The Effect of Breast Cancer Subtype on Symptom Improvement Following Palliative Radiotherapy for Bone Metastases.

AIM: To assess the relationship between breast cancer subtypes and patient-reported outcomes (PRO) following palliative radiotherapy for bone metastases. MATERIALS AND METHODS: Prospectively collected PRO for all breast cancer patients treated with palliative, bone metastasis-directed radiotherapy from 2013 to 2016 in the province of British Columbia were analysed. The PRO questionnaire scored pain severity, level of function and symptom frustration at baseline and at 3-4 weeks following palliative radiotherapy using a 12-point scale. The primary outcome was the rate of overall response (any improvement in score); the secondary outcome was the rate of complete improvement in PRO (final PRO score of 0). Multivariate logistic analysis was used to compare response rates between molecular subgroup approximations of luminal A (LumA), luminal B (LumB), HER2-enriched (HER2) and triple negative (TN), as defined by grade and immunohistochemical staining. RESULTS: There were 376 patients who underwent 464 courses of palliative radiation for bone metastases. Subtypes included: 243 LumA, 146 LumB, 46 HER2 and 29 TN. There were 216 multifraction radiotherapy courses (median dose 20 Gy) and 248 single-fraction radiotherapy courses (median dose 8 Gy). The overall response rate was 85% and the complete response rate was 25%. In comparison with LumA breast cancers, TN breast cancers were associated with a lower rate of overall response (69% versus 86%, P = 0.021) and a lower rate of complete response (10% versus 28.8%, P = 0.045) on multivariate analyses. CONCLUSION: Patients with TN breast cancer have lower rates of pain, function and symptom frustration improvement following palliative radiation for bone metastases.

Whole Brain Radiotherapy Versus Stereotactic Radiosurgery in Poor-Prognosis Patients with One to 10 Brain Metastases: A Randomised Feasibility Study.

AIMS: A significant proportion of patients with brain metastases have a poor prognosis, with a life expectancy of 3-6 months. To determine the optimal radiotherapeutic strategy for brain metastases in this population, we conducted a randomised feasibility study of whole brain radiotherapy (WBRT) versus stereotactic radiosurgery (SRS). MATERIALS AND METHODS: Patients with a life expectancy of 3-6 months and between one and 10 brain metastases with a diameter ≤4 cm were enrolled at six Canadian cancer centres. Patients were randomly assigned (1:1) to receive either WBRT (20 Gy in five fractions) or SRS (15 Gy in one fraction). The primary end point was the rate of accrual per month. Secondary feasibility and clinical end points included the ratio of accrued subjects to screened subjects. This trial is registered with ClinicalTrials.gov (number NCT02220491). RESULTS: In total, 210 patients were screened to enrol 22 patients into the trial; 20 patients were randomised between the two arms. Two patients did not receive treatment because one patient died and another patient withdrew consent after being enrolled. Patients were accrued between January 2015 and November 2017; the accrual rate was 0.63 patients/month. The most common reasons for exclusion were anticipated median survival outside the required range (n = 40), baseline Karnofsky Performance Score below 70 (n = 28) and more than 10 brain metastases (n = 28). The median follow-up was 7.0 months and the median survival was 7.0 months for all patients in the trial. The median intracranial progression-free survival was 1.8 months in the SRS arm and 9.2 months in the WBRT arm. There were five grade 3+ toxicities in the SRS arm and one grade 3+ toxicity in the WBRT arm; no grade 5 toxicities were observed. The cumulative rates of retreatment were 40% in the SRS arm and 40% in the WBRT arm. CONCLUSIONS: A randomised trial evaluating WBRT versus SRS in patients with one to 10 metastases and a poor prognosis is feasible. A slower than expected accrual rate and difficulties with accurate prognostication were identified as issues in this feasibility study. A larger phase III randomised trial is planned to determine the optimal treatment in this patient population.

In the Era After the European Organisation for Research and Treatment of Cancer 'Boost' Study, is the Additional Radiotherapy to the Breast Tumour Bed Still Beneficial for Young Women?

AIMS: The European Organisation for Research and Treatment of Cancer (EORTC) 22,881-10,882 trial showed significant benefit of a radiotherapy boost (RTB) in women ≤40 years in a pre-hormone therapy (HT) era. We determined how the use of HT and RTB changed in response to clinical guidelines and whether the benefit of routine RTB was still observed in the HT era. MATERIALS AND METHODS: Between 1996 and 2004, a provincial database identified all women ≤40 years with breast cancer who met the inclusion criteria of the EORTC trial. In total, 411 patients were classified into three eras defined by the guidelines: era 1 (discretionary HT, discretionary RTB); era 2 (routine HT, discretionary RTB); era 3 (routine HT, routine RTB). HT use, RTB use and cumulative incidence of local recurrence were calculated and compared across eras. RESULTS: HT use increased after the first policy change from 13% to 75% for oestrogen receptor-positive patients (P < 0.01). RTB use also increased from 33% to 76% following the second policy change (P < 0.01). At 10 years, the cumulative incidence of local recurrence was 12% in era 1, 6% in era 2 and 6% in era 3 (era 2 versus era 3, P = 0.92). For patients in the routine HT era (eras 2 and 3 combined) there was no significant difference in local recurrence between RTB and 'no RTB' patients (6% versus 7%, P = 0.81). CONCLUSIONS: The routine use of HT and RTB increased significantly after new practice guidelines. Introduction of the HT guideline was associated with a 6% improvement in local recurrence at 10 years. No improvement in local recurrence was associated with the introduction of the RTB guideline in the HT era. The routine use of a boost in unselected young women with negative margins should be re-evaluated in the current HT era.

The effect of a low-dose naloxone infusion on the incidence of respiratory depression after intrathecal morphine administration for major open hepatobiliary surgery: a randomised controlled trial.

Intrathecal morphine is an analgesic option for major hepatopancreaticobiliary procedures but is associated with a risk of respiratory depression. We hypothesised that a postoperative low-dose naloxone infusion would reduce the incidence of respiratory depression without an increase in pain scores. Patients scheduled for major open hepatopancreaticobiliary surgery and who were receiving 10 µg.kg-1 intrathecal morphine were eligible for inclusion. Patients were allocated randomly to receive a postoperative infusion of naloxone 5 µg.kg-1 .h-1 (naloxone group) or saline at an identical infusion rate (control group) until the morning after surgery. Clinicians, nursing staff and patients were blinded to group allocation. The primary outcome measure was the incidence of respiratory depression (respiratory rate < 10 breaths.min-1 and/or oxygen saturation < 90%). Secondary outcome measures included: arterial partial pressure of carbon dioxide; pain score; requirement for supplemental analgesic; and incidence of nausea and vomiting, pruritus and sedation. In total, data from 95 patients (48 in the naloxone group and 47 in the control group) were analysed. The incidence of respiratory depression was lower in the naloxone group compared with the control group (10/48 vs. 21/47 patients, respectively; p = 0.037, relative risk 0.47 (95%CI 0.25-0.87). Maximum pain scores were greater for patients allocated to the naloxone group compared with control (median 5 (95%CI 4-6) vs. 4 (95%CI 2-4), respectively; p < 0.001). A low-dose naloxone infusion decreases the incidence of respiratory depression following intrathecal morphine administration in patients having major hepatopancreaticobiliary surgery at the expense of a small increase in postoperative pain.

Laparoscopic Ovarian Transposition and Ovariopexy for Fertility Preservation in Patients Treated with Pelvic Radiotherapy with or without Chemotherapy.

BACKGROUND: Preservation of fertility in cancer patients of reproductive age is a concern for both the patient and the clinician. In this study, we aimed to study the effectiveness of laparoscopic ovarian transposition or ovariopexy in preserving ovarian function in women undergoing pelvic radiotherapy with or without chemotherapy for pelvic tumours. METHODS: The records of patients who underwent laparoscopic ovarian transposition or ovariopexy prior to pelvic radiation therapy between 2002 and 2018 were reviewed retrospectively. RESULTS: Thirty-nine women or adolescent girls with a diagnosis of cervical cancer (n=15), Hodgkin's lymphoma (n=6) or other types of pelvic tumours (n=18) were included in the study. The majority of patients had bilateral (n=25) or unilateral (n=8) ovarian transposition prior to radiotherapy. Nine out of 10 (90%) patients with soft tissue tumors, Ewing sarcoma or ependymoma, five out of seven (71.4%) patients with Hodgkin's lymphoma, two patients (100%) with rectal and anal cancer, and six out of 15 (40%) with cervical cancer retained ovarian function. Patients with cervical cancer, those who received concomitant chemotherapy and those older than 30 years were more likely to experience ovarian failure. Five patients conceived spontaneously and two women had four live births. CONCLUSION: Laparoscopic repositioning of the ovaries out of the radiation field in order to protect ovarian function in patients receiving radiotherapy appears to be effective in the majority of patients. The procedure seems safe and should be considered either as a sole procedure or in association with other fertility preservation methods prior to pelvic radiotherapy.

Patterns of spread and prognostic implications of lung cancer metastasis in an era of driver mutations.

BACKGROUND: In the present study, we examined the pattern of metastatic spread in patients with advanced non-small-cell lung cancer (nsclc) and the effect of EGFR mutations. METHODS: Patients were identified from a provincial cancer registry, and individual medical records were reviewed. Patients were included if they had stage iv nsclc and underwent diagnostic EGFR mutation testing. Patients were divided into EGFR mutation-positive (EGFR+) and EGFR wild type (wt) cohorts. The primary endpoint was the cumulative incidence for each metastatic site: lung, bone, brain, liver, adrenal glands, distant nodes, and other. Cumulative incidence curves were estimated using a competing-risks method. The secondary outcome was survival. RESULTS: Of the 543 identified patients, 121 (22.3%) tested as EGFR+, and 422 (77.7%) tested as EGFR wt. The incidence of brain (39.2% vs. 28.2%, p = 0.038) and lung (61.2% vs. 51.0%, p = 0.048) metastasis was higher in the EGFR+ cohort than in the EGFR wt cohort. In the EGFR+ cohort, a higher incidence of liver metastasis was associated with the exon 21 mutation subtype than with the exon 19 deletion subtype [23% vs. 7%, p < 0.01; hazard ratio (hr): 3.47]. Median survival was significantly longer for the EGFR+ cohort than for the EGFR wt cohort (22.4 months vs. 7.9 months, p < 0.001). In multivariable analysis, brain (hr: 1.73), liver (hr: 1.69), and bone (hr: 1.89) metastases were associated with worse survival. CONCLUSIONS: Rates of lung and brain metastases are higher in EGFR mutation carriers, even when adjusted for differences in survival. Brain, liver, and bone metastases are independent negative prognostic factors for survival.

Population-based analysis of the impact and generalizability of the NSABP-B24 study on endocrine therapy for patients with ductal carcinoma in situ of the breast.

BACKGROUND: In 1999, the National Surgical Adjuvant Breast and Bowel Project (NSABP)-B24 trial demonstrated that tamoxifen reduced relapse risk in women with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery (BCS) and radiotherapy (RT). In 2002, Allred's subgroup analysis showed that tamoxifen mainly benefitted estrogen receptor (ER)-positive disease. This study evaluates the impact and generalizability of these trial findings at the population level. PATIENTS AND METHODS: From 1989 to 2009, 2061 women with DCIS underwent BCS + RT in British Columbia. The following cohorts were analyzed: (1) pre-NSABP-B24 era (1989-1998, N = 417); (2) post-NSABP-B24 era (2000-2009, N = 1548). Cohort 2 was further divided into pre- and post-Allred eras. RESULTS: Endocrine therapy (ET) was used in 404/2061 (20%) patients. Median age of patients treated with compared with without ET, was 53 versus 57 years, (P < 0.0005). One of 417 (0.2%) versus 399/1548 (26%) patients took ET before versus after NSABP-B24. Among the post-Allred era cohort treated with ET (N = 227), tumors were ER-positive in 65%, ER-negative in 1%, and ER-unknown in 33%; whereas of those treated without ET (N = 801), ER was positive in 43%, negative in 15%, and unknown in 42% (P < 0.0005). On multivariable analysis of the post-NSABP-B24 era, ET was associated with improved event-free survival (EFS) (hazard ratio 0.6; P = 0.02); 5-year EFS were 96.9% with ET versus 94.5% without ET. CONCLUSIONS: ET use in DCIS patients treated with BCS + RT increased significantly after the NSABP-B24 study. ER+ disease and younger age were associated with increased ET use. ET was associated with improved EFS, confirming the generalizability of trial data at a population level.

Minimally invasive surgery plus recombinant tissue-type plasminogen activator for intracerebral hemorrhage evacuation decreases perihematomal edema.

BACKGROUND AND PURPOSE: Perihematomal edema (PHE) can worsen outcomes after intracerebral hemorrhage (ICH). Reports suggest that blood degradation products lead to PHE. We hypothesized that hematoma evacuation will reduce PHE volume and that treatment with recombinant tissue-type plasminogen activator (rt-PA) will not exacerbate it. METHODS: Minimally invasive surgery and rt-PA in ICH evacuation (MISTIE) phase II tested safety and efficacy of hematoma evacuation after ICH. We conducted a semiautomated, computerized volumetric analysis on computed tomography to assess impact of hematoma removal on PHE and effects of rt-PA on PHE. Volumetric analyses were performed on baseline stability and end of treatment scans. RESULTS: Seventy-nine surgical and 39 medical patients from minimally invasive surgery and rt-PA in ICH evacuation phase II (MISTIE II) were analyzed. Mean hematoma volume at end of treatment was 19.6±14.5 cm(3) for the surgical cohort and 40.7±13.9 cm(3) for the medical cohort (P<0.001). Edema volume at end of treatment was lower for the surgical cohort: 27.7±13.3 cm(3) than medical cohort: 41.7±14.6 cm(3) (P<0.001). Graded effect of clot removal on PHE was observed when patients with >65%, 20% to 65%, and <20% ICH removed were analyzed (P<0.001). Positive correlation between PHE reduction and percent of ICH removed was identified (ρ=0.658; P<0.001). In the surgical cohort, 69 patients underwent surgical aspiration and rt-PA, whereas 10 underwent surgical aspiration only. Both cohorts achieved similar clot reduction: surgical aspiration and rt-PA, 18.9±14.5 cm(3); and surgical aspiration only, 24.5±14.0 cm(3) (P=0.26). Edema at end of treatment in surgical aspiration and rt-PA was 28.1±13.8 cm(3) and 24.4±8.6 cm(3) in surgical aspiration only (P=0.41). CONCLUSIONS: Hematoma evacuation is associated with significant reduction in PHE. Furthermore, PHE does not seem to be exacerbated by rt-PA, making such neurotoxic effects unlikely when the drug is delivered to intracranial clot.

4D VMAT, gated VMAT, and 3D VMAT for stereotactic body radiation therapy in lung.

Four-dimensional volumetric modulated arc therapy (4D VMAT) is a treatment strategy for lung cancers that aims to exploit relative target and tissue motion to improve organ at risk (OAR) sparing. The algorithm incorporates the entire patient respiratory cycle using 4D CT data into the optimization process. Resulting treatment plans synchronize the delivery of each beam aperture to a specific phase of target motion. Stereotactic body radiation therapy treatment plans for 4D VMAT, gated VMAT, and 3D VMAT were generated on three patients with non-small cell lung cancer. Tumour motion ranged from 1.4-3.4 cm. The dose and fractionation scheme was 48 Gy in four fractions. A B-spline transformation model registered the 4D CT images. 4D dose volume histograms (4D DVH) were calculated from total dose accumulated at the maximum exhalation. For the majority of OARs, gated VMAT achieved the most radiation sparing but treatment times were 77-148% longer than 3D VMAT. 4D VMAT plan qualities were comparable to gated VMAT, but treatment times were only 11-25% longer than 3D VMAT. 4D VMAT's improvement of healthy tissue sparing can allow for further dose escalation. Future study could potentially adapt 4D VMAT to irregular patient breathing patterns.

The meaning of acute kidney injury and its relevance to intensive care and anaesthesia.

Acute kidney injury (AKI) is the new consensus term for acute renal failure. The term describes a continuum of kidney injury, a common condition in the critically ill and after major surgery, which is associated with increased mortality. The incidence of AKI in intensive care unit patients in Australia is >30% and sepsis is a major contributory factor. However, there is limited knowledge about its incidence after major surgery, except for cardiac surgery. The creation of staged AKI classification systems (RIFLE [Risk, Injury, Failure, Loss, End-stage], Acute Kidney Injury Network and the new Kidney Disease: Improving Global Outcomes criteria) has accelerated progress in critical care nephrology research by showing that even small changes in serum creatinine are associated with increased risk of death and that this risk increases progressively with severity of AKI. Recent thought and research has cast doubt over previously accepted pathophysiological views of AKI. Moreover, terms such as 'prerenal azotaemia' and 'acute tubular necrosis' are now being challenged as lacking validity, having little supportive evidence and carrying limited clinical utility. In this review, we explore the limitations of animal and human models of AKI and the implications of recent research on our current understanding of the pathophysiology of AKI. In addition, we describe conventional and novel diagnostic methods and therapies, and explore the clinical implications of the effect of fluid administration and perioperative management. Finally, we identify priorities for clinical investigations and future directions in AKI research.

Sci-Thur PM: YIS - 03: Comparing 4D-VMAT, Gated-VMAT and 3D-VMAT in SBRT treatment of lung cancer.

PURPOSE: To evaluate the treatment plan qualities of 4D-VMAT, gated-VMAT and 3D-VMAT in the treatment of non-small cell lung cancer (NSCLC) in stereotactic body radiation therapy (SBRT). METHODS: 4D-VMAT is a motion compensation strategy that aims to exploit relative target and OAR motion to increase OAR sparing over 3D-VMAT without the long treatment times associated with gated-VMAT. The 4D-VMAT algorithm incorporates the entire patient respiratory cycle and 4D-CT in the optimization process. Resulting treatment plans synchronize the delivery of each MLC aperture to a specific phase of the target motion. Using software developed in Matlab™, SBRT treatment plans for 4D-VMAT, gated-VMAT and 3D-VMAT were generated on 3 patients with NSCLC. Tumour motion ranged from 1.4-3.4 cm. The fractionation scheme was 48Gy in 4 fractions with the GTV receiving 100% of the prescribed dose. For gated-VMAT, the treatment window constrained residual tumour motion to 3 mm or less corresponding to duty cycles of 40-60%. In 3D-VMAT, the ITV was generated by merging the GTV from all phases. A b-spline transformation model was used to register the 4D-CT images and DVHs were calculated from total dose accumulated on the max expiration phase. RESULTS AND CONCLUSION: For the majority of OARs, gated-VMAT provided the greatest radiation sparing but significantly extended treatment times (25-35 gantry interruptions/arc). For 3D-VMAT, only 2 patients had clinically acceptable plans that met all the strict dose limits. OAR sparing in 4D-VMAT was comparable to gated-VMAT but with significantly improved delivery efficiency.

SU-E-T-637: 4D-VMAT Vs. Gated VMAT in Lung Cancer SBRT.

PURPOSE: To assess plan quality and treatment efficiency of 4D-VMAT and gated-VMAT in the treatment of non-small cell lung cancer using SBRT. METHODS: Treatment planning software was developed in Matlab to simulate both 4D-VMAT and gated-VMAT on patients with stage I lung cancer and at least 1 cm of tumour motion. Gated-VMAT delivers radiation to the tumour during only a portion of the respiratory cycle and hence requires frequent start and stop motions of the gantry. In the 4D-VMAT algorithm, target and organ motion from the entire respiratory cycle is incorporated during optimization. Gantry moves continuously but delivery of each MLC aperture is synchronized to specific phases of target motion. All 4D-CT scan consisted of 10 phases and were acquired with the patients breathing freely. The SBRT fractionation scheme was 48 Gy in 4 fractions with at least 95% of the PTV receiving 100% of the prescription dose. For gated-VMAT, the PTV was derived from the ITV of the relevant respiratory phases plus a 5mm margin. In the 4D VMAT algorithm, the GTV was defined on a single phase and the PTV created with a 5mm margin. PTVs for the other respiratory phases were determined through 4D-image registration and deformation using a bspline transformation model. For both treatment deliveries, dose was accumulated on the maximum exhale phase and DVHs generated. RESULTS: Findings show gated-VMAT and 4D-VMAT deliveries resulted in maximum doses to most OARs far below SBRT protocol constraints. The 4D-VMAT beam on time is on average 8 min. Gated-VMAT will have similar beam on time but treatment time can more than double after accounting for 25 to 35 beam interruptions per arc. CONCLUSIONS: Gated-VMAT and 4D-VMAT were able to produce dosimetrically acceptable lung SBRT plans. The advantage of 4D-VMAT is the greater efficiency in treatment delivery.

Biomarkers of acute kidney injury in anesthesia, intensive care and major surgery: from the bench to clinical research to clinical practice.

Acute kidney injury (AKI) is common after major surgery and reportedly occurs in approximately 36% of ICU patients (RIFLE Risk/Injury/ Failure categories). It is associated with increased mortality, greater cost, and prolonged Intensive Care Unit (ICU) and hospital stay, despite attempts to develop therapies to prevent or attenuate AKI, which have had limited success. One major reason for this lack of success may be the result of delayed implementation due to the inability to detect AKI early. Traditional biomarkers of AKI (creatinine and urea) do not detect injury early enough. Thus, it is a priority to find reliable, early biomarkers that predict subsequent AKI. Innovative technologies such as functional genomics and proteomics have facilitated detection of several promising early biomarkers of AKI, such as neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (CyC), liver-type fatty acid binding protein (L-FABP), interleukin-18 (IL-18), and kidney injury molecule-1 (KIM-1). These biomarkers have many potential applications during anesthesia and in the ICU. They can be used to evaluate the effect of new techniques and therapies on kidney function, as safety markers to monitor toxicity and as measures of treatment effect. For example, NGAL and cystatin C have been used in a safety monitoring trial of hydroxyethylstarch therapy and to detect AKI early, during or immediately after cardiac surgery. Clinical use beyond research settings is rapidly expanding.

Sci-Fri AM: YIS-06: On-line adaptive radiation therapy based on the intra-fractional digital tomosynthesis images.

PURPOSE: To investigate the feasibility of performing on-line adaptive radiation therapy (ART) based on the intra-fractional digital tomosynthesis (DTS) images. METHOD AND MATERIALS: Intra-fractional DTS images were reconstructed as the gantry rotated between treatment positions. An edge detection algorithm was used to automatically segment the DTS images as the gantry arrived at each treatment position. The original treatment plan was then re-optimized for the most recent DTS image contours and dose was delivered from each treatment position based on the newly re-optimized plan. Plan re-optimization was performed using modified direct aperture optimization (DAO). To test our system, a model representing typical prostate, bladder and rectum anatomy was generated. First, a treatment plan based on this original anatomy was created using our DAO system. To simulate prostate deformations, three clinically relevant deformations (small, medium and large) were modeled by systematically deforming the original anatomy. The ability of our approach to adapt the original treatment plan and account for the anatomy deformations was investigated. RESULTS: Based on the dose-volume constraints from the RTOG 0415 prostate protocol, the original treatment plan would have been clinically unacceptable for all three deformations. Using our approach to on-line ART, the original treatment plan was successfully adapted to arrive at a clinically acceptable plan for all three anatomy deformations. CONCLUSION: We have shown that performing on-line ART based on intra-fractional DTS images is feasible. The advantages are reduced treatment time and the ability to detect and account for patient motion during the treatment fraction.

Intra-prostatic fiducial markers and concurrent androgen deprivation.

AIMS: To document the case of a man with adenocarcinoma of the prostate treated with external beam radiotherapy and concurrent androgen deprivation. MATERIALS AND METHODS: The man, who received 79.8 Gy in 42 fractions of radiotherapy over 8.5 weeks using three intra-prostatic gold fiducial markers for on-line set-up correction, started an anti-androgen 2.5 weeks before radiotherapy, on the day of his planning computed tomography, and a gonadotropin-releasing hormone agonist on his first day of radiotherapy. RESULTS: In the sixth week of radiotherapy, the distance between the fiducial markers had diminished: superior to posterior-mid (from 19 to 11 mm), posterior-mid to inferior (from 19 to 15 mm), and superior to inferior (from 31 to 22 mm), so the patient was rescanned. Between the two planning computed tomographies, the prostate volume had decreased from 44.3 to 28.3 cm3 (-36%). Had the planned radiotherapy been delivered to the anatomy of the rescan, the dose to the rectal wall would have exceeded the planned dose-volume histogram constraints. However, with the patient set up to the fiducial markers, the dose-volume histogram constraints for the rectal wall and bladder wall were met throughout the course of radiotherapy. CONCLUSION: Involution of the prostate owing to concurrent androgen deprivation may cause in-migration of implanted fiducial markers and excessive dose to the rectal wall. With concurrent androgen deprivation, daily on-line set-up correction to fiducial markers can aid in safe dose escalation.

Analysis of treatment parameters for conformal shaped field stereotactic irradiation: comparison with non-coplanar arcs.

The change in configuration from circular convergent arcs to shaped static fields for stereotactic radiosurgery raises questions regarding comparability of dose distributions between the techniques. This study aims to quantify the optimization of planning parameters to achieve dose distributions minimizing dose to healthy tissue. Dose volume histograms were calculated and averaged from several patient treatments to measure dose homogeneity and healthy tissue irradiation inherent in variable PTV margins, the effect of increasing numbers of static shaped fields, the dose fall-off outside the PTV and of field placement. Our results show that adding a 2 mm margin around the target volume when defining field shapes maximizes dose coverage and homogeneity without substantially increasing the volume of healthy tissue irradiated to high dose levels. We demonstrate that 5-6 static fields may be optimal for typical lesions and that placement of these fields may not always play a major role in healthy tissue sparing. This work illustrates a systematic approach to conformal static field treatment plan optimization which relies on the prior determination of parameters such as optimum margin width to account for field penumbra. Complex irregularly shaped lesions still require careful patient-specific assessment of healthy tissue irradiation.

Lactoperoxidase haem, an iron-porphyrin thiol.

The haem prosthetic group of lactoperoxidase can be prepared from the enzyme in high yield by reductive cleavage with mercaptoethanol in 8 M-urea under mild conditions. The product yields porphyrins, after removal of iron, which show visible spectroscopic properties similar to protoporphyrin but are considerably more polar. In the presence of iodoacetamide, a different product is obtained by reductive cleavage. The proton n.m.r. and mass spectra of this compound indicate that the prosthetic group of the enzyme is the iron complex of 18-mercaptomethyl-2,7,12-trimethyl-3,8-divinylporphyrin-13,17-d ipropionic acid. It is proposed that the unusual strength of binding of the prosthetic group to the apoprotein is due to formation of a disulphide bond from a cysteine residue to the porphyrin thiol.

A comparative study of porphyrin accumulation in tissue cultures of chicken embryo hepatocytes treated with organophosphorous pesticides.

Thirty-two organophosphorous pesticides have been examined for their ability to cause porphyrin accumulation in cultures of chicken embryo hepatocytes. Greatest porphyrin accumulation is associated with compounds which have an aromatic leaving group and are phosphate or thiono-phosphate ethyl esters. Compounds of this type cause accumulation of uroporphyrin in the medium. Paraoxon and diazoxon cause inhibition of uroporphyrinogen decarboxylase in the cells. The ability to cause accumulation of uroporphyrin in the medium does not correlate with the alkylating properties of the compound as measured by its rate of alkylation of 4-(p-nitrobenzyl)-pyridine.