Geographic variation in the use of lymphadenectomy and external-beam radiotherapy for endometrial cancer: a cross-sectional analysis of population-based data.

OBJECTIVE: To quantify geographic variation in the use of lymphadenectomy and/or external-beam radiotherapy (EBRT) for endometrial cancer in England. DESIGN: Cross-sectional analysis of population-based data. SETTING: English cancer registry data, linked to chemotherapy, radiotherapy and hospital episodes statistics data. POPULATION: Twenty-two thousand four hundred and eighty-three women with endometrial cancer presenting without clinical or radiological evidence of distant metastatic spread, diagnosed in England from 2013 to 2016. METHODS: Proportions of patients receiving lymphadenectomy and/or EBRT were compared across 19 Cancer Alliances, to identify variations in clinical practice. Two separate logistic regression models assessed the impact on variation of adjustment for tumour and patient characteristics. MAIN OUTCOME MEASURES: Receipt of lymphadenectomy, receipt of EBRT. RESULTS: There was substantial variation by Cancer Alliance in the adjusted proportion of women with endometrial cancer receiving lymphadenectomy (range 5% [95% CI 4-6%] to 48% [95% CI 45-52%]) and EBRT (range 10% [95% CI 7-12%] to 31% [95% CI 28-33%]), after adjusting for variation in pathological grade, age, comorbidities, deprivation, ethnic group and (EBRT only) FIGO stage. Different approaches to clinical practice were identified; (i) one Cancer Alliance had significantly higher than average lymphadenectomy and significantly lower than average EBRT use, (ii) three had high use of both lymphadenectomy and EBRT, (iii) one had low lymphadenectomy use and high EBRT use, and (iv) three had low use of both lymphadenectomy and EBRT. CONCLUSIONS: Lymphadenectomy is probably used to triage for EBRT when lymphadenectomy use is high and EBRT use is low. This is probably a result of variation in local endometrial cancer management guidelines, suggesting that UK recommendations should be clarified. TWEETABLE ABSTRACT: There is geographic variation in England in the use of lymphadenectomy and radiotherapy to treat endometrial cancer.

Expectations for treatment outcomes in neck/back patients regarding improvements in pain and function. A cross-sectional pilot study.

BACKGROUND: Literature has suggested that patients' pretreatment expectations may influence both prognosis and outcome. Investigation of these possible benefits requires knowledge about what is actually expected among these patients. AIM: To investigate neck/back patients' expectations for treatment outcomes (pain and functional improvement) prior to their first meetings with specialists in physical medicine and rehabilitation (PMR). DESIGN: Cross-sectional pilot study. SETTING: PMR Neck/Back Outpatient Clinic, Oslo University Hospital. POPULATION: Patients with neck/back pain and/or functional problems referred for the first time to a neck/back PMR outpatient clinic. METHODS: Questionnaires were completed prior to an appointment with a PMR specialist. The forms consisted of one earlier designed instrument (PSOE) and one self-constructed part with six 11-point numeric rating scales (11-NRS). Eligible patients were randomly selected between January and June 2012. RESULTS: Approximately 42 % expected their status to remain un-changed. A total of 17 % expected exacerbation of their status. No differences were found between expectations regarding pain and function. Full recovery was not expected. Highly educated patients, and those reporting high usage of analgesics, had higher expectations for improvement. CONCLUSION: Few of the selected patients seemed to expect improvement. These expectations are quite pessimistic, in our opinion. More elaborate studies are needed to confirm these results.

Association between baseline IL-6 and 1-year recovery in lumbar radicular pain.

BACKGROUND: In the present study, the influence of cytokines on 1-year recovery in lumbar radicular pain was examined. METHODS: In total, 110 patients with symptomatic lumbar disc herniation were followed for 1 year. Uni- and multivariate linear regression was used to assess the influence of interleukin (IL)-6, IL-8, disc degeneration and endplate changes (Modic changes) on the changes in the Oswestry Disability Index (ODI change; primary outcome) and visual analogue scale (VAS) for low back pain (LBP) and leg pain (secondary outcomes). RESULTS: Less favourable ODI outcome correlated with higher serum IL-6 levels (B = -3.41, 95% CI -5.52 to -1.30, p = 0.002), non-surgical treatment (B = -7.03, 95% CI 1.21 to 12.84, p = 0.018), higher baseline back pain intensity (B = -2.28, 95% CI -3.21 to -1.35, p < 0.001) and low educational level (B = -5.57, 95% CI 0.66 to 10.47, p = 0.027). High VAS for LBP and leg pain at 1 year was associated with high levels of serum IL-6, higher back pain intensity and longer duration of lumbar radicular pain at baseline. CONCLUSIONS: High serum IL-6 levels, but not disc degeneration or Modic changes, were associated with less favourable recovery in patients with lumbar radicular pain. Intense initial back pain, non-surgical treatment, lower educational level and longer duration of radicular pain before treatment also correlated with a slower recovery the first year after disc herniation.

Cancer linked to Alzheimer disease but not vascular dementia.

OBJECTIVE: To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD). METHODS: Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study-Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer. RESULTS: The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.20-0.84) and pure AD (HR = 0.31, 95% CI = 0.12-0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52-0.997) and pure AD (HR = 0.57; 95% CI = 0.36-0.90) among white subjects after adjustment for demographics, number of APOE epsilon4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD. CONCLUSIONS: In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration.

A common biological mechanism in cancer and Alzheimer's disease?

Cancer and Alzheimer's disease (AD) are two common disorders for which the final pathophysiological mechanism is not yet clearly defined. In a prospective longitudinal study we have previously shown an inverse association between AD and cancer, such that the rate of developing cancer in general with time was significantly slower in participants with AD, while participants with a history of cancer had a slower rate of developing AD. In cancer, cell regulation mechanisms are disrupted with augmentation of cell survival and/or proliferation, whereas conversely, AD is associated with increased neuronal death, either caused by, or concomitant with, beta amyloid (Abeta) and tau deposition. The possibility that perturbations of mechanisms involved in cell survival/death regulation could be involved in both disorders is discussed. Genetic polymorphisms, DNA methylation or other mechanisms that induce changes in activity of molecules with key roles in determining the decision to "repair and live"- or "die" could be involved in the pathogenesis of the two disorders. As examples, the role of p53, Pin1 and the Wnt signaling pathway are discussed as potential candidates that, speculatively, may explain inverse associations between AD and cancer.

Alzheimer disease and cancer.

Cross-sectional studies raise the possibility of protective relationships between, or a common mechanism underlying, the development of dementia of the Alzheimer type (DAT) and cancer. Using a prospective longitudinal design, the authors found that the risk of developing cancer is less among participants with DAT vs nondemented participants (p < 0.001) and that the risk of developing DAT may be less for participants with a history of cancer (p = 0.060).

Effects of direct periaqueductal grey administration of a cannabinoid receptor agonist on nociceptive and aversive responses in rats.

The analgesic potential of cannabinoids may be hampered by their ability to produce aversive emotion when administered systemically. We investigated the hypothesis that the midbrain periaqueductal grey (PAG) is a common substrate mediating the anti-nociceptive and potential aversive effects of cannabinoids. The rat formalin test was used to model nociceptive behaviour. Intra-PAG microinjection of the excitatory amino acid D,L-homocysteic acid (DLH) was used to induce an aversive, panic-like reaction characteristic of the defensive "fight or flight" response. Administration of the cannabinoid receptor agonist HU210 (5 microg/rat) into the dorsal PAG significantly reduced the second phase of formalin-evoked nociceptive behaviour, an effect which was blocked by co-administration of the CB(1) receptor antagonist SR141716A (50 microg/rat). This anti-nociceptive effect was accompanied by an HU210-induced attenuation of the formalin-evoked increase in Fos protein expression in the caudal lateral PAG. Intra-dorsal PAG administration of HU210 (0.1, 1 or 5 microg/rat) significantly reduced the aversive DLH-induced explosive locomotor response. The anti-nociceptive effect of HU210 is likely to result from activation of the descending inhibitory pain pathway. Mechanisms mediating the anti-aversive effects of cannabinoids in the PAG remain to be elucidated. These data implicate a role for the PAG in both cannabinoid-mediated anti-nociceptive and anti-aversive responses.

Long-chain 3-hydroxyacylCoA dehydrogenase deficiency: a new case presenting with liver dysfunction, cholestasis and fibrosis.

UNLABELLED: A cholestatic 6-mo-old girl was admitted to our department because she recently presented with hypotonia and lethargy, apparently due to moderate and transient hypoglycaemia. Her urine contained 3-hydroxy-dicarboxylic acids of 12 to 14 carbons in length and her plasma acylcarnitine profile was consistent with long-chain 3-hydroxyacylCoA dehydrogenase deficiency. This diagnosis was confirmed by enzyme studies. This deficiency was due to a G1528C mutation on the paternal allele (mutation on the maternal allele as yet not identified). The patient improved dramatically with medium-chain triglyceride supplementation. CONCLUSION: Early cholestasis and hepatic fibrosis must lead to search for long-chain 3-hydroxyacylCoA dehydrogenase deficiency, particularly when hypoketotic hypoglycaemia is present.

Prenatal diagnosis of multiple acyl-CoA dehydrogenase deficiency: association with elevated alpha-fetoprotein and cystic renal changes.

We report the occurrence of multiple acyl-CoA dehydrogenase deficiency (MADD) in two consecutive pregnancies in a young, Caucasian, non-consanguineous couple. In the first pregnancy, the maternal serum alpha-fetoprotein was elevated. A sonogram showed growth delay, cystic renal disease, and oligohydramnios; the parents decided to terminate the pregnancy. Postmortem examination confirmed the cystic renal disease and showed hepatic steatosis, raising the suspicion of a metabolic disorder. The diagnosis of MADD was made by immunoblot studies on cultured fibroblasts. In the subsequent pregnancy, a sonogram at 15 weeks' gestation showed an early growth delay but normal kidneys. The maternal serum and amniotic fluid concentrations of alpha-fetoprotein were elevated, and the amniotic fluid acylcarnitine profile was consistent with MADD. In vitro metabolic studies on cultured amniocytes confirmed the diagnosis. A follow-up sonogram showed cystic renal changes. These cases provide additional information regarding the evolution of renal changes in affected fetuses and show a relationship with elevated alpha-fetoprotein, which may be useful in counseling the couple at risk. MADD should be considered in the differential diagnosis of elevated alpha-fetoprotein and cystic renal disease. Early growth delay may be an additional feature.

Infantile fibre type disproportion, myofibrillar lysis and cardiomyopathy: a disorder in three unrelated Dutch families.

An apparently new cardioskeletal myopathy is reported in three unrelated families. Five infants were affected by rapidly progressive generalized muscle weakness, with onset shortly after birth, and dilated cardiomyopathy. All had generalized tremor (clonus) starting in the first week of life. The disease was lethal in all cases between 4 and 6 months. Muscle biopsy, performed in four of the five patients, showed a light microscopic pattern of small type I and normal-sized type II fibres. By electron microscopy small fibres were affected by myofibrillar disruption and swelling of organelles. Findings in blood and urine suggested a disturbance in energy metabolism but an extensive search for respiratory chain disorders and disorders of mitochondrial fatty acid oxidation in frozen muscle and cultured fibroblasts was negative. The findings support a new progressive autosomal recessive infantile cardioskeletal myopathy in which type I muscle fibres are preferentially affected.

Secreted protein acidic and rich in cysteine expression after subtotal nephrectomy and blockade of the renin-angiotensin system.

Secreted protein acidic and rich in cysteine (SPARC) is an extracellular matrix-associated protein with antiadhesive, antiproliferative, and matrix remodeling properties. SPARC gene and protein expression were investigated after subtotal nephrectomy (STNx), a model of noninflammatory progressive renal injury. In addition, the effect of blockade of the renin-angiotensin system by the angiotensin-converting enzyme inhibitor ramipril or by the angiotensin II receptor antagonist valsartan was examined. The STNx rats developed hypertension, proteinuria, and renal impairment. These changes were associated with a 2.4-fold increase in SPARC gene expression in STNx compared with SHAM kidneys (P < 0.001). In situ hybridization revealed increased SPARC mRNA in glomeruli and interstitial cells, as well as de novo expression by tubular epithelial cells at sites of renal injury. Immunofluorescence studies confirmed concordant changes in SPARC protein. Both ramipril and valsartan ameliorated renal injury and significantly reduced SPARC overexpression in the STNx animals. The findings of the present study suggest that SPARC, in the context of its known biological actions, may influence some of the pathological features associated with significant renal mass reduction.

Portal film enhancement: technique and clinical utility.

We report on the results a 3-year project which had as its goal the development of methods to enhance radiation portal films to improve their readability. We had previously reported on a portal film enhancement technique, contrast limited adaptive histogram equalization, which could enhance low contrast detail, but degraded sharply contrasted edges. A new method, unsharp masking followed by contrast limited adaptive histogram equalization, now appears to overcome this problem. A clinical trial to test whether enhanced portal films could be read more accurately than standard ones was undertaken. The trial involved 12 readers from two institutions doing 276 readings. In this trial the enhanced films were judged to be of higher quality than the non-enhanced films (p < .001) and were read more accurately (p = .026). The usefulness and difficulties of routinely performing portal film enhancement in a busy radiation therapy department are discussed.

The effect of an amino acid-lowering diet on the rate of melphalan entry into brain and xenotransplanted glioma.

Melphalan (L-phenylalanine mustard, L-PAM, alkeran; molecular weight, 305,000) is transported across tumor cell membranes and the blood-brain barrier by the large neutral amino acid (LNAA) transport system. Normally, plasma LNAA levels are high enough and the affinity low enough that this system does not transport much melphalan into the brain. However, plasma amino acids can be reduced by fasting and protein-free diet. We used this method to reduce competition and to increase melphalan transport into brain tumors. In nude mice fasted for 12 h and then fed a protein-free diet for 2 and 6 h, mean plasma LNAA levels were 46% and 42% of control values. Nude mice with xenotransplanted D-54MG human gliomas were used to study tissue distribution and uptake kinetics of [3H]melphalan in a control group and a diet group (after a 12-h fast and 2 h of a 0% protein diet). The K1 (blood-to-tissue transfer constant) of melphalan, determined by graphical analysis and by nonlinear fitting to a 2-compartment model, was higher in the diet group in all tumor regions except the necrotic center of subcutaneous tumors; the increase was significant in the tumor periphery of brain and s.c. tumors. The ratio of K1s (diet to control) varied from 1.2 to 1.3 in brain tumors, 1.9 to 2.1 in subcutaneous tumors, and 1.8 to 3.1 in tumor-free brain. The apparent [3H]melphalan distribution space was significantly higher in the tumor periphery of both brain and subcutaneous tumors of the 15- and 30-min diet group. We also measured blood-brain barrier transport of [alpha-14C]aminoisobutyric acid and blood flow (with [131I]iodoantipyrine): the K1 of [alpha-14C]aminoisobutyric acid was 28.1 +/- 6.6 (SE) in brain tumors and 24.3 +/- 8.9 microliters/g/min in subcutaneous tumors. Blood flow was 58.2 --> 3.9 in brain tumors and 5.2 +/- 0.4 ml/100 g/min in subcutaneous tumors. Fasting, when combined with a protein-free diet, reduces plasma amino acid levels and thereby reduces competition between melphalan and LNAAs. This may increase the amount of melphalan that can enter a brain tumor without increasing the administered drug dose and suggests a therapeutic manipulation that can be used to increase the delivery of melphalan.

Single-dose antibiotic prophylaxis for patients undergoing extended pelvic surgery for gynecologic malignancy.

The comparative efficacy of single-dose antibiotic prophylaxis was retrospectively evaluated in 116 patients undergoing extended pelvic surgical procedures with curative intent. During the 24-month period, other important variables such as surgeon's experience, duration of preoperative hospitalization, preoperative preparation, method of hair removal, suture type, suture size, use of drains, use of cautery, and abdominal closure were controlled. The overall surgical site infection rate was 4.3% after radical hysterectomy with lymphadenectomy and 4.5% after total hysterectomy with lymphadenectomy. In this clinical situation the use of a single dose of antibiotic prophylaxis theoretically decreases cost and patient exposure and appears to be as efficacious as a multiple-dose regimen.

Therapeutic approaches to cobalamin-C methylmalonic acidemia and homocystinuria.

The use of hydroxocobalamin (OH-B12), betaine, carnitine, and folinic acid were studied in two children with the cobalamin C form of methylmalonic acidemia and homocystinuria. When daily injections of 1 mg OH-B12 were discontinued for 3 weeks, there was no significant change in total plasma homocysteine or methionine levels and only a modest increase in methylmalonate. Orally administered OH-B12 1 mg/d in one patient was associated with an increase in plasma homocystine and a decrease in methionine within 1 month. Withdrawal of betaine 250 mg/kg/d was also associated with a rise in plasma homocystine and a fall in methionine levels. Carnitine 100 mg/kg/d lead to an increase in urinary excretion of propionylcarnitine, but did not affect plasma methylmalonate levels. No beneficial biochemical effect of folinic acid could be documented at a dose of 25 mg/d. Our results suggest that daily injections of OH-B12 are not necessary to maintain metabolic control and that orally administered OH-B12 is unlikely to be effective. Betaine appears to act synergistically with OH-B12 and should be part of the treatment regimen. Although there are theoretical reasons for using L-carnitine and folinic acid, we could not document their effectiveness in these two patients.

Metabolic response to carnitine in methylmalonic aciduria. An effective strategy for elimination of propionyl groups.

Patients with methylmalonic aciduria have an excessive intramitochondrial accumulation of acylcoenzyme A compounds that may reduce the availability of free coenzyme A (CoA) for normal metabolic requirements, producing profound metabolic disturbances. Giving carnitine to a patient with methylmalonic aciduria produced an increase in hippurate excretion (an index of intramitochondrial adenosine triphosphate (ATP) and CoA availability), a large increase in short chain urinary acylcarnitines, and a reduction in excretion of methylmalonate and methylcitrate. These acylcarnitines were shown by fast atom bombardment and B/E linked scan mass spectrometry to be propionylcarnitine and acetylcarnitine. Carnitine acts by removing (detoxifying) propionyl groups, thereby releasing CoA and restoring ATP biosynthesis and concentrations towards normal. L-carnitine may play a central role in maintenance of mitochondrial and cellular homoeostasis in methylmalonic aciduria and propionic acidaemia. These principles may provide an approach to the treatment of this and other disorders, inherited and acquired, in which accumulation of acyl CoA metabolites results in sequestration of free CoA, thereby perturbing metabolic homoeostasis.

Anti-inflammatory action of dexamethasone in vitrectomy infusion fluid.

Vitrectomy and lensectomy were performed in rabbits with infusion fluid containing dexamethasone. No ocular toxicity was observed in eyes that received dexamethasone up to a concentration of 400 micrograms/ml. Utilizing sensitive radioimmunoassay techniques after surgery, we observed significant reduction in ocular albumin levels in eyes treated with dexamethasone when compared with control eyes in which dexamethasone was not used. However, there was no significant difference in immunoglobulin levels between eyes from both groups.

Hepatic enzymes of tyrosine metabolism in tyrosinemia II.

A middle-aged adult male with a mild form of tyrosinemia II (Richner-Hanhart syndrome) is described. Treatment with a low-tyrosine diet caused a fall in plasma tyrosine and clearing of the hyperkeratosis of the soles. Liver biopsy of this patient revealed low but measurable levels of cytoplasmic tyrosine aminotransferase and elevated levels of the mitochondrial tyrosine-metabolizing enzyme aspartate aminotransferase. It is hypothesized that these enzymes have been induced in sufficient amounts to account for the mild clinical course.

Relation of creatine kinase isoenzyme MB to postoperative electrocardiographic diagnosis in patients undergoing coronary-artery bypass surgery.

We compared (a) the frequency of detection of isoenzyme MB of creatine kinase (CK; EC 2.7.3.2) in serum of patients undergoing coronary-artery bypass surgery, (b) the interval during uhich its activity was supranormal in serum, and (c) an index of the amount of CK released into blood ("CK-MB area") with postoperative electrocardiographic changes in 80 patients. The frequency of detection of CK-MB is a function of frequency of sampling during the early postoperative period. Because the duration of appearance and the calculated CK-MB area increased as the electrocardiogram became more specific for infarction (p less than 0.01), a twice-daily sampling schedule proved clinically relevant. Only 5.4% of patients had electrocardiographic evidence of infarction when CK-MB was absent by the second postoperative morning. When CK-MB was still detected at that time, 69.6% of patients had persistent new Q waves, consistent with infarction. In three patients who died postoperatively, significant myocardial necrosis was demonstrated. All three had had persistently increased values for CK-MB, related to electrocardiographic changes of infarction in one patient and ischemic changes in two. Evidently CK-MB is a more sensitive indicator of myocardial necrosis than the electrocardiogram and CK-MB area should be a useful criterion in evaluating methods of intra-operative myocardial protection.