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.

High throughput quantification of the functional genes associated with RDX biodegradation using the SmartChip real-time PCR system.

The explosive hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) is a contaminant at many military sites. RDX bioremediation as a clean-up approach has been gaining popularity because of cost benefits compared to other methods. RDX biodegradation has primarily been linked to six functional genes (diaA, nfsI, pnrB, xenA, xenB, xplA). However, current methods for gene quantification have the risk of false negative results because of low theoretical primer coverage. To address this, the current study designed new primer sets using the EcoFunPrimer tool based on sequences collected by the Functional Gene Pipeline and Repository and these were verified based on residues and motifs. The primers were also designed to be compatible with the SmartChip Real-Time PCR system, a massively parallel singleplex PCR platform (high throughput qPCR), that enables quantitative gene analysis using 5,184 simultaneous reactions on a single chip with low volumes of reagents. This allows multiple genes and/or multiple primer sets for a single gene to be used with multiple samples. Following primer design, the six genes were quantified in RDX-contaminated groundwater (before and after biostimulation), RDX-contaminated sediment, and uncontaminated samples. The final 49 newly designed primer sets improved upon the theoretical coverage of published primer sets, and this corresponded to more detections in the environmental samples. All genes, except diaA, were detected in the environmental samples, with xenA and xenB being the most predominant. In the sediment samples, nfsI was the only gene detected. The new approach provides a more comprehensive tool for understanding RDX biodegradation potential at contaminated sites.

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.

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.

Vision following helium ion radiotherapy of uveal melanoma: a Northern California Oncology Group study.

One hundred eighty-six uveal melanoma patients were treated with helium ion radiotherapy at Lawrence Berkeley Laboratory and followed for at least 6 months. (Follow-up times ranged from 6 to 90 months; median 26.4 months.) At last examination, 92 of 186 patients (49%) had visual acuity of 20/200 or better in the treated eye. Univariate statistical analysis revealed that post-treatment vision correlated with tumor size, distance between tumor and optic disc, distance between tumor and fovea, pretreatment visual acuity, dose delivered to the optic disc, and dose delivered to the fovea (p less than .05). Neither the maximum tumor dose nor site of tumor origin (ciliary body vs. choroid) correlated with post-treatment vision on a univariate basis. However, multivariate statistical analysis revealed that the strongest independent risk factors influencing vision outcome (p less than .05) were tumor size, pretreatment visual acuity, tumor-fovea distance, and maximum tumor dose. Neither the fovea dose nor the dose to optic disc appeared to significantly affect vision outcome when other variables were taken into account. These results suggest that post-treatment visual acuity of 20/200 or better can be achieved in one-half of uveal melanoma patients treated using helium ion irradiation. Several independent risk factors affecting vision outcome have been identified.

Treatment planning study for carcinoma of the esophagus: helium ions versus photons.

Helium ion radiotherapy significantly reduces dose to adjoining critical structures in the treatment of carcinoma of the esophagus when the same treatment plan is compared with megavoltage photon therapy. A five-field 18 MV photon treatment plan, selected to minimize lung dose, is compared with helium ions using the same field configuration. Dose volume histograms show target coverage, as well as dose delivered to critical structures lung, heart, mediastinum, and spinal cord. Although both helium ions and photons deliver approximately the same lung dose for this treatment plan, radiation to the heart and spinal cord from this field arrangement is significantly reduced with the helium ion beam. The concentration of dose at the tumor site, while sparing surrounding normal tissue, is characteristic of charged particle therapy, particularly with light ions, which includes particles with Z from that of protons (Z = 1) through that of neon (Z = 10).

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.

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.

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 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.

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.

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.

Precision, high dose radiotherapy: helium ion treatment of uveal melanoma.

We report on 75 patients with uveal melanoma who were treated by placing the Bragg peak of a helium ion beam over the tumor volume. The technique localizes the high dose region very tightly around the tumor volume. This allows critical structures, such as the optic disc and the macula, to be excluded from the high dose region as long as they are 3 to 4 mm away from the edge of the tumor. Careful attention to tumor localization, treatment planning, patient immobilization and treatment verification is required. With a mean follow-up of 22 months (3 to 60 months) we have had only five patients with a local recurrence, all of whom were salvaged with another treatment. Pretreatment visual acuity has generally been preserved as long as the tumor edge is at least 4 mm away from the macula and optic disc. The only serious complication to date has been an 18% incidence of neovascular glaucoma in the patients treated at our highest dose level. Clinical results and details of the technique are presented to illustrate potential clinical precision in administering high dose radiotherapy with charged particles such as helium ions or protons.

Precision, high dose radiotherapy. II. Helium ion treatment of tumors adjacent to critical central nervous system structures.

In this paper we present a technique for treating relatively small, low grade tumors located very close to critical, radiation sensitive central nervous system structures such as the spinal cord and the brain stem. A beam of helium ions is used to irradiate the tumor. The nearby normal tissues are protected by exploiting the superb dose localization properties of this beam, particularly its well defined and controllable range in tissue, the increased dose deposited near the end of this range (i.e., the Bragg peak), the sharp decrease in dose beyond the Bragg peak, and the sharp penumbra of the beam. To execute this type of treatment, extreme care must be taken in localization of the tumor and normal tissues, as well as in treatment planning and dosimetry, patient immobilization, and verification of treatment delivery. To illustrate the technique, we present a group of 19 patients treated for chordomas, meningiomas and low grade chondrosarcomas in the base of the skull or spinal column. We have been able to deliver high, uniform doses to the target volumes (doses equivalent to 60 to 80 Gy of cobalt-60) while keeping the doses to the nearby critical tissues below the threshold for radiation damage. Follow-up on this group of patients is short, averaging 22 months (2 to 75 months). Currently, 15 patients have local control of their tumor. Two major complications, a spinal cord transection and optic tract damage, are discussed in detail. Our treatment policies have been modified to minimize the risk of these complications in the future, and we are continuing to use this method to treat such patients. We are enthusiastic about this technique, since we believe there is no other potentially curative treatment for these patients.

A phase I-II trial of heavy charged particle irradiation of malignant glioma of the brain: a Northern California Oncology Group Study.

Thirty-nine patients with primary or recurrent glioma of the brain were irradiated wholely or in part with heavy charged particle beams at the University of California Lawrence Berkeley Laboratory in a Phase I-II clinical trial of the Northern California Oncology Group. During the course of this trial, treatment techniques have been developed and tumor doses have been escalated in order to obtain data on normal brain toxicity and response of malignant glioma of the brain. Toxicity has been acceptable with a low level of brain injury. Survival and tumor control has been approximately the same as historical results in glioma of the brain. Further dose escalation is planned together with possible trial of combined modality therapy.

Treatment of cancer with heavy charged particles.

A clinical radiotherapeutic trial using heavy charged particles in the treatment of human cancers has accrued over 400 patients since 1975, 378 of whom were treated with particles and 28 with low LET photons as control patients. Heavy charged particle radiotherapy offers the potential advantages of improved dose localization and/or enhanced biologic effect, depending on particle selected for treatment. Target sites have included selected head and neck tumors, ocular melanomata, malignant gliomata of the brain, carcinoma of the esophagus, carcinoma of the stomach, carcinoma of the pancreas, selected juxtaspinal tumors and other locally advanced, unresectable tumors. A Phase III prospective clinical trial has been started in carcinoma of the pancreas using helium ions. Phase I-II studies are underway with heavier particles such as carbon, neon and argon ions in order to prepare for prospective Phase III trials. Silicon ions are also under consideration for clinical trial. These studies are supported by the United States Department of Energy and National Institutes of Health.

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.

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.