydrating and TEWL increasing features. However, the multiple emulsion as well as liposomes was identified to be well-tolerated vehicles for skin which might qualify them for the use in cosmetic formulations.

Spatial Aspects of Light Leaf Spot (Pyrenopeziza brassicae) Epidemic Development on Winter Oilseed Rape (Brassica napus) in the United Kingdom.

ABSTRACT In microplot experiments in 1998-99 and 1999-2000, the start of light leaf spot epidemics could be predicted from weather data, using empirical equations for Pyrenopeziza brassicae apothecial (ascospore) development, ascospore infection criteria, and the latent period of P. brassicae. The dates when P. brassicae sporulation was first observed fitted predictions and initial spread of light leaf spot from an inoculum source was mostly in the prevailing wind direction, with differences between the two growing seasons attributable to differences in wind patterns. Subsequent secondary spread of disease could be predicted using temperature and rainfall data, and observations fitted predicted dates. In both 1998-99 and 1999-2000, initial spatial patterns of observed disease in January were random, because data were not significantly different from a binomial distribution (P = 0.18). Analysis of spatial data from samples in February and March indicated aggregation, because data fit was significantly different from a binomial distribution (P

[Reconstruction of isolated lower leg arteriovenous occlusions in the critical foot ischemia stage--assessment of current status]. / Rekonstruktionen bei isolierten Unterschenkelarterienverschlüssen im Stadium der kritischen Fussischämie--eine Bestandsaufnahme.

Between May 1, 1986 and November 1, 1994 94 distal reconstructions were performed in diabetics with isolated tibioperoneal vessel occlusive disease. Mostly the below knee popliteal artery was used as inflow site and most grafts were anastomosed distally to a malleolar artery. Autologous vein was implanted throughout. Mortality at 30 days was 1.06%. Primary and secondary cumulative patency rates were 78% and 82% at 1 year, 65% and 78% at 5 years. Limb salvage rates were 76% at 1 year and 72% at 5 years. Major amputations became inevitable in 12 cases of uncontrollable foot infections despite patent grafts. This is probably due to the diabetic immunopathy. The experience we have gained suggests that distal bypasses in patients with peripheral vascular occlusive disease and critical foot ischemia are excellently suited to attain limb salvage.