The effect of intra-operative hypotension on acute kidney injury, postoperative mortality and length of stay following emergency hip fracture surgery.

The association between intra-operative hypotension and postoperative acute kidney injury, mortality and length of stay has not been comprehensively evaluated in a large single-centre hip fracture population. We analysed electronic anaesthesia records of 1063 patients undergoing unilateral hip fracture surgery, collected from 2015 to 2018. Acute kidney injury, 3-, 30- and 365-day mortality and length of stay were evaluated to assess the relationship between intra-operative hypotension absolute values (≤ 55, 60, 65, 70 and 75 mmHg) and duration of hypotension. The rate of acute kidney injury was 23.7%, mortality at 3-, 30- and 365 days was 3.7%, 8.0% and 25.3%, respectively, and median (IQR [range]) length of stay 8 (6-12 [0-99]) days. Median (IQR [range]) time ≤ MAP 55, 60, 65, 70 and 75 mmHg was 0 (0-0.5[0-72.1]); 0 (0-4.4 [0-104.9]); 2.2 (0-8.7 [0-144.2]); 6.6 (2.2-19.7 [0-198.8]); 17.5 (6.6-37.1 [0-216.3]) minutes, and percentage of surgery time below these thresholds was 1%, 2.5%, 7.9%, 12% and 21% respectively. There were some univariate associations between hypotension and mortality; however, these were no longer evident in multivariable analysis. Multivariable analysis found no association between hypotension and acute kidney injury. Acute kidney injury was associated with male sex, antihypertensive medications and cardiac/renal comorbidities. Three-day mortality was associated with delay to surgery ? 48 hours, whilst 30-day and 365-day mortality was associated with delay to surgery ≥ 48 hours, impaired cognition and cardiac/renal comorbidities. While the rate of acute kidney injury was similar to other studies, use of vasopressors and fluids to reduce the time spent at hypotensive levels failed to reduce this complication. Intra-operative hypotension at the levels observed in this cohort may not be an important determinant of acute kidney injury, postoperative mortality and length of stay.

Very early mobilisation and complications in the first 3 months after stroke: further results from phase II of A Very Early Rehabilitation Trial (AVERT).

BACKGROUND: Interventions that may reduce the number and severity of potentially harmful post-stroke complications are desirable. This study explored whether very early and frequent mobilisation (VEM) affected complication type (immobility/stroke related), number and severity. METHODS: Secondary analysis from phase II, randomised controlled trial. Patients admitted within 24 h of stroke, whose physiological parameters fell within set limits, were randomised to either VEM, commencing <24 h, or standard care. Complications to 3 months were recorded by a blinded assessor and classified by a neurologist. Analysis was intention to treat. RESULTS: Seventy-one patients were recruited (standard care 33; VEM 38).There were no significant group differences in the number, type or severity of complications by 3 months, and most patients (81.6%) experienced one or more complications. Falls were common, while depression was absent. The multivariate analysis showed older age (OR 1.10, 95% CI: 1.02-1.18, p = 0.009) and longer length of stay (OR 1.18, 95% CI: 1.06-1.32, p = 0.002) were associated with experiencing an immobility-related complication. CONCLUSION: Interventions that promote recovery and reduce complications may consequently reduce length of stay. The larger phase III trial currently underway may shed light on whether increasing mobilisation reduces complications after stroke.

Hepatic inflammatory responses to alphaalpha-cross-linked hemoglobin infusion in rats.

Cross-linked hemoglobin (alphaalpha-Hb) may be a useful red blood cell substitute if it can be administered safely. However, cell-free hemoglobin has inherent properties that may cause oxidant-mediated toxicity. We investigated whether alphaalpha-Hb induces oxidative or inflammatory responses that lead to liver damage. alphaalpha-Hb (0.5 or 1.0 gm/kg) was infused into rats, and indices of liver injury, inflammation, and oxidative stress were examined. Although focal hepatic necrosis was noted at 24 hours, plasma alanine aminotransferase activity was not increased and lesions were resolved by 48 hours. Modest neutrophil accumulation in hepatic vessels, but not sinusoids, occurred at 24 hours. Heme oxygenase-1 (HO-1) protein and activity were induced in a dose- and time-dependent manner, with maximal induction at 24 hours. Plasma tumor necrosis factor-alpha levels were not significantly increased. Additional cytokine- and oxidant-mediated events such as nuclear transcription factor-kappaB activation and nitric oxide synthase induction were not observed. These results suggest that alphaalpha-Hb-derived products such as heme and ferric iron (Fe3+), potent inducers of HO-1, are responsible for increasing HO-1. HO-1 induction may be a protective response by the liver to metabolize excess heme and Fe3+, thereby providing antioxidative products to counter the potentially damaging oxidants produced by Fe3+-catalyzed reactions.

Neon heavy charged particle radiotherapy of glioblastoma of the brain.

PURPOSE: High-linear energy transfer (LET) radiation beams have potential applications in the treatment of glioblastoma, but have not yet demonstrated significant improvement in results. However, some patients have had local control of glioblastoma with high-LET irradiations such as neutrons and heavy charged particles. METHODS AND MATERIALS: In this collaborative study, 15 patients were entered into a randomized protocol comparing two dose levels of 20 and 25 Gy in 4 weeks of neon ion irradiation. This trial was intended to determine the optimal neon dose in terms of survival and effects of radiation. RESULTS: Fourteen patients were evaluable with no significant differences in median survival (13 and 14 months; p = NS) or median time to failure (7 and 9 months; p = NS) between the two dose arms. Three patients died of nontumor-related causes, of whom one (who died 19 months posttreatment) had autopsy confirmation of no tumor on pathological exam. The other two patients had stable magnetic resonance imaging scans at 6 and 22 months posttreatment. CONCLUSION: Although the results did not demonstrate the optimal high-LET dose level, there is an intriguing effect in that two patients had control of glioblastoma until death at 19 and 22 months. This suggests that better conformation of the high-LET dose to the tumor with neutron capture therapy or dynamic conformal heavy charged particle therapy might control glioblastoma while minimizing brain damage from radiation.

Protein tyrosine kinase activity regulates nitric oxide synthase induction in rat hepatocytes.

Regulation of induced nitric oxide synthase (NOS) in isolated rat hepatocytes is poorly understood. The specific protein tyrosine kinase inhibitor genistein was used to determine if NOS induction is dependent on protein tyrosine kinase activation. Genistein inhibited tumor necrosis factor-alpha (TNF-alpha)-stimulated induction of NOS activity and NOS protein in a dose-dependent manner. Genistein also impaired TNF-alpha-induced NOS mRNA accumulation, suggesting protein tyrosine kinase regulation of NOS induction occurred at the level of transcription-translation. Like TNF-alpha, genistein inhibited induction of NOS protein by a second proinflammatory cytokine, interleukin-1beta, suggesting similar activation mechanisms by proinflammatory cytokines. NOS induction by other stimuli, including phorbol 12-myristate 13-acetate and the superoxide-generating system xanthine/xanthine oxidase, was also inhibited by genistein. Finally, cytokine-stimulated protein tyrosine kinase activity in hepatocytes was demonstrated by increased tyrosine phosphorylation of five high molecular mass protein bands. Genistein inhibited this cytokine-induced phosphotyrosine increase. The commonality of genistein inhibition suggests that protein tyrosine kinase activity is critical for NOS induction by a variety of stimuli.

Helium-ion-induced human cataractogenesis.

Retrospective and ongoing analyses of clinical records from 347 primary intraocular melanoma patients treated with helium ions at LBL will allow examination of the exposure-response data for human cataract; which is a complication of the therapy from incidental exposure of the lens. Direct particle beam traversal of at least a portion of the lens usually is unavoidable in treatment of posterior intraocular tumors. The precise treatment planned for each patient permits quantitative assessment of the lenticular dose and its radiation quality. We are reporting our preliminary results on the development of helium-ion-induced lens opacifications and cataracts in 54 of these patients who had 10% or less of their lens in the treatment field. We believe these studies will be relevant to estimating the human risk for cataract in space flight.

Experience in charged particle irradiation of tumors of the skull base: 1977-1992.

PURPOSE: To review the experience at University of California Lawrence Berkeley Laboratory in using charged particles to irradiate primary neoplasms of the skull base and those extending to the skull base from the nasopharynx and paranasal sinuses. METHODS AND MATERIALS: During the period from 1977 to 1992, 223 patients were irradiated with charged particles at the Lawrence Berkeley Laboratory for tumors either arising in or extending to the skull base, of whom 48 (22%) had recurrent lesions, either post previous surgery or radiotherapy. One hundred twenty-six patients had lesions arising in the cranial base, mostly chordoma (53), chondrosarcoma (27), paraclival meningioma (27) with 19 patients having other histologies such as osteosarcoma or neurofibrosarcoma. There were also 31 patients with primary or recurrent squamous carcinoma of the nasopharynx extending to the skull base, 44 patients with major or minor salivary gland tumors, mostly adenocarcinoma, and 22 patients with squamous carcinoma of the paranasal sinuses, all with cranial base extension. RESULTS: Local control and survival appeared improved in tumors arising in the skull base, following the ability with charged particles to deliver high doses (mean of 65 Gy-equivalent) with relative sparing of the adjacent normal tissues. The Kaplan-Meier 5-year local control was 85% for meningioma, 78% for chondrosarcoma, 63% for chordoma and 58% for other sarcoma. Follow-up ranged from 4-191 months with a median of 51 months. CONCLUSION: Charged particle radiotherapy is highly effective in controlling cranial base lesions which have have been partially resected. Better tumor localization with CT and MRI, improved 3-D treatment planning and beam delivery techniques have continued to reduce the level of serious complications and increase local control and survival.

Evaluation of fixed- versus variable-modulation treatment modes for charged-particle irradiation of the gastrointestinal tract.

The clinical usefulness of variable-modulation dose delivery of neon ion and proton beams over fixed-modulation beams is evaluated for several patients with tumors in the gastrointestinal tract by comparing dose distributions, dose volume histograms, and predictions of normal tissue complication probabilities calculated with the two methods. Both techniques provide excellent coverage of the target volume with neon ion and proton beams. The advantage of variable modulation is that less dose is delivered proximal to the target volume. For tumors in the gastrointestinal tract, this implies that less dose is given to the liver, gut, kidneys, and lungs. For the ten patients considered in this study, variable-modulation reduced the total integral dose by an average of 17% for neon ion beams and by 18% for protons as compared to fixed-modulation. If the tumor volume is excluded, the reduction in the integral dose to normal tissues ranged from 15% to 32% for neon ions and from 18% to 34% for proton beams. These gains are larger than those anticipated on the basis of an analytic study by Goitein and Chen [Med. Phys. 10, 831-840 (1983)], which predicted integral dose reductions of the order of 10% for protons and 14% for neon ions. They are also larger than those reported in a similar study by Urie and Goitein [Med. Phys. 16, 593-601 (1989)] for proton irradiation of skull-base tumors. This is probably because the tumors in the GI tract considered in this study were more irregularly shaped than Goitein and Chen's analytic model assumes. The results of this study also suggest that due to increased sparing of normal tissues, the number of different portal directions required to achieve a satisfactory treatment plan will be reduced for variable-modulation beam delivery systems. This implies that variable-modulation treatment plans will be easier to execute than current fixed-modulation plans.

Ellagic acid protects rat embryos in culture from the embryotoxic effects of N-methyl-N-nitrosourea.

Ellagic acid is a naturally occurring plant phenol that has demonstrated anticarcinogenic and antimutagenic activity in several test systems. Given the common proposed etiopathogenic processes of mutagenesis, carcinogenesis, and teratogenesis induced by genotoxic chemicals, the present study was initiated to determine whether ellagic acid would protect rat embryos in culture from the teratogenic effects of N-methyl-N-nitrosourea (MNU). Ellagic acid alone (as used in these experiments; 50 microM in DMSO) was not embryotoxic. Ellagic acid (50 microM) significantly (P less than 0.01) prevented MNU (75 microM)-induced effects including mortality (absence of heart beat), abnormal formation of the cephalic neural tube derivatives, and delayed differentiation as assessed by a morphological scoring system. These embryoprotective effects were dose responsive. Sequential treatment of embryos with ellagic acid followed by MNU in fresh media also was embryoprotective with no diminution of effect. The site at which ellagic acid interrupts the critical teratogenic events induced by MNU is apparently within the embryo and/or placenta. This model of chemical embryoprotection may be useful in determining the role of cell death and/or mutation in the teratogenic mechanism of action of methylating agents.

Flow cytometric analysis of thymic lymphosarcoma induced by N-methyl-N-nitrosourea in C57B1/6J mice.

N-Methyl-N-nitrosourea (MNU) induces thymic lymphosarcoma in numerous mouse strains. We determined the neoplastic phenotype induced by MNU in 20 C57B1/6J mice. Eleven neoplasms were composed of cells that were CD4-CD8+, four neoplasms were composed of cells that were CD4+CD8+, two neoplasms were mixtures of CD4+CD8+ and CD4-CD8+ cells, and three neoplasms were made up of cells that expressed neither CD4 nor CD8. Expanded populations of CD4+CD8- cells were observed within individual neoplasms. Of 10 neoplasms that were further classified, all were composed of cells that were J11d+, indicating immaturity. CD3 expression was generally negative, while IL2R expression was variable in these neoplasms. These data from C57B1/6J mice, a strain with a low incidence of spontaneous (viral-associated) thymic lymphosarcoma, indicate that a continuous spectrum of immature phenotypes are produced by MNU. The finding that each immature cell population can be expanded in this model system differs from previous reports. Our data do confirm the general finding in AKR mice, a strain with a high incidence of spontaneous thymic lymphosarcoma, that cells with immature phenotypes, particularly CD4-CD8+J11d+, make up MNU-induced thymic lymphosarcomas.

Preliminary results in heavy charged particle irradiation of bone sarcoma.

Between 1979 and 1989, 17 patients with unfavorable bone sarcoma were treated wholly or in part with heavy charged particle irradiation (helium and/or neon ions) at the University of California Lawrence Berkeley Laboratory. The majority of tumors were located near critical structures such as the spinal cord or brain. Gross tumor was present in all but two patients at the time of irradiation. Six patients were treated for recurrent disease. Histologies included osteosarcoma, Ewing's sarcoma, and recurrent osteoblastoma. Four of the osteosarcomata were believed to have been induced by previous therapeutic irradiation for various tumors. Follow-up time since initiation of radiation ranged from 7 to 118 months (median 40 months). The 5-year Kaplan-Maier local control rate was 48%; the corresponding survival rate was 41%. Over half the patients succumbed to distant metastases despite the majority of patients receiving chemotherapy. In this preliminary study, we have shown that heavy charged particle irradiation can be effectively used for control of bone sarcoma. A Phase II trial is warranted to determine optimal treatment for unresectable or gross residual disease.

Clinical gain from improved beam delivery systems.

The feasibility of dynamic conformal heavy charged particle radiotherapy has been investigated at UCLBL, and shows high promise of: 1. an improved therapeutic ratio and 2. reduction in the number of treatment portals required for efficient treatment delivery. Assessment of dose to tumor and critical structures for several anatomical sites have been carried out using a normal tissue complication algorithm developed at LBL. For high-LET charged particle treatment delivery, dynamic conformal therapy using a raster scanned beam with variable modulation and multileaf collimator appears to be the optimal technique for treatment delivery.

Recurrent locally advanced nasopharyngeal carcinoma treated with heavy charged particle irradiation.

Between June 1981 and May 1990, 11 patients with recurrent locally advanced nasopharyngeal carcinoma were treated with heavy charged particle radiation at Lawrence Berkeley Laboratory. All patients had previously undergone full course radiotherapy to a median dose of 70.2 Gy [range 61-81 Gy]. Median time to recurrence was 18.2 months. At the time of heavy charged particle radiotherapy treatment, all had evidence of invasion of the base of skull and 7 of 11 had cranial nerve deficits. None of the patients were candidates for brachytherapy because of tumor extent or poor geometry. The tumor histology was squamous cell carcinoma in 10 patients and lymphoepithelioma in one patient. Ten of the 11 patients had received chemotherapy prior to re-irradiation. The heavy charged particle tumor dose delivered ranged from 31.80 GyE to 62.30 GyE (average 50.25 GyE, median 50 GyE). Local control was achieved in 45%. Median survival was 42 months. Actuarial survival was 59% at 3 years and 31% at 5 years (Kaplan-Meier). There were no fatal complications. The results in treating locally advanced recurrent nasopharyngeal carcinoma with heavy charged particles appear superior to those reported by others using photon therapy.

Charged particle radiotherapy of paraspinal tumors.

Between 1976 and 1987, 52 patients with tumors adjacent to and/or involving the cervical, thoracic, or lumbar spinal cord were treated with charged particles at the University of California Lawrence Berkeley Laboratory. The histologies included chordoma and chondrosarcoma (24 pts), other bone and soft tissue sarcoma (14 pts), and metastatic or unusual histology tumors (14 pts). Radiation doses ranged from 29 to 80 Gray-equivalent (GyE), with a median dose of 70 GyE. Twenty-one patients received a portion of their treatment with photons. Median followup was 28 months. For 36 previously untreated patients, local control was achieved in 21/36 patients and the 3-year actuarial survival was 61%. Of 16 patients treated for recurrent disease, 7/16 were locally controlled and the 3-year actuarial survival was 51%. For patients treated for chordoma and chondrosarcoma, probability of local control was influenced by tumor volume (less than 100 cc or greater than 150 cc) and whether disease was recurrent or previously untreated. Complications occurred in 6/52 patients, including one spinal cord injury, one cauda equina and one brachial plexus injury, and three instances of skin or subcutaneous fibrosis. Charged particle radiotherapy can safely deliver high tumor doses to paraspinal tumors with good local control.

The effect of patient motion on dose uncertainty in charged particle irradiation for lesions encircling the brain stem or spinal cord.

A specialized charged-particle radiotherapy technique developed at Lawrence Berkeley Laboratory (LBL) is applied to patients with lesions abutting or surrounding the spinal cord or brain stem. This technique divides the target into two parts, one partially surrounding the critical structure (brain stem or spinal cord) and a second excluding the critical structure and abutting the first portion of the target. Compensators are used to conform the dose distribution to the distal surface of the target. This technique represents a novel approach in treating unresectable or residual tumors surrounding the spinal cord or brain stem. Since the placement of the patient with respect to beam-shaping devices is critical for divided-target treatments, a method for calculating dose distributions reflecting random patient motion is proposed, and the effects of random patient motion are studied for two divided-target patient examples. Dose-volume histograms and a normal-tissue complication probability model are used in this analysis. For the patients considered in this study, the normal-tissue-complication probability model predicts that random patient motion less than or equal to 0.2 cm is tolerable in terms of spinal cord complications.

A therapeutic benefit from combining normobaric carbogen or oxygen with nicotinamide in fractionated X-ray treatments.

The ability of normobaric oxygen and carbogen (95% O2 + 5% CO2) combined with nicotinamide to enhance the radiosensitivity of two rodent adenocarcinomas and of mouse skin and kidneys, using a 10 fraction radiation schedule, was compared with the effect of radiation in air with and without the drug. Tumour response was assayed using local control and regrowth delay, and compared with acute skin reactions, decreased renal 51Cr-EDTA clearance and reduction in haematocrit. Nicotinamide increased the radiation sensitivity of CaNT tumours under all three different oxygen concentrations tested (21, 95 and 100% oxygen). The effect was statistically significant for oxygen and carbogen but not for air; the combination of nicotinamide with carbogen gave the greatest increase in tumour radiosensitivity. Relative to treatments in air without the drug, the enhancement ratios (ER) at the TCD50 level were 1.17, 1.65 and 1.83 for CaNT tumours irradiated in air, oxygen or carbogen and injected with nicotinamide 1 h before each fraction. The ER in CaRH tumours irradiated in carbogen plus the drug was 1.83, which was greater, but statistically not significantly different, to that seen with carbogen alone (ER = 1.68). In skin, relative to air without the drug, the increase in radiosensitivity by nicotinamide was greater in oxygen and carbogen than in air (1.29, 1.36 and 1.08, respectively). The ERs for both assays of renal damage were similar and lower than those in skin: less than or equal to 1.07, less than or equal to 1.13 and less than or equal to 1.16 for irradiations done in air, oxygen and carbogen plus nicotinamide, relative to air alone. A comparison of these results in the tumours and normal tissues showed that a significant therapeutic benefit was obtained with normobaric oxygen and carbogen combined with nicotinamide. This benefit is greater than observed with other radiosensitizers tested so far. Toxic side effects of the treatment are unlikely in a clinical situation, since prolonged administration of nicotinamide is well tolerated in man. The combination of normobaric carbogen with nicotinamide could be an effective method of enhancing tumour radiosensitivity in clinical radiotherapy where hypoxia limits the outcome of treatment.

Design of beam-modulating devices for charged-particle therapy.

The computer modeling program used to design beam-modulating devices for charged-particle therapy at Lawrence Berkeley Laboratory has been improved to allow a more realistic description of the beam. The original program used a single calculated Bragg peak to design the spread Bragg peak. The range of this curve was shifted so that Bragg curves of varying ranges could be superimposed. The new version of the program allows several measured Bragg curves with different ranges to be used as input, and interpolates between them to obtain the required data for the superposition calculation. The experimental configuration for measuring these input curves simulated therapy conditions. Seven beam-modulating propellers with spread Bragg-peak widths ranging from 2.2 to 14.4 cm were designed and constructed for a 215-MeV/u helium beam using this new design program. Depth-dose distributions produced by these new propellers were in good agreement with predicted distributions, and these propellers are currently being used clinically.

Charged particle radiotherapy for lesions encircling the brain stem or spinal cord.

Since 1981, a specialized technique has been under development at the University of California Lawrence Berkeley Laboratory for charged particle irradiation of tumors partially or completely encircling the brain stem or spinal cord. By dividing the target volume into two or more portions and using a combination of beams, a reasonably homogeneous irradiation of the target volume can be obtained which protects critical CNS structures from over-irradiation. This technique requires knowledge of the physical and biological effects of charged particles, precise, reproducible patient immobilization, careful treatment planning based upon Metrizamide contrast CT and/or MRI scanning, compensation for tissue inhomogeneities, and accurate, verifiable radiation delivery. Uncertainties in the dose distribution must be taken into account when prescribing treatment. We have used this technique in 47 patients with a variety of tumors abutting the brain stem and spinal cord, including chordoma, chondrosarcoma, meningioma, osteosarcoma and metastatic tumors. The results have shown a significant local control rate (62%) and the incidence of serious complications has been acceptable (13%). The median follow-up is 20 months with a range of 6-90 months. We conclude that charged particles can be safely and effectively used to irradiate lesions encircling the brain stem or spinal cord to doses higher than can be achieved with low-LET irradiation.

Charged particle irradiation of chordoma and chondrosarcoma of the base of skull and cervical spine: the Lawrence Berkeley Laboratory experience.

Forty-five consecutive patients with chordoma or chondrosarcoma at the base of skull or cervical spine were treated at the University of California Lawrence Berkeley Laboratory (UCLBL) and University of California School of Medicine, San Francisco (UCSF) between November 1977 and October 1986. All patients had undergone a subtotal surgical resection. Twenty-three patients were treated definitively with charged particles, 13 patients were treated with photons and particles, and 9 patients were treated for recurrent disease. Total doses ranged from 36 to 80 Gray equivalent (GyE). Thirty-three patients are alive with a minimum followup of 1 year. The actuarial survival and local control for all patients at 5 years is 62% and 59%, respectively. Patients treated for primary disease had a 78% actuarial local control rate at 2 years, whereas the rate for patients with recurrent disease was 33%. Patients with smaller visible tumor volumes (less than 20 cc) had a significantly better local control rate than patients with larger tumor volumes (80% vs 33% actuarial rate at 5 years). Patients with chondrosarcoma had the highest local control rate, as did patients treated with particles alone. Complications included 3 patients with unilateral visual loss, two patients who became blind, and 4 patients with radiation injury to the brainstem.