Effectiveness of adjuvant trastuzumab in daily clinical practice

Background

Human epidermal growth factor receptor 2 (HER2) positive breast cancer is an entity with aggressive behaviour. One year of adjuvant trastuzumab significantly improves the disease free survival in the range of 40–50% and reduces the risk of dying from HER2 positive breast cancer by one third. Adjuvant treatment with trastuzumab became available in Slovenia in 2005 and the aim of this study is to explore, if the exceptional results reported in adjuvant clinical trials are achieved also in daily clinical practice.

Patients and methods.

An analysis of tumour and patient characteristics, type of treatment and outcome (relapse free and overall survival) of 313 patients (median age 52 years) treated at the Institute of Oncology Ljubljana in years 2005–2009 was performed.

Results

Median follow-up was 4.4 years. Sixty-one patients relapsed and 24 died. Three and four years relapse free survival was 84.2% and 80.8% and the overall survival was 94.4% and 92.5%, respectively. Independent prognostic factors for relapse were tumour grade (HR 2.10; 95% CI 1.07–4.14; p = 0.031) and nodal stage (HR 1.35; 1.16–1.56; p < 0.0001) and for the overall survival nodal stage only (HR 1.36; 1.05–1.78; p = 0.021).

Conclusions

The outcome in patients with adjuvant trastuzumab in daily clinical practice, treated by medical oncologists, is comparable to results obtained in international adjuvant studies.     

Prostitutes and criminals: beginnings of eugenics in Croatia in the works of Fran Gundrum from Oriovac (1856-1919)

Fran Gundrum (1856-1919) was a Croatian physician, encyclopedist, and an advocate of medical enlightenment and healthy lifestyle. In order to identify and analyze Gundrum's ideas about the problems of prostitution and criminality, we studied all of his books, booklets, and articles published between 1905 and 1914. We showed that Gundrum's theories of heredity, morality, and sexual hygiene incorporated many of the important discussions of his time, especially those related to the Darwinian paradigm. Gundrum's project of collecting statistics on prostitutes was the first such study published on the territory of today's Croatia. Although he rejected the notions of born prostitutes and born criminals, defended by Italian criminal anthropologist Cesare Lombroso, he still regarded eugenics as a convenient method of dealing with the ills of society. He believed that criminals were degenerate individuals representing a violent threat to the society and that it was legitimate to use radical means, such as sterilization and deportation, to deal with this problem. Organicistic view of the society prevented him from seeing the individual rights as important as that of the society to protect itself. Nevertheless, this view led to many humanistic ideas, such as the binomial illness/poverty in case of prostitution, which influenced many prominent works of social medicine movement.     

CART peptides in the central control of feeding and interactions with neuropeptide Y

While CART peptides have been implicated as novel, putative peptide neurotransmitters/cotransmitters, behavioral effects of these peptides have not yet been demonstrated. In this study, we show the first behavioral effect of CART peptides. Icv administration of CART peptide fragments inhibits feeding in rats. Moreover, injection of an antibody to CART peptide 82–103 stimulates feeding, suggesting that endogenous CART peptides exert an inhibitory tone on feeding. Injection of CART peptide 82–103 five min before NPY reduces the increase in feeding caused by injection of NPY alone. Also, in light microscopic immunohistochemical studies, NPY-positive varicosities were observed around CART peptide-positive cell bodies in the paraventricular nucleus of the hypothalamus. These data suggest functional interactions between CART peptides and NPY. These results indicate that CART peptides play a role in the control of food intake by the brain. Synapse 29:293–298, 1998. © 1998 Wiley-Liss, Inc.     

Effect of dopaminergic drugs on the in vivo binding of [3H]WIN 35,428 to central dopamine transporters

[¹¹C]WIN 35,428 (also designated [¹¹C]CFT) is now being used in several positron emission tomography (PET) centers to image dopamine (DA) transporter sites in the mammalian brain. Whether and to what extent in vivo WIN 35,428 binding is influenced by intra- and extrasynaptic dopamine levels are largely unknown. The purpose of the present study was to evaluate the effects of various drugs, known to affect DA levels and release, on the binding of [³H]WIN 35,428 to central DA transporters in the mouse brain. D-Amphetamine, which releases DA from neurons and blocks the DA transporter directly, inhibited striatal [³H]WIN 35,428 binding in dose-dependent manner. Similarly, α-methyl-DL-p-tyrosine, an inhibitor of tyrosine hydroxylase, blocked [³H]WIN 35,428 binding, possibly via competitive inhibition by the metabolite p-hydroxyamphetamine. Specific binding of [³H]WIN 35,428 was insensitive to changes in synaptic DA levels caused by pretreatment of the animals with high doses of D₂ receptor agonists (apomorphine, bromocriptine), antagonists (haloperidol) or the inhibitor of dopaminergic neuron firing γ-butyrolactone (GBL). High doses (>50 mg/kg) of L-DOPA (in combination with benserazide), however, reduced [³H]WIN 35,428 binding significantly, yet for a relatively short time (approximately 2.5 h). Chronic treatment with L-deprenyl elicited no changes in in vivo [³H]WIN 35,428 accumulation in the striatum. Neurotoxic damage of DA neurons caused by administration of high doses of amphetamine was detected in the striatum by a significant reduction in [³H]WIN 35,428 binding 7 days after cessation of amphetamine treatment. Thus, [³H]WIN 35,428 binding was only affected by neurotoxic loss of neurons, by administration of uptake inhibitors, or by some treatments which significantly elevate DA levels. Compounds which inhibit DA release or deplete DA acutely do not increase [³H]WIN 35,428 binding, suggesting that normal or “resting” levels of DA are not sufficient to alter [³H]WIN 35,428 binding in vivo. These findings are important for our understanding of the function and regulation of the DA transporter, as well as the in vivo binding of the radioligand [³H/¹¹C]WIN 35,428. Moreover, they will be important for the interpretation of PET studies in which [¹¹C]WIN 35,428 is used to assess the integrity of dopaminergic neurons. © 1996 Wiley-Liss, Inc.     

CART Peptides Regulate Psychostimulants and May be Endogenous Antidepressants

CART peptides are endogenous neurotransmitters that are involved in a variety of physiologic functions. Injection of CART 55-102 into the nucleus accumbens produces no effect, but when co-administered with cocaine, it reduces the locomotor and rewarding properties of cocaine. In a human study, subjects carrying a missense mutation of the CART gene exhibited increased anxiety and depression. Also, several animal studies support the idea that CART is involved in anxiety and depression, and they also suggest several possible mechanisms by which this may occur. Thus, there is interesting evidence that CART peptides play a role in anxiety and depression, and that CART peptides may be endogenous antidepressants.     

Weissella confusa bacteremia in a liver transplant patient with hepatic artery thrombosis

N.P. Harlan, R.R. Kempker, S.M. Parekh, E.M. Burd, D.T. Kuhar. Weissella confusa bacteremia in a liver transplant patient with hepatic artery thrombosis
Transpl Infect Dis 2011: 13: 290–293. All rights reserved Abstract: A 54‐year‐old man with a history of nonalcoholic steatohepatitis and hepatocellular carcinoma presented 2 months after an orthotopic liver transplant with fever and abdominal pain. Two weeks earlier, he had an hepatic artery thrombosis and a biliary stricture, for which an hepatic artery stent and a biliary stent were placed. Laboratory workup was significant for leukocyte count of 7800/mcL with 92% segmented neutrophils, hemoglobin 9.4 g/dL, alanine aminotransferase 98 U/L, aspartate aminotransferase 72 U/L, alkaline phosphatase 358 U/L, albumin 2.8 mg/dL, and total bilirubin 1.6 mg/dL. A computed tomography scan of the abdomen and pelvis revealed multiple small fluid collections in the liver consistent with bilomas, and an hepatic angiogram showed complete occlusion of the common hepatic artery. Two sets of blood cultures were positive for an organism initially identified by MicroScan^® analysis as an α‐hemolytic Streptococcus species that was resistant to vancomycin. Further testing confirmed the organism as Weissella confusa 2 days later. W. confusa is a gram‐positive coccobacillus that may be misidentified as a Lactobacillus when cultured. It is commonly found in sewage, carrots, sugar cane, fermented foods, and intestinal flora. Although only 4 cases of clinical infection with W. confusa have been described previously, W. confusa has been isolated from the stool of liver transplant patients, and may be an underreported cause of infection owing to improper identification. As it can cause clinical infection in these immunosuppressed hosts, identification of this organism is paramount because it is vancomycin resistant, and incorrect identification could lead to improper antimicrobial selection and ultimately worsened patient morbidity or mortality.     

Coinfection with hepatitis C virus,oxidative stress and antioxidant status in HIV‐positive drug users in Miami*

Background

The pathogenesis of HIV/hepatitis C virus (HCV) coinfection is poorly understood. We examined markers of oxidative stress, plasma antioxidants and liver disease in HIV/HCV‐coinfected and HIV‐monoinfected adults.

Methods

Demographics, medical history, and proof of infection with HIV, hepatitis A virus (HAV), hepatitis B virus (HBV) and HCV were obtained. HIV viral load, CD4 cell count, complete blood count (CBC), complete metabolic panel, lipid profile, and plasma concentrations of zinc, selenium, and vitamins A and E were determined. Malondialdehyde (MDA) and glutathione peroxidase concentrations were obtained as measures of oxidative stress. Aminotransferase to platelet ratio index (APRI) and fibrosis index (FIB‐4) markers were calculated.

Results

Significant differences were found between HIV/HCV‐coinfected and HIV‐monoinfected participants in levels of alanine aminotransferase (ALT) (mean±standard deviation: 51.4±50.6 vs. 31.9±43.1 U/L, respectively; P=0.014), aspartate aminotransferase (AST) (56.2±40.9 vs. 34.4±30.2 U/L; P<0.001), APRI (0.52±0.37 vs. 0.255±0.145; P=0.0001), FIB‐4 (1.64±.0.91 vs. 1.03±0.11; P=0.0015) and plasma albumin (3.74±0.65 vs. 3.94±0.52 g/dL; P=0.038). There were no significant differences in CD4 cell count, HIV viral load or antiretroviral therapy (ART) between groups. Mean MDA was significantly higher (1.897±0.835 vs. 1.344± 0.223 nmol/mL, respectively; P=0.006) and plasma antioxidant concentrations were significantly lower [vitamin A, 39.5 ± 14.1 vs. 52.4±16.2 μg/dL, respectively (P=0.0004); vitamin E, 8.29±2.1 vs. 9.89±4.5 μg/mL (P=0.043); zinc, 0.61±0.14 vs. 0.67±0.15 mg/L (P=0.016)] in the HIV/HCV‐coinfected participants than in the HIV‐monoinfected participants, and these differences remained significant after adjusting for age, gender, CD4 cell count, HIV viral load, injecting drug use and race. There were no significant differences in glutathione peroxidase concentration, selenium concentration, body mass index (BMI), alcohol use or tobacco use between groups. Glutathione peroxidase concentration significantly increased as liver disease advanced, as measured by APRI (β=0.00118; P=0.0082) and FIB‐4 (β=0.0029; P=0.0177). Vitamin A concentration significantly decreased (β=?0.00581; P=0.0417) as APRI increased.

Conclusion

HIV/HCV coinfection is associated with increased oxidative stress and decreased plasma antioxidant concentrations compared with HIV monoinfection. Research is needed to determine whether antioxidant supplementation delays liver disease in HIV/HCV coinfection.