Treating Brain Metastases from Breast Cancer: Outcomes after Stereotactic Radiosurgery.

AIMS: Stereotactic radiosurgery (SRS) is an alternative to surgery or whole brain radiotherapy for the control of single or multiple brain metastases in patients with breast cancer. To date, there is no clear consensus on factors that might predict overall survival following SRS. The aim of this study was to assess the overall survival of breast cancer patients with brain metastases treated with SRS at a single centre and to examine the factors that might influence survival. MATERIALS AND METHODS: A retrospective analysis of consecutive patients with breast cancer and brain metastases, considered suitable for SRS by the regional neuro-oncology multidisciplinary team. All patients were treated at a single National Health Service centre. RESULTS: In total, 91 patients received SRS between 2013 and 2017, of whom 15 (16.5%) were alive at the time of analysis. The median overall survival post-SRS was 15.7 months (interquartile range 7.7-23.8 months) with no significant effect of age on survival (67 patients ≤ 65 years, 16.3 months; 26 patients > 65 years, 11.4 months, P = 0.129). The primary tumour receptor status was an important determinant of outcome: 31 oestrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) patients had a median overall survival of 13.8 months, 14 ER+/HER2+ patients had a median overall survival of 21.4 months, 30 ER-/HER2+ patients had a median overall survival of 20.4 months and 16 patients with triple negative breast cancer (TNBC) had a median overall survival of 8.5 months. A larger total volume of tumour treated (>10 cm3), but not the number of individual metastases treated, was associated with worse survival (P = 0.0002) in this series. Patients with stable extracranial disease at the time of SRS had improved overall survival compared with those with progressive extracranial disease (30 patients stable extracranial disease overall survival = 20.1 months versus 33 patients progressive extracranial disease overall survival = 11.4 months; P = 0.0011). Seventeen patients had no extracranial disease at the time of SRS, with a median overall survival of 13.1 months. CONCLUSIONS: This single-centre series of consecutive patients with brain metastases from breast cancer, treated with SRS, had a similar overall survival compared with previous studies of SRS. TNBC and ER+/HER2- histology, metastatic volumes >10 cm3 and progressive extracranial disease at the time of SRS were associated with worse survival.

Does initial spacing influence crown and hydraulic architecture of Eucalyptus marginata?

Long-term declines in rainfall in south-western Australia have resulted in increased interest in the hydraulic characteristics of jarrah (Eucalyptus marginata Donn ex Smith) forest established in the region's drinking water catchments on rehabilitated bauxite mining sites. We hypothesized that in jarrah forest established on rehabilitated mine sites: (1) leaf area index (L) is independent of initial tree spacing; and (2) more densely planted trees have less leaf area for the same leaf mass, or the same sapwood area, and have denser sapwood. Initial stand densities ranged from about 600 to 9000 stems ha(-1), and trees were 18 years old at the time of sampling. Leaf area index was unaffected by initial stand density, except in the most sparsely stocked stands where L was 1.2 compared with 2.0-2.5 in stands at other spacings. The ratio of leaf area to sapwood area (A(l):A(s)) was unaffected by tree spacing or tree size and was 0.2 at 1.3 m height and 0.25 at the crown base. There were small increases in sapwood density and decreases in leaf specific area with increased spacing. Tree diameter or basal area was a better predictor of leaf area than sapwood area. At the stand scale, basal area was a good predictor of L (r(2) = 0.98, n = 15) except in the densest stands. We conclude that the hydraulic attributes of this forest type are largely independent of initial tree spacing, thus simplifying parameterization of stand and catchment water balance models.

Growth hormone therapy and growth in children with Noonan's syndrome: results of 3 years' follow-up.

Growth data from the first 3 yr of a multicenter study examining the efficacy and safety of recombinant human GH [rhGH; 4 IU (1.3 mg)/m(2).day, sc] in children with Noonan's syndrome (NS) are reported for 23 subjects. Sixteen male and seven female patients (age, 9.3 +/- 2.6 yr at onset of GH therapy, mean +/- SD; range, 4.8-13.7) were each assessed at 1, 2, and 3 yr after starting treatment. Comparisons were made with a group of eight subjects (six males and two females, age, 9.0 +/- 4.1 yr; range, 4.1-14.8) with NS, not treated with rhGH, measured over the same period. All treated subjects underwent annual cardiac assessment. Height SD score increased from -2.7 +/- 0.4 at the start of GH therapy to -1.9 +/- 0.9 3 yr later (P < 0.001, two-tailed t test). This corresponded to an increase in height from 116.1 +/- 13.2 to 137.3 +/- 14.0 cm. Height velocity increased from 4.4 +/- 1.7 cm/yr in the year before treatment to 8.4 +/- 1.7 (P < 0.001), 6.2 +/- 1.7 (P < 0.001), and 5.8 +/- 1.8 (P = 0.01, two-tailed t test compared with baseline) during the first, second, and third years of GH treatment, respectively. Height acceleration was not significant during the second or third years when pubertal subjects were excluded. The comparison group showed an increase in height from 116.0 +/- 19.8 to 131.9 +/- 21.1 cm over the 3 yr (height SD score, -2.7 +/- 0.6 to -2.4 +/- 0.7, P = 0.3). None of the 23 children developed hypertrophic cardiomyopathy during GH treatment. The increase in growth rate in NS resulting from 1 yr of GH therapy seems to be maintained during the second year, although height velocity shows a less significant increase over pretherapy values. Possible abnormal anabolic effects of rhGH on myocardial thickness were not confirmed, and no treated patient developed features of hypertrophic cardiomyopathy.

The pharmacology of RS-15385-197, a potent and selective alpha 2-adrenoceptor antagonist.

1. RS-15385-197 ((8aR, 12aS, 13aS)-5,8,8a,9,10,11,12,12a,13,13a-decahydro- 3-methoxy-12-(methylsulphonyl)-6H-isoquino [2,1-g][1,6]-naphthyridine) was evaluated in a series of in vitro and in vivo tests as an antagonist at alpha 2-adrenoceptors. 2. RS-15385-197 had a pKi of 9.45 for alpha 2-adrenoceptors in the rat cortex (pA2 in the guinea-pig ileum of 9.72), whereas the 8aS, 12aR, 13aR enantiomer, RS-15385-198, had a pKi of only 6.32 (pA2 6.47) indicating a high degree of stereoselectivity. The racemate RS-15385-196 had a pKi of 9.18. 3. RS-15385-197 showed unprecedented alpha 2 vs. alpha 1 adrenoceptor selectivity in vitro. In the rat cortex, RS-15385-197 had a pKi of 9.45 in displacing [3H]-yohimbine and 5.29 in displacing [3H]-prazosin (alpha 2/alpha 1 selectivity ratio in binding experiments > 14000). The compound had a pA2 of 9.72 as a competitive antagonist of the inhibitory effects of UK-14,304 in transmurally-stimulated guinea-pig ileum and 10.0 against BHT-920-induced contractions in dog saphenous vein (DSV); this latter value was unaltered by phenoxybenzamine. An apparent pKB of 5.9 was obtained against cirazoline-induced contractions in DSV, whilst a pA2 of 6.05 was obtained against phenylephrine-induced contractions in the rabbit aorta (alpha 2/alpha 1 selectivity ratio in functional experiments > 4000). 4. RS-15385-197 was highly selective for alpha 2-adrenoceptors over other receptors: the compound showed low affinity for 5-HT1A (pKi 6.50) and 5-HT1D (pKi 7.00) receptor subtypes, and even lower affinity (pKi < or = 5) for other 5-HT receptor subtypes, dopamine receptors, muscarinic cholinoceptors, beta-adrenoceptors and dihydropyridine binding sites. RS-15385-197 was devoid of affinity for the non-adrenoceptor imidazoline binding site, labelled by [3H]-idazoxan, which provides further evidence that these sites are not related to alpha 2-adrenoceptors. In the DSV, contractile responses to 5-hydroxytryptamine (5-HT) were unaffected by a concentration of 1 microM RS-15385-197. 5. RS-15385-197 was non-selective for the alpha 2A- and alpha 2B-adrenoceptor subtypes in that the pKi for the alpha 2A-adrenoceptor in human platelets was 9.90 and the pKi for the alpha 2B-adrenoceptor in rat neonate lung was 9.70. However, RS-15385-197 showed lower affinity for the alpha 2-adrenoceptor subtype in hamster adipocytes (pKi 8.38). 6. In anaesthetized rats, RS-15385-197 was a potent antagonist of the mydriasis response induced by UK-14,304 or clonidine (AD50 5 and 7 microg kg-1, i.v., respectively; 96 microg kg-1, p.o.) and of UK-14,304-induced pressor responses in pithed rats (AD50 7 microg kg-1, i.v.); the compound therefore is both centrally and orally active. Even at a high dose (10 mg kg-1, i.v.), RS-15385-197 did not antagonize pressor responses to cirazoline in pithed rats, indicating that the selectivity for alpha2 vs. alpha1-adrenoceptors was maintained in vivo.8 RS-15385-197 is therefore a very potent, selective, competitive alpha2-adrenoceptor antagonist, both in vitro and in vivo, is orally active and readily penetrates the brain. It will thus be a powerful pharmacological tool for exploring the various physiological roles of alpha2-adrenoceptors.

In vitro influence of sublethal hypoxia on differentiation of the 3T3-L1 preadipose cell line and its physiological implications.

Exposure of cultures of 3T3-L1 preadipose cells to nitrogen for 16 hours kills almost all of the cells, but after exposure to 5% oxygen for 16 hours most of the cells survive, and recover when culture is continued in 20% oxygen. The extent of recovery depends on the insulin concentration of the medium. Isotope incorporation and flow cytometry experiments show that exposure to 5% oxygen for 16 hours growth arrests the cells and leads to an elongation of the G1-phase of the cell cycle. When 3T3-L1 cells are growth arrested in the presence of 5% oxygen and allowed to recover in the presence of 5 microg/ml insulin under 20% oxygen, they can be induced to differentiate by treatment with carbacyclin during the period of growth arrest. Activity of the marker enzyme glycerol-3-phosphate dehydrogenase increases from 46.5+/-17 mU/mg protein to 1506+/-271 mU/mg protein. The extent of differentiation is exponentially related to the concentration of carbacyclin in the medium.

The role of oxygen deficiency and cytosolic reactions in cell growth.

It has been suggested that a decrease in the availability of oxygen to certain tissues may lead to increased metabolism of glucose through the hexose monophosphate shunt pathway and to increased synthesis of polyols, in particular myoinositol. It is further suggested that these "cytosolic reactions" result in stimulation of the phosphatidylinositol cycle by increasing substrate availability (i.e. phosphatidate, diglyceride and inositol). A relative decrease in local oxygen availability may therefore play a role in cell proliferation and differentiation and in the etiology of cancer, diabetic sequelae and obesity.

Secondary changes in diabetes mellitus with particular reference to retinopathy and neuropathy.

It has previously been suggested (1) that respiratory modulation of the action of insulin on glucose metabolism may contribute to macrosomia in neonates from diabetic mothers. It was proposed that this was due to a relative hypoxaemia which resulted in an increase in glucose metabolised through the hexose monophosphate shunt pathway in fetal adipocytes. This could be understood on the basis of the Crabtree-Pasteur Effects. It is now suggested that a similar mechanism may lead, in certain tissues, to an increase in the metabolism of glucose through polyol pathways and that this may play a role in the development of diabetic sequelae.

Relative fetal hypoxia as a contributing factor to fetal macrosomia in diabetic pregnancy.

Results from Ogata et al (5) have shown that the initial increase in fetal size in the macrosomic neonates of diabetic mothers occurs after approximately 26 weeks gestation, and that a further more dramatic increase occurs at approximately 34 weeks until term. It is proposed that the initial increase is caused by fetal hyperinsulinism (Pedersen Hypothesis), and that the latter increase results from an induced relative fetal hypoxia. It is suggested that the mechanism responsible for the latter increase in fetal size is an increase in the amount of fetal glucose which is metabolised through the hexose monophosphate shunt pathway.

Growth hormone therapy in Noonan's syndrome: non-cardiomyopathic congenital heart disease does not adversely affect growth improvement.

Twenty-three children with Noonan's syndrome were treated with growth hormone (GH) and followed for at least three years. The presence of cardiomyopathy was a contraindication to treatment. Height SDS and velocity increased during treatment. None of the 23 children developed hypertrophic cardiomyopathy during GH treatment. Children with any cardiac abnormality at the start of treatment did not show a reduced growth trend when compared with patients with normal hearts.

Determining the collateral effects of peer tutor training on a student with severe disabilities.

In one experiment and two case studies, we evaluated the impact of training peer tutors without disabilities to provide effective instructional procedures with a student with severe disabilities who exhibited aberrant behaviors in the classroom. Peer tutors received training on how to provide appropriate commands and specific praise statements, as well as to decrease negative statements. In the experiment, two peer tutors were taught these skills in a multiple baseline design. Two case studies further clarified the impact of the peer tutor training. In Case Study 1, one peer tutor received training on the three skills concurrently and data were assessed in an AB design. In Case Study 2, one peer tutor was trained prior to working with the student to determine if a peer tutor who had no prior history with the student could work effectively with minimal disruptions from the onset. Data were also measured on the student's aberrant behaviors and his compliance before, during, and after training the peer tutors. Results indicated that the peer tutors learned to provide appropriate commands and specific praise and to reduce negative statements. More important, as a collateral effect of the training program, the student's aberrant behaviors decreased and his compliance to requests improved.

Aide memoire for the management of gunshot wounds.

The hospitals in Johannesburg deal with about 4,000 gunshot wounds a year. Although most are from hand guns, a number are from high velocity, military-type weapons. Extensive experience has been built up and many lessons learned. Attention is directed to the actual damage inflicted rather than on theoretical predictions based on presumed velocity of the bullets involved, as this can often be misleading. Some patients are delayed in their presentation to emergency departments, in other cases several gunshot wound patients arrive at the same time, requiring appropriate triage and urgent management.

Management of gunshot wounds: the Johannesburg experience.

The Johannesburg hospitals see large numbers of gunshot wounds and there is, therefore, considerable experience in their management. Historically, management has been dictated by experimental theories of wounding mechanisms. More modern work has indicated that some of these theories have been somewhat misleading, and some traditional means of management have changed. The basic military surgical lessons of the excision of dead tissue, delayed primary suture remain valid, it is the understanding of tissue damage and the more logical response which has changed. It is the wound as encountered which is managed, irrespective or the theoretical velocity of the bullet. The Johannesburg practice is outlined with regard to regions of the body, with discussion of, among others, the conservative management of gunshot wounds of the abdomen, primary repair of the colon, non operative management of certain limb wounds. The practice is summarised, based on considerable experience and the logistic implications of large numbers and may be useful to surgeons less experienced in gunshot wound management.

Hyperbaric oxygen and surgery.

Hyperbaric oxygen (HBO) therapy, that is the administration of 100% oxygen delivered under pressure, has a beneficial effect in several surgical conditions. Its use has been assessed and audited and its pharmacological effects demonstrated. It is appropriate for use in several surgical conditions as evidence-based therapy. These are: (i) gas gangrene; (ii) crush injuries, compartment syndromes and acute traumatic ischemias; (iii) enhancement of healing in selected problem wounds; (iv) exceptional blood loss anaemia; (v) necrotising soft-tissue infections; (vi) refractory osteomyelitis; (vii) radionecrosis; (viii) compromised skin grafts and flaps; (ix) thermal burns; (x) intracranial abscess. HBO therapy has been used inappropriately in the past; there is also lack of knowledge regarding its application, and scarce hyperbaric facilities. Hyperbaric therapy, when properly supervised by a physician trained in its use, working closely with a surgeon, and ethically used for appropriate indications, can be a useful adjunct to surgical practice.

'Doc, it's about a sick diver...' Guidelines for the management of a victim of a deep water diving accident.

If you are consulted about a sick diver this summer the problem probably will be related to diving rather than an intercurrent illness. Consequent major injury is likely and the patient will need specialised assessment and treatment.

Primary closure of battle wounds of the colon: is it an option for the military surgeon?

The management of battle wounds of the colon has been safely established for many years, with primary closure of the wounds being discouraged. More recent work, involving large numbers of patients from civilian trauma centres, has challenged this. The appropriateness of these conclusions for the battle situation is discussed, including the nature of injury, the medical logistics and the combat scenario. Parameters are indicated and guide lines given, incorporating battle-proven military surgical principles and modern trauma experience. This includes damage control and possible primary closure of selected wounds. In this way the military surgeon can take an informed decision in providing optimal care for patients with battle wounds of the colon.

Battle injuries of the rectum: options for the field surgeon.

Historically, battle wounds of the rectum have had high mortality and morbidity. This has improved greatly over several decades as a result of battle experience. This article highlights the value of civilian gunshot experience and its possible use in the military setting. The standard principles of rectal examination, followed by proctosigmoidoscopy after initial resuscitation, remain unchanged. Thereafter, the surgical decisions are made at laparotomy. Rectal injuries commonly have other injuries in association which must also be dealt with. In the stable patient rectal repair may be possible. Where repair is hazardous due to extensive injury (rectum or adjacent structures), the well-proven protective colostomy is used. A loop colostomy with or without distal closure is effective and is used to protect most injuries; possible exceptions being injuries dealt with early, in which there is minimal contamination and repair is easy. Presacral drainage can generally be reserved for severely destructive wounds or those in which repair has not been done. Rectal washout remains an option in patients with inspissated faeces. The basic military surgical principles remain valid, their extent and degree of implementation depending on the anatomical location of injury, degree of damage and any delay in presentation to surgery.

Hyperbaric oxygen in trauma and surgical emergencies.

Hyperbaric oxygen therapy (HBO), that is the administration of 100% oxygen delivered under pressure, has a beneficial effect in several surgical conditions. Its use has been assessed and audited and its pharmacological effects demonstrated. It is appropriate for use in several acute surgical conditions as evidence-based therapy. These are: Gas Gangrene Crush Injuries, Compartment Syndromes & Acute Traumatic Ischaemias Enhancement of Healing in Selected Problem Wounds Exceptional Blood loss Anaemia Necrotising Soft Tissue Infections Compromised Skin Grafts & Flaps Thermal Burns HBO therapy suffers from previous inappropriate use, lack of knowledge, and scarce hyperbaric facilities. Hyperbaric therapy, when properly supervised by a physician trained in its use, working closely with a surgeon, and ethically used for appropriate indications, can be a useful adjunct to surgical practice. Military surgeons may be in a situation in which they can utilize HBO in acute surgical conditions and trauma. They are urged to identify HBO facilities, both fixed and portable, and to establish communication with hyperbaric therapy colleagues.