Clinical Outcome of Sacral Chordoma Patients Treated with Pencil Beam Scanning Proton Therapy.

AIMS: Sacral chordomas are locally aggressive, radio-resistant tumours. Proton therapy has the potential to deliver high radiation doses, which may improve the therapeutic ratio when compared with conventional radiotherapy. We assessed tumour control and radiation-induced toxicity in a cohort of sacral chordoma patients treated with definitive or postoperative pencil beam scanning proton therapy. METHODS AND MATERIALS: Sixty patients with histologically proven sacral chordoma treated between November 1997 and October 2018 at the Paul Scherrer Institute with postoperative (n = 50) or definitive proton therapy (n = 10) were retrospectively analysed. Only 10 (17%) patients received combined photon radiotherapy and proton therapy. Survival rates were calculated using the Kaplan-Meier actuarial method. The Log-rank test was used to compare different functions for local control, freedom from distant recurrence and overall survival. Acute and late toxicity were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. RESULTS: The median follow-up was 48 months (range 4-186). Local recurrence occurred in 20 (33%) patients. The 4-year local control, freedom from distant recurrence and overall survival rates were 77%, 89% and 85%, respectively. On univariate analysis, subtotal resection/biopsy (P = 0.02), tumour extension restricted to bone (P = 0.01) and gross tumour volume >130 ml (P = 0.04) were significant predictors for local recurrence. On multivariate analysis, tumour extension restricted to bone (P = 0.004) and gross total resection (P = 0.02) remained independent favourable prognostic factors for local recurrence. Twenty-four (40%), 28 (47%) and eight (11%) patients experienced acute grade 1, 2 and 3 toxicities, respectively. The 4-year late toxicity-free survival was 91%. Two patients developed secondary malignancies to the bladder 3-7 years after proton therapy. CONCLUSIONS: Our data indicate that pencil beam scanning proton therapy for sacral chordomas is both safe and effective. Gross total resection, tumour volume <130 ml and tumour restricted to the bone are favourable prognostic factors for local tumour control.

Assessing the advantages of CFR-PEEK over titanium spinal stabilization implants in proton therapy-a phantom study.

High-density materials, such as titanium, used for spinal stabilization, introduces several critical issues in proton therapy (PT). Artefacts affect both contouring and dose calculation. Subsequently, artefacts need to be corrected which is a time-consuming process. Besides, titanium causes proton interactions that are unaccounted for in dose calculation. The result is a suboptimal treatment plan, and indeed decreased local controls have been reported for these patients. Carbon fiber reinforced polyetheretherketone (CFR-PEEK) implant material, which is of low density, potentially solves these issues. For this study, we designed a unique phantom to compare the effects of titanium and CFR-PEEK implants in PT. The phantom contains four interchangeable spinal inserts representing a native spine, and three different spinal stabilizations consisting of titanium only, CFR-PEEK only, and a combination of titanium and CFR-PEEK. All phantom scenarios received the standard treatment workup. Two planning approaches were investigated: a single field plan and a multi-field optimized plan with spinal cord sparing. For both plans we analyzed the following aspects: total volume of artefacts on CT images, time required for artefact correction, effect of planning CT correction on dose calculation, plan robustness to range and set up uncertainties, and finally the discrepancy between the calculated dose and the delivered dose with Gafchromic® film. The CFR-PEEK implant had a 90% reduction of artefacts on CT images and subsequently severely reduced the time for artefact correction with respect to the titanium-only implant. Furthermore, the CFR-PEEK as opposed to titanium did not influence the robustness of the plan. Finally, the titanium implants led to hardware-related discrepancies between the planned and the measured dose while the CFR-PEEK implant showed good agreement. As opposed to titanium, CFR-PEEK has none to minor effects on PT. The use of CFR-PEEK is expected to optimize treatment and possibly improve outcomes for patients that require spinal stabilization.

Outcomes, Prognostic Factors and Salvage Treatment for Recurrent Chordoma After Pencil Beam Scanning Proton Therapy at the Paul Scherrer Institute.

AIMS: The outcome of chordoma patients with local or distant failure after proton therapy is not well established. We assessed the disease-specific (DSS) and overall survival of patients recurring after proton therapy and evaluated the prognostic factors affecting DSS. MATERIALS AND METHODS: A retrospective analysis was carried out of 71 recurring skull base (n = 36) and extracranial (n = 35) chordoma patients who received adjuvant proton therapy at initial presentation (n = 42; 59%) or after post-surgical recurrence (n = 29; 41%). The median proton therapy dose delivered was 74 GyRBE (range 62-76). The mean age was 55 ± 14.2 years and the male/female ratio was about one. RESULTS: The median time to first failure after proton therapy was 30.8 months (range 3-152). Most patients (n = 59; 83%) presented with locoregional failure only. There were only 12 (17%) distant failures, either with (n = 5) or without (n = 7) synchronous local failure. Eight patients (11%) received no salvage therapy for their treatment failure after proton therapy. Salvage treatments after proton therapy failure included surgery, systemic therapy and additional radiotherapy in 45 (63%), 20 (28%) and eight (11%) patients, respectively. Fifty-three patients (75%) died, most often from disease progression (47 of 53 patients; 89%). The median DSS and overall survival after failure was 3.9 (95% confidence interval 3.1-5.1) and 3.4 (95% confidence interval 2.5-4.4) years, respectively. On multivariate analysis, extracranial location and late failure (≥31 months after proton therapy) were independent favourable prognostic factors for DSS. CONCLUSION: The survival of chordoma patients after a treatment failure following proton therapy is poor, particularly for patients who relapse early or recur in the skull base. Although salvage treatment is administered to most patients with uncontrolled disease, they will ultimately die as a result of disease progression in most cases.

Pencil Beam Scanning Proton Therapy for Paediatric Neuroblastoma with Motion Mitigation Strategy for Moving Target Volumes.

AIMS: More efforts are required to minimise late radiation side-effects for paediatric patients. Pencil beam scanning proton beam therapy (PBS-PT) allows increased sparing of normal tissues while maintaining conformality, but is prone to dose degradation from interplay effects due to respiratory motion. We report our clinical experience of motion mitigation with volumetric rescanning (vRSC) and outcomes of children with neuroblastoma. MATERIALS AND METHODS: Nineteen patients with high-risk (n = 16) and intermediate-risk (n = 3) neuroblastoma received PBS-PT. The median age at PBS-PT was 3.5 years (range 1.2-8.6) and the median PBS-PT dose was 21 Gy (relative biological effectiveness). Most children (89%) were treated under general anaesthesia. Seven patients (37%) underwent four-dimensional computed tomography for motion assessment and were treated with vRSC for motion mitigation. RESULTS: The mean result of maximum organ motion was 2.7 mm (cranial-caudal), 1.2 mm (left-right), 1.0 mm (anterior-posterior). Four anaesthetised children (21%) showing <5 mm motion had four-dimensional dose calculations (4DDC) to guide the number of vRSC. The mean deterioration or improvement to the planning target volume covered by 95% of the prescribed dose compared with static three-dimensional plans were: 4DDC no vRSC, -0.6%; 2 vRSC, +0.3%; 4 vRSC, +0.3%; and 8 vRSC, +0.1%. With a median follow-up of 14.9 months (range 2.7-49.0) there were no local recurrences. The 2-year overall survival was 94% and distant progression-free survival was 76%. Acute grade 2-4 toxicity was 11%. During the limited follow-up time, no late toxicities were observed. CONCLUSIONS: The early outcomes of mainly high-risk patients with neuroblastoma treated with PBS-PT were excellent. With a subset of our cohort undergoing PBS-PT with vRSC we have shown that it is logistically feasible and safe. The clinical relevance of vRSC is debatable in anaesthetised children with small pre-PBS-PT motion of <5 mm.

Development and evaluation of a pan-dermatophyte polymerase chain reaction with species-level identification using sloppy molecular beacon probes.

BACKGROUND: Conventional laboratory diagnosis of dermatophyte infection is cumbersome and time-consuming. OBJECTIVES: We aimed to establish a simple, robust and rapid molecular diagnostic assay for the detection of dermatophytes and optionally nondermatophytes in clinical specimens. MATERIALS AND METHODS: We developed a two-tube pan-dermatophyte polymerase chain reaction (PCR) assay using six sloppy molecular beacon (SMB) probes. The first PCR uses dermatophyte-specific primers and enables detection and identification of most dermatophyte species. The second PCR with pan-fungal primers allows further differentiation of Trichophyton interdigitale and T. mentagrophytes/T. quinckeanum, T. violaceum and T. soudanense, and T. tonsurans and T. equinum, and detection of nondermatophytes. The test was evaluated with 306 clinical specimens by comparing it with the results of microscopy and culture. RESULTS: In melting-curve analyses, species-specific melting temperature signatures of the SMBs were defined, and thus, our new PCR enabled detection and species-level identification of at least 19 dermatophyte species. Sensitivity and specificity of PCR for detection of dermatophytes in clinical samples were estimated to be 96·9% and 90·4%, for culture 46·7% and 98·7%, and for microscopy 91·4% and 84·0%, respectively. The detection of nondermatophytes by PCR and culture did not correlate. CONCLUSIONS: The new assay showed excellent performance characteristics for the detection of dermatophytes and is significantly faster than culturing techniques, which makes it very promising for routine diagnostics of dermatophytosis. We noted that the detection of nondermatophytes in our assay currently has no benefit.

Acetaldehyde exchange above a managed temperate mountain grassland.

An overview of acetaldehyde exchange above a managed temperate mountain grassland in Austria over four growing seasons is presented. The meadow acted as a net source of acetaldehyde in all four years, emitting between 7 and 28 mg C m-2 over the whole growing period. The cutting of the meadow resulted in huge acetaldehyde emission bursts on the day of harvesting or one day later. During undisturbed conditions, both uptake and emission fluxes were recorded. The bidirectional nature of acetaldehyde fluxes was also reflected by clear diurnal cycles during certain time periods, indicating strong deposition processes before the 1st cut and emission towards the end of the growing season. The analysis of acetaldehyde compensation points revealed a complex relationship between ambient acetaldehyde mixing ratios and respective fluxes, significantly influenced by multiple environmental parameters and variable throughout the year. As a major finding of this study, we identified both a positive and negative correlation between concentration and flux on a daily scale, where soil temperature and soil water content were the most significant factors in determining the direction of the slope. In turn, this bidirectional relationship on a daily scale resulted in compensation points between 0.40 ppbv and 0.54 ppbv, which could be well explained by collected ancillary data. We conclude that in order to model acetaldehyde fluxes at the site in Neustift on a daily scale over longer time periods, it is crucial to know the type of relationship, i.e. the direction of the slope, between mixing ratios and fluxes on a given day.

Gap-filling strategies for annual VOC flux data sets.

Up to now the limited knowledge about the exchange of volatile organic compounds (VOCs) between the biosphere and the atmosphere is one of the factors which hinders more accurate climate predictions. Complete long-term flux data sets of several VOCs to quantify the annual exchange and validate recent VOC models are basically not available. In combination with long-term VOC flux measurements the application of gap-filling routines is inevitable in order to replace missing data and make an important step towards a better understanding of the VOC ecosystem-atmosphere exchange on longer time scales. We performed VOC flux measurements above a mountain meadow in Austria during two complete growing seasons (from snowmelt in spring to snow reestablishment in late autumn) and used this data set to test the performance of four different gap-filling routines, mean diurnal variation (MDV), mean gliding window (MGW), look up tables (LUT) and linear interpolation (LIP), in terms of their ability to replace missing flux data in order to obtain reliable VOC sums. According to our findings the MDV routine was outstanding with regard to the minimization of the gap-filling error for both years and all quantified VOCs. The other gap-filling routines, which performed gap-filling on 24 h average values, introduced considerably larger uncertainties. The error which was introduced by the application of the different filling routines increased linearly with the number of data gaps. Although average VOC fluxes measured during the winter period (complete snow coverage) were close to zero, these were highly variable and the filling of the winter period resulted in considerably higher uncertainties compared to the application of gap-filling during the measurement period. The annual patterns of the overall cumulative fluxes for the quantified VOCs showed a completely different behavior in 2009, which was an exceptional year due to the occurrence of a severe hailstorm, compared to 2011. Methanol was the compound which contributed with 381.5 mgCm-2 and 449.9 mgCm-2 most to the cumulative VOC carbon emissions in 2009 and 2011, respectively. In contrast to methanol emissions, however, considerable amounts of monoterpenes (-327.3 mgCm-2) were deposited to the mountain meadow in consequence to the hailstorm in 2009. Other quantified VOCs had considerably lower influences on the annual patterns.

Identification by genome scanning approach (GSA) of a microsatellite tightly associated with the apple scab resistance gene Vm.

For all known major apple scab resistance genes except Vr, molecular markers have been published. However, the precise position of some of these genes, in the apple genome, remains to be identified. Knowledge about the relative position of apple scab resistance genes is necessary to preliminarily evaluate the probability of success of their pyramidization. Pyramidization of different resistance genes into the same genotype is a reliable way to create cultivars with durable apple scab resistance. Applying the genome scanning approach (GSA), we identified the linkage group of the scab resistance gene Vm, derived from Malus micromalus, and we found a new molecular marker tightly associated with the gene. The simple sequence repeat Hi07h02, previously mapped on linkage group 17, cosegregates with the Vm gene (no recombinants in the 95 plants tested). The already published sequence-characterized amplified region Vm marker OPB12(687) was found to be linked at about 5 cM from the resistance gene and, therefore, this marker also maps on linkage group 17 of apple. This is the first report of the discovery of a major apple scab resistance gene on linkage group 17. The advantages of using GSA for the identification of molecular markers for qualitative traits are discussed.

Randomized double-blind trial of oral essential amino acids for dialysis-associated hypoalbuminemia.

BACKGROUND: Hypoalbuminemia is associated with substantial morbidity and mortality in dialysis patients. METHODS: Subjects with a mean three-month prestudy serum albumin of 3.8 g/dL or less and who demonstrated >/=90% compliance during a two-week run-in period were randomized to 3.6 g of essential amino acids (EAAs) or placebo three times daily with meals for three months. Randomization was stratified by dialysis modality and by severity of the hypoalbuminemia. The primary study outcome was change in the average of three monthly serum albumin measurements between baseline and follow-up. RESULTS: Fifty-two patients were randomized; 47 patients (29 hemodialysis and 18 peritoneal dialysis) met the predetermined primary analysis criteria. The mean compliance rates averaged 75, 70, and 50% at months 1, 2, and 3, respectively, and were similar for EAAs and placebo. Serum albumin in the hemodialysis patients, EAA versus placebo, improved [(mean +/- SE) 0.22 +/- 0.09 g/dL, P = 0.02]. Changes in peritoneal dialysis patients were not significant (0.01 +/- 0.15 g/dL), but approached significance for the total study group (0.14 +/- 0.08 g/dL, P = 0.08). Patients in the very low albumin strata (<3.5 g/dL) improved more than those in the low albumin strata (3.5 to 3.8 g/dL, P < 0.01). There was a significant correlation (r = 0.83, P = 0.001) within the hemodialysis EAA group between the baseline C-reactive protein level and improvement in serum albumin. Improvements were also seen in grip strength and SF-12 mental health score, but not in serum amino acid levels, SF-12 physical health score, or anthropometric measurements. CONCLUSIONS: Oral EAAs induce a significant improvement in the serum albumin concentration in hemodialysis but not peritoneal dialysis subjects. Further study of their long-term effects on morbidity and mortality is warranted.

Effect of dietary phosphorus, calcium, and phytase on performance of growing turkeys.

Female and male turkeys were fed 110, 73, 52, and 30% of the NRC (1994) nonphytate P (NPP) requirement without and with 500 phytase units (FTU)/kg during 4 to 14 or 16 wk of age, respectively. At 110% P (control; also 110% of NRC Ca), phytase was without effect. At 73% of NPP (100% Ca), without phytase, performance was similar to the control; with phytase, performance was equivalent, and in some stages, superior to the control. At 52% of NPP (90% Ca), performance was inferior without phytase and was variably similar or poorer than the control with phytase. At 30% NPP without phytase, poults gained poorly and showed a high incidence of leg disorder at 8 wk when they were removed from experiment; poults gained better with 80% NRC Ca compared with 110%. At 30% NPP with phytase, turkeys performed remarkably well, although suboptimally, at 80 or 110% NRC Ca. Phytase at 400, 300, and 200 FTU/kg with increasing age periods performed as well as 500 FTU/kg with 73% of NRC NPP (100% Ca) and 52% NRC NPP (90% Ca). These lower phytase levels were not as sufficient as 500 FTU/kg with 30% of NRC NPP; this inadequacy was more severe with higher dietary calcium. Phytase was effective in reducing dietary P requirements of growing turkeys when the NPP levels were below NRC (1994) requirements.

Hepatoblastoma with erythrocytosis in a young female horse.

A 2.5-year-old female Thoroughbred was examined because of lethargy, anorexia, and weight loss. Analysis of a CBC revealed erythrocytosis and an increase in PCV. Serum biochemical analysis revealed increases in activities of several hepatic enzymes. Ultrasonography revealed hepatomegaly and a heterogeneous appearance of the hepatic parenchyma. The horse did not improve despite supportive care, and it was euthanatized. Necropsy revealed numerous raised white to gray foci in the liver. Histologically, these foci consisted of neoplastic cells that resembled fetal hepatocytes, embryonal-type cells, and cells with features intermediate between those 2 cell types. Immunohistochemical staining revealed that hepatocytes stained strongly with anti-alpha-fetoprotein. On the basis of these results, hepatoblastoma was diagnosed. Diagnosis of hepatoblastoma is difficult, because it can appear histologically similar to other hepatic tumors, such as hepatocellular carcinomas. Definitive diagnosis requires histologic evaluation of tumor architecture and cell morphology. Immunohistochemical staining for alpha-fetoprotein in tumor cells may serve as a tumor marker but is not pathognomonic of hepatoblastoma. Paraneoplastic syndromes, such as erythrocytosis, can accompany hepatoblastoma. The prognosis for horses with hepatoblastoma is grave.

Enteral infusion of sodium 2-ketoisocaproate in endotoxic rats.

OBJECTIVE: In view of our previous finding that the intravenous infusion of 2-ketoisocaproate (KIC) improved survival in septic rats, we endeavored to determine whether the enteral infusion of KIC improves survival in endotoxic rats, and, if so, the mechanism of this effect. SUBJECTS: Eighty-five rats were given 15 mg/kg of Escherichia coli lipopolysaccharide (026:B6). INTERVENTIONS: KIC, sodium pyruvate (PYR), or sodium bicarbonate (HCO3) was infused continuously intragastrically at 18.75 mmol/kg/day. MEASUREMENTS AND MAIN RESULTS: KIC administration increased circulating concentrations of KIC and ketone bodies. Survival rates were: KIC 17/32; PYR 2/22; and HCO3 8/31. The significant improvement in survival with KIC, in contrast with HCO3 (p<.04) or PYR (p<.002), points to an effect specific to KIC rather than to ketoacids generally, and argues against an antioxidant mechanism to explain improved survival with enteral administration. To determine whether altered nitric oxide production was responsible, plasma nitrite plus nitrate concentrations were measured sequentially in rats given a lower dose of lipopolysaccharide plus continuous intragastric KIC, PYR, or HCO3. All rats exhibited pronounced increases in plasma nitrite plus nitrate concentrations, peaking at 8 hrs, but both KIC and PYR caused greater increases than HCO3. Thus, differences in nitric oxide production cannot account for the different effects of PYR and KIC on survival. However, KIC infusion for 8 hrs substantially increased ketone bodies in blood and liver, in comparison with the infusion of HCO3 or PYR. CONCLUSION: Continuous enteral infusion of KIC improves survival in endotoxemia, probably by its conversion to ketone bodies, which serve as an alternative energy substrate.

Synovial chondromatosis in raptors.

Fourteen raptors, consisting of 13 great horned owls (Bubo virginianus) and one red-tailed hawk (Buteo jamaicensis), from central and north central Minnesota, western Wisconsin, and eastern South Dakota (USA) were admitted to a raptor rehabilitation center between June 1992 and June 1995, with perisynovial and synovial chondromatosis affecting multiple joints. Birds were severely debilitated primarily due to loss of shoulder motion. The etiology of these lesions in raptors is unknown.

Can renal replacement be deferred by a supplemented very low protein diet?

Patients with chronic renal failure are commonly started on renal replacement therapy (RRT) as soon as (or, in some centers, before) the usual criteria for severity are met, i.e., GFR <10 ml/min for nondiabetic patients and <15 ml/min for diabetic patients. To determine whether RRT can safely be deferred beyond this point, adults with all types of chronic renal failure who met these criteria on presentation (23 patients) or who reached these levels of severity during treatment (53 patients) were managed conservatively until RRT was judged necessary by their chosen dialysis or transplantation team, without input into this decision from the present authors. Patients were prescribed a very low protein diet (0.3 g/kg) plus supplemental essential amino acids and/or ketoacids and followed closely. The intervals between the time at which GFR became less than 10 ml/min (15 ml/min in diabetic patients) and the date at which renal replacement therapy was started were used as estimates of renal survival on nutritional therapy. Kaplan-Meier analysis showed median renal survival of 353 d. Acidosis and hypercholesterolemia were both predictive of shorter renal survival. Signs of malnutrition did not develop. Final GFR averaged 5.6 +/- 1.9 ml/min. Two patients died; thus, annual mortality was only 2.5%. Hospitalizations totaled 19 in 93 patient-years of treatment, or 0.2 per year. Thus, these well motivated patients with GFR <10 ml/min (<15 ml/min in diabetic patients) were safely managed by diet and close follow-up for a median of nearly 1 yr without dialysis. It is concluded that further study of this approach is indicated.