Adam Januszewski

Dexmedetomidine Attenuates Isoflurane-induced Neurocognitive Impairment in Neonatal Rats

Background:Neuroapoptosis is induced by the administration of anesthetic agents to the young. As α2 adrenoceptor signaling plays a trophic role during development and is neuroprotective in several settings of neuronal injury, the authors investigated whether dexmedetomidine could provide functional protection against isoflurane-induced injury. Methods:Isoflurane-induced injury was provoked in organotypic hippocampal slice cultures in vitro or in vivo in postnatal day 7 rats by a 6-h exposure to 0.75% isoflurane with or without dexmedetomidine. In vivo, the α2 adrenoceptor antagonist atipamezole was used to identify if dexmedetomidine neuroprotection involved α2 adrenoceptor activation. The γ-amino-butyric-acid type A antagonist, gabazine, was also added to the organotypic hippocampal slice cultures in the presence of isoflurane. Apoptosis was assessed using cleaved caspase-3 immunohistochemistry. Cognitive function was assessed in vivo on postnatal day 40 using fear conditioning. Results:In vivo dexmedetomidine dose-dependently prevented isoflurane-induced injury in the hippocampus, thalamus, and cortex; this neuroprotection was attenuated by treatment with atipamezole. Although anesthetic treatment did not affect the acquisition of short-term memory, isoflurane did induce long-term memory impairment. This neurocognitive deficit was prevented by administration of dexmedetomidine, which also inhibited isoflurane-induced caspase-3 expression in organotypic hippocampal slice cultures in vitro; however, gabazine did not modify this neuroapoptosis. Conclusion:Dexmedetomidine attenuates isoflurane-induced injury in the developing brain, providing neurocognitive protection. Isoflurane-induced injury in vitro appears to be independent of activation of the γ-amino-butyric-acid type A receptor. If isoflurane-induced neuroapoptosis proves to be a clinical problem, administration of dexmedetomidine may be an important adjunct to prevent isoflurane-induced neurotoxicity.

Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain.

Background:Anesthetics, including isoflurane and nitrous oxide, an antagonist of the N-methyl-d-aspartate subtype of the glutamate receptor, have been demonstrated to induce apoptotic neurodegeneration when administered during neurodevelopment. Xenon, also an N-methyl-d-aspartate antagonist, not only lacks the characteristic toxicity produced by other N-methyl-d-aspartate antagonists, but also attenuates the neurotoxicity produced by this class of agent. Therefore, the current study sought to investigate xenons putative protective properties against anesthetic-induced neuronal apoptosis. Method:Separate cohorts (n = 5 or 6 per group) of 7-day-old rats were randomly assigned and exposed to eight gas mixtures: air, 75% nitrous oxide, 75% xenon, 0.75% isoflurane, 0.75% isoflurane plus 35% or 75% nitrous oxide, 0.75% isoflurane plus 30% or 60% xenon for 6 h. Rats were killed, and cortical and hippocampal apoptosis was assessed using caspase-3 immunostaining. In separate cohorts, cortices were isolated for immunoblotting of caspase 3, caspase 8, caspase 9, and cytochrome c. Organotypic hippocampal slices of postnatal mice pups were derived and cultured for 24 h before similar gas exposures, as above, and subsequently processed for caspase-3 immunostaining. Results:In vivo administration of isoflurane enhances neuronal apoptosis. When combined with isoflurane, nitrous oxide significantly increases whereas xenon significantly reduces apoptosis to a value no different from that of controls. In vitro studies corroborate the ability of xenon to attenuate isoflurane-induced apoptosis. Isoflurane enhanced expression of indicators of the intrinsic and common apoptotic pathways; this enhancement was increased by nitrous oxide but attenuated by xenon. Conclusions:The current study demonstrates that xenon prevents isoflurane-induced neonatal neuronal apoptosis.

Breast cancer: Current and future endocrine therapies

Endocrine therapy forms a central modality in the treatment of estrogen receptor positive breast cancer. The routine use of 5 years of adjuvant tamoxifen has improved survival rates for early breast cancer, and more recently has evolved in the postmenopausal setting to include aromatase inhibitors. The optimal duration of adjuvant endocrine therapy remains an active area of clinical study with recent data supporting 10 years rather than 5 years of adjuvant tamoxifen. However, endocrine therapy is limited by the development of resistance, this can occur by a number of possible mechanisms and numerous studies have been performed which combine endocrine therapy with agents that modulate these mechanisms with the aim of preventing or delaying the emergence of resistance. Recent trial data regarding the combination of the mammalian target of rapamycin (mTOR) inhibitor, everolimus with endocrine therapy have resulted in a redefinition of the clinical treatment pathway in the metastatic setting. This review details the current endocrine therapy utilized in both early and advanced disease, as well as exploring potential new targets which modulate pathways of resistance, as well as agents which aim to modulate adrenal derived steroidogenic hormones.

Irosustat: a first-generation steroid sulfatase inhibitor in breast cancer

Endocrine therapy is a key modality in the management of breast cancer, with current options for postmenopausal women including tamoxifen, aromatase inhibitors and fulvestrant. Unfortunately, in spite of these advances, many women still relapse or progress on endocrine therapy. Given that resistance (de novo or acquired resistance) is a major limiting factor in the use of endocrine therapy, additional endocrine therapies with novel methods of action are required. Steroid sulfatase, which is responsible for the conversion of estrone sulfate to estrone, as well as dehydroepiandrosterone sulfate to dehydroepiandrosterone, has been implicated in endocrine resistance. In this article, we summarize the preclinical and clinical data to support the potential role of steroid sulfatase in breast cancer, as well as the current data on the first available steroid sulfatase inhibitor named irosustat (STX64; 667 Coumate; BN83495), and discuss its potential clinical development.

Multicenter experience of nonpegylated liposomal doxorubicin use in the management of metastatic breast cancer.

BACKGROUND This study aimed to investigate the use of nonpegylated liposomal doxorubicin (NPLD) in the management of metastatic breast cancer (MBC) within routine UK clinical practice and to assess its efficacy and tolerability. PATIENTS AND METHODS All patients that received NPLD for MBC at 5 institutions were identified. Clinicopathologic details, echocardiographic data, and toxicities were documented. Response to treatment, outcome, cardiotoxicity, and safety were assessed. RESULTS 63 patients (median age at NPLD therapy, 53.5 years) who had received NPLD were identified; 18 (29%) were anthracycline-naïve, and 42 (67%) were anthracycline-pretreated (median cumulative dose of epirubicin, 450 mg/m(2)). In 3 cases, prior treatment history was not available. NPLD was most frequently (16 [25%] of 63 patients) administered as first-line chemotherapy (median, third-line; range, 1-9), although it was given later in anthracycline-pretreated patients (median, fourth-line; range, 1-9). Overall, 14 (29%) of 49 evaluable patients achieved an objective response, which increased to 10 (71%) of 14 when NPLD was given first-line (anthracycline-naïve, 8 [100%] of 8; anthracycline-pretreated, 2 [50%] of 4; adjuvant treatment unknown, 2). Median progression-free survival was 7 months (first-line, 18 months, vs. ≥ second-line, 6 months; P = .0066), and median overall survival was 10 months (first-line, 18 months, vs. ≥ second-line, 10 months; P = .0971). Toxicities tended to be grade 1 or 2. Three patients had cardiotoxicity (left ventricular ejection fraction < 50% or a fall of ≥ 10% from baseline), which resolved during treatment. CONCLUSION NPLD was used in both anthracycline-naïve patients and those with prior exposure. There is evidence of clinical activity in those with prior exposure to anthracyclines, with a low incidence of cardiotoxicity.

Ethnic variation in breast cancer incidence and outcomes--the debate continues.

Ethnic variation in breast cancer outcomes has been known for many decades. Much of the data derives from the US, whereas disparities seen in the United Kingdom are less well studied. Epidemiologic data suggest that the incidence of breast cancer in black women is less than that of white women, while their outcomes are significantly worse (Bowen et al, 2006). Despite advances in the treatment and detection of breast cancer, these ethnic disparities have persisted over recent years (Colditz et al, 2006). Causative factors are complex and multifaceted but those suggested to be influential include biologic variations in tumour characteristics, differential presentation, variations in co-morbidities, differences in treatment and of course socioeconomic status.

Role of fulvestrant in the management of postmenopausal breast cancer

Fulvestrant is a form of endocrine therapy used in the treatment of postmenopausal breast cancer. It has a unique mechanism of action in that it causes the degradation of estrogen receptor and therefore has been labeled a selective estrogen receptor downregulator. Unlike the selective estrogen receptor modulator tamoxifen, it has no agonistic properties and is therefore a pure anti-estrogen. Given its low level of bioavailability and presystemic metabolism, it has been formulated as an intramuscular injection. A number of dosing regimens have been utilized – these include a dose of 250 mg monthly (‘approved dose’), an initial 500 mg followed by 250 mg on days 14 and 28, and thereafter 250 mg every 28 days (‘loading dose’), or 500 mg on days 0, 14 and 28, and thereafter every 28 days (‘high dose’). This article will review its unique mode of action and preclinical data, as well as clinical data for different dosing regimens and data for its combination with aromatase inhibitors. Fulvestrant is a well-tolerated drug and its toxicities will also be reviewed. The optimal position of fulvestrant in sequential endocrine therapy has yet to be defined.

Evaluation of the red cell distribution width as a biomarker of early mortality in hepatocellular carcinoma

BACKGROUND The red cell distribution width is a biomarker of early mortality across various disease states. AIM To verify whether it may refine estimates of survival in hepatocellular carcinoma. METHODS The red cell distribution width measured at diagnosis was analyzed in relationship to mortality by any cause both in a retrospective training cohort (N=208), and in an independent prospectively collected validation cohort (N=106) of patients with hepatocellular carcinoma. Based on Cox proportional hazards modelling, a prognostic index was validated. RESULTS In the training and the validation cohort, median survival time was respectively 1026 and 868 days in patients with red cell distribution width ≤14.6%, vs. 282 and 340 days in patients with red cell distribution width >14.6%; the corresponding hazard ratios were 0.43 (95% CI: 0.31-0.60), p<0.0001 and 0.28 (95% CI: 0.17-0.47), p<0.0001. At multivariate analysis, the red cell distribution width remained an independent predictor of survival (p<0.001) in a Cox model including other widely accepted prognostic factors. Applying to the validation dataset the prognostic index derived from the training dataset, the ability of the model to discriminate the survival probabilities of patients was confirmed (Harrells C=0.769). CONCLUSIONS The red cell distribution width is a novel, reproducible, prospectively validated predictor of survival in patients with hepatocellular carcinoma.

Plasma Kisspeptin: A Potential Biomarker of Tumor Metastasis in Patients with Ovarian Carcinoma

To the Editor: More than 15 000 women in the US die from ovarian carcinoma annually (1). The most important determinant of survival in ovarian carcinoma cases is tumor stage. Most patients presenting with disease confined to the ovaries (stage 1) can be cured, with a 5-year survival rate of >90% (1). Spread of the tumor outside the ovaries (stages 2 to 4) confers a much poorer prognosis, however. Cure is uncommon in patients with tumor spread into the pelvis (stage 2), the abdomen (stage 3), or the liver/extra-abdominal region (stage 4), with a 5-year survival rate as low as 22% (1). It is therefore critically important to develop novel biochemical markers of ovarian carcinoma to stratify patients according to prognosis. Serum cancer antigen 125 (CA125) is a useful marker for screening and monitoring disease response but cannot be reliably used for staging, because 20% of tumors do not secrete CA125 (2). There is currently no diagnostic marker of tumor spread in patients with diagnosed ovarian carcinoma. Kisspeptin, a peptide that activates the kisspeptin receptor, is encoded by the KISS1 (KiSS-1 metastasis-suppressor) gene. KISS1 expression negatively correlates with metastasis risk in lung, pancreatic, esophago-gastrointestinal, endometrial, renal cell, and bladder carcinomas (3). In ovarian carcinoma, low KISS1 expression is associated with aggressive disease and a poor prognosis, and KISS1 overexpression inhibits cell migration and reduces metastasis (4). Kisspeptin is therefore a putative metastasis suppressor in ovarian …

An Association of Cancer Physicians’ strategy for improving services and outcomes for cancer patients

The Association of Cancer Physicians in the United Kingdom has developed a strategy to improve outcomes for cancer patients and identified the goals and commitments of the Association and its members.