Intermediate-term Outcomes Following a Case Series of Reoperations for Medtronic Freestyle Stentless Aortic Valves.

Background: Data are limited on long-term outcomes in patients who have undergone a reoperation following failure of a stentless aortic valve. Methods: Between 2006 and 2016, a retrospective analysis was performed on 24 patients who underwent open aortic valve replacement surgery for a failed stentless aortic valve prosthesis at Health Sciences North, Sudbury, Ontario, Canada. The primary outcome was a low mortality rate from cardiac-related deaths after 5 years. Results: All patients underwent insertion of a Medtronic Freestyle bioprosthesis (Minneapolis, MN) implanted using the modified subcoronary technique for their initial operation. The interval from the first operation to the stentless redo surgery ranged from 6 to 13 years. Aortic valve reoperation was performed for structural valve deterioration in 96% (n = 23) of the cases. Reoperations involved a removal of the stented valve leaflets and standard aortic valve replacement within the stentless casing in 20% (n = 5) of the cases, with the remaining cases requiring complete removal of the stentless prosthesis and aortic valve replacement. In those in whom a complete removal of the stentless valve was possible (n = 19), no disruption of the native aortic root occurred, with a 0% rate of conversion to a Bentall procedure. No intraoperative mortality occurred. The 30-day and 10-year operative mortality rates were 4% and 16%, respectively. Conclusions: Redo surgery for failing stentless valves can be done with relatively low risk and with acceptable long-term outcomes without resorting to root-replacement techniques.

Contexte: Il existe peu de données sur les résultats à long terme chez les patients qui ont subi une réintervention chirurgicale après une défaillance d'une valve aortique sans armature (stentless) ayant été implantée. Méthodologie: Nous avons réalisé une analyse rétrospective, de 2006 à 2016, auprès de 24 patients ayant subi une intervention chirurgicale invasive de remplacement de valve aortique en raison de la défaillance d'une prothèse aortique sans armature à l'hôpital Health Sciences North situé à Sudbury (Ontario), au Canada. Le paramètre principal d'évaluation était un faible taux de mortalité d'origine cardiaque après 5 ans. Résultats: Tous les patients avaient initialement subi l'implantation d'une bioprothèse Medtronic Freestyle (Minneapolis, Minnesota) par la technique sous-coronaire modifiée. La période écoulée entre la première intervention chirurgicale et la réintervention au niveau de la valve sans armature allait de 6 à 13 ans. Dans 96 % des cas (n = 23), la réintervention était réalisée en raison d'une détérioration de structure de la valve aortique. La réintervention avait consisté en un retrait des cuspides avec armature et un remplacement de valve aortique standard dans la membrane sans armature dans 20 % des cas (n = 5) et un retrait complet de la prothèse sans armature avec remplacement de la valve aortique avait été nécessaire dans les autres cas. Chez les patients pour qui le retrait complet de la valve sans armature a été possible (n = 19), aucune déchirure de la racine aortique native n'est survenue et le taux de passage à une intervention de Bentall était de 0 %. Aucun décès peropératoire n'est survenu. Les taux de mortalité à 30 jours et à 10 ans s'élevaient à 4 % et à 16 %, respectivement. Conclusions: La réintervention chirurgicale après la défaillance d'une valve aortique sans armature peut être réalisée avec des risques re-lativement faibles et des résultats à long terme acceptables sans avoir recours à des techniques de remplacement de la racine aortique.

Molecular Mechanisms Associated with Antifungal Resistance in Pathogenic Candida Species.

Candidiasis is a highly pervasive infection posing major health risks, especially for immunocompromised populations. Pathogenic Candida species have evolved intrinsic and acquired resistance to a variety of antifungal medications. The primary goal of this literature review is to summarize the molecular mechanisms associated with antifungal resistance in Candida species. Resistance can be conferred via gain-of-function mutations in target pathway genes or their transcriptional regulators. Therefore, an overview of the known gene mutations is presented for the following antifungals: azoles (fluconazole, voriconazole, posaconazole and itraconazole), echinocandins (caspofungin, anidulafungin and micafungin), polyenes (amphotericin B and nystatin) and 5-fluorocytosine (5-FC). The following mutation hot spots were identified: (1) ergosterol biosynthesis pathway mutations (ERG11 and UPC2), resulting in azole resistance; (2) overexpression of the efflux pumps, promoting azole resistance (transcription factor genes: tac1 and mrr1; transporter genes: CDR1, CDR2, MDR1, PDR16 and SNQ2); (3) cell wall biosynthesis mutations (FKS1, FKS2 and PDR1), conferring resistance to echinocandins; (4) mutations of nucleic acid synthesis/repair genes (FCY1, FCY2 and FUR1), resulting in 5-FC resistance; and (5) biofilm production, promoting general antifungal resistance. This review also provides a summary of standardized inhibitory breakpoints obtained from international guidelines for prominent Candida species. Notably, N. glabrata, P. kudriavzevii and C. auris demonstrate fluconazole resistance.

A Comparison Between the Rates of Radiation Oncologist and Urologist Consultations in Men Diagnosed With Prostate Cancer in Northern Ontario, Canada.

Purpose: Recommendations from Cancer Care Ontario stress the importance of multidisciplinary care from radiologists and urologists for prostate cancer treatment. The present study sought to examine what percentage of patients had a consultation with a radiation oncologist before undergoing a radical prostatectomy in Ontario, Canada, between 2010 and 2019. Methods and Materials: Administrative health care databases were used to analyze the number of consultations billed to the Ontario Health Insurance Plan from radiologists and urologists who treated men with a first prostate cancer diagnosis (n = 22,169). Results: In Ontario, 94.70% of Ontario Health Insurance Plan billings for patients with prostate cancer who had a prostatectomy within 1 year of a prostate cancer diagnosis were from urology, and 37.66% and 1.77% of billings were received from radiation oncology and medical oncology specialties, respectively. When sociodemographic variables were examined, having a lower neighborhood income (adjusted odds ratio [aOR], 0.69; confidence interval [CI], 0.62-0.76) and a rural residence (aOR, 0.72; CI, 0.65-0.79) were associated with lower odds of receiving a consultation from a radiation oncologist. When billings for consultations were examined geographically by region, Northeast Ontario (Local Health Integrated Network 13) had the lowest odds of receiving a radiation consultation compared with the rest of Ontario (aOR, 0.50; CI, 0.42-0.59). Conclusions: The results of this study show that differences in equitable access to multidisciplinary health care exist for men with a first prostate cancer diagnosis who reside in more northern and rural regions within Ontario, relative to the rest of the province. The reasons for these findings are likely multifactorial and may include factors such as patient treatment preference and distance/travel to receive treatment. However, as diagnosis year increased, so did the chances of receiving a radiation oncologist consultation, and this upward trend may reflect the implementation of Cancer Care Ontario guidelines.

Rates of Smoking Cessation at 6 and 12 Months after a Clinical Tobacco Smoking Cessation Intervention in Head and Neck Cancer Patients in Northern Ontario, Canada.

Smoking during cancer treatment is associated with reduced treatment response and cancer recurrence in patients with tobacco-related cancers. The purpose of this study was to examine smoking characteristics in head and neck cancer patients (n = 503) with a history of smoking and examine the impact of an intensive clinical tobacco intervention to patients who were currently smoking. All participants completed an interviewer-administered questionnaire at study enrollment which examined smoking behaviours, motivations to quit, and strategies used to cessate smoking. Follow-up assessments were completed at 6- and 12-months which monitored whether patients had quit smoking, remained cessated, or continued to smoke since study recruitment. For those who were currently smoking (n = 186, 37.0%), an intensive clinical tobacco intervention that utilized the 3A's-Ask, Advise, Arrange-and the Opt-Out approach was offered to assist with smoking cessation at their new patient visit and followed-up weekly during their head and neck radiation therapy for 7 weeks. At 6 months, 23.7% (n = 41) of those who were smoking successfully quit; 51.2% quit 'cold turkey' (defined as using no smoking cessation assistance, aids or pharmacotherapy to quit), while 34.9% used pharmacotherapy (varenicline (Champix)) to quit. On average, it took those who were smoking 1-5 attempts to quit, but once they quit they remained cessated for the duration of the study. Although the head and neck cancer patients in this study reported high levels of nicotine dependence, many were able to successfully cessate.

Impact of comprehensive hospice palliative care on end-of-life care: a propensity-score-matched retrospective observational study.

BACKGROUND: Access to hospice palliative care may improve quality of life, reduce the use of potentially aggressive end-of-life care and allow for death to occur outside of an acute care hospital. The aim of this study was to examine the impact of an ambulatory hospice palliative care program on end-of-life care compared to care received by a matched control group of deceased patients. METHODS: This retrospective study included patients who received hospice palliative care through the Symptom Management Program in Sudbury, Ontario, during 2012-2015. Using linked administrative health records, we defined a propensity-matched control group and derived 4 previously defined variables associated with aggressive end-of-life care (chemotherapy received in the last 2 wk of life, > 1 emergency department visit within 30 d of death, > 1 hospital admission within 30 d of death and at least 1 intensive care unit admission within 30 d of death). We also examined place of death. We measured family/caregiver satisfaction with care 3 months after the patient's death using the FAMCARE questionnaire. RESULTS: Of 914 eligible decedents enrolled in the Symptom Management Program, 754 (82.5%) were matched. Receiving care through the program was protective for most measures of aggressive end-of-life care (absolute risk reduction [ARR] 12.73, 95% confidence interval [CI] 12.65-12.81 for any end-of-life care outcome) and death in an acute care setting (ARR 19.89, 95% CI 19.78-20.00). Of the 450 family caregivers invited to complete the FAMCARE questionnaire, 190 (42.2%) returned completed surveys; following data linkage and matching, 96 (21.3%) were available for analysis. Satisfaction with care received within the program appeared high (mean total score 85.72/100). INTERPRETATION: Provision of hospice palliative care through this ambulatory program was associated with lower use of aggressive end-of-life care and death outside of an acute care hospital. Improving access could be expected to provide positive benefits at the individual and system level.

Access to Palliative Care for Cancer Patients Living in a Northern and Rural Environment in Ontario, Canada: The Effects of Geographic Region and Rurality on End-of-Life Care in a Population-Based Decedent Cancer Cohort.

BACKGROUND: Access to palliative care has been associated with improving quality of life and reducing the use of potentially aggressive end-of-life care. However, many challenges and barriers exist in providing palliative care to residents in northern and rural settings in Ontario, Canada. AIM: The purpose of this study was to examine access to palliative care and associations with the use of end-of-life care in a decedent cohort of northern and southern, rural and urban, residents. DESIGN: Using linked administrative databases, residents were classified into geographic and rural categories. Regression methods were used to define use and associations of palliative and end-of-life care and death in acute care hospital. SETTING/PARTICIPANTS: A decedent cancer cohort of Ontario residents (2007-2012). RESULTS: Northern rural residents were less likely to receive palliative care (adjusted odds ratio [OR] = 0.90, 95% confidence interval [CI]: 0.83-0.97). Those not receiving palliative care were more likely to receive potentially aggressive end-of-life care and die in an acute care hospital (adjusted OR = 1.20, 95% CI: 1.02-1.41). CONCLUSIONS: Palliative care was significantly associated with reduced use of aggressive end-of-life care; however, disparities exist in rural locations, especially those in the north. Higher usage of emergency department (ED) and hospital resources at end of life in rural locations also reflects differing roles of rural community hospitals compared with urban hospitals. Improving access to palliative care in rural and northern locations is an important care issue and may reduce use of potentially aggressive end-of-life care.

Role of autophagy and lysosomal drug sequestration in acquired resistance to doxorubicin in MCF-7 cells.

BACKGROUND: The roles and mechanisms involved in starvation-induced autophagy in mammalian cells have been extensively studied. However, less is known about the potential role for autophagy as a survival pathway in acquired drug resistance in cancer cells under nutrient-rich conditions. METHODS: We selected MCF-7 breast tumor cells for survival in increasing concentrations of doxorubicin and assessed whether the acquisition of doxorubicin resistance was accompanied by changes in doxorubicin and lysosome localization and the activation of autophagy, as assessed by laser scanning confocal microscopy with or without immunohistochemical approaches. The ultrastructure of cells was also viewed using transmission electron microscopy. Cellular levels of autophagy and apoptosis-related proteins were assessed by immunoblotting techniques, while protein turnover was quantified using a flux assay. RESULTS: As cells acquired resistance to doxorubicin, the subcellular location of the drug moved from the nucleus to the perinuclear region. The location of lysosomes and autophagosomes also changed from being equally distributed throughout the cytoplasm to co-localizing with doxorubicin in the perinuclear region. There was an apparent temporal correlation between the acquisition of doxorubicin resistance and autophagy induction, as measured by increases in monodansylcadaverine staining, LC3-II production, and co-localization of LAMP1 and LC3-II immunofluorescence. Electron microscopy revealed an increase in cytoplasmic vacuoles containing mitochondria and other cellular organelles, also suggestive of autophagy. Consistent with this view, a known autophagy inhibitor (chloroquine) was highly effective in restoring doxorubicin sensitivity in doxorubicin-resistant cells. Moreover, this induction of autophagy correlated temporally with increased expression of the selective cargo receptor p62, which facilitates the delivery of doxorubicin-damaged mitochondria and other organelles to autophagosomes. Finally, we suggest that autophagy associated with doxorubicin resistance may be distinct from classical starvation-induced autophagy, since Beclin 1 and Atg7 expression did not change upon acquisition of doxorubicin resistance, nor did recombinant Bcl2 overexpression or an Atg7 knockdown alter doxorubicin cytotoxicity. CONCLUSION: Taken together, our findings suggest that doxorubicin resistance in MCF-7 breast cancer cells is mediated, at least in part, by the activation of autophagy, which may be distinct from starvation-induced autophagy.

A case-control study of breast cancer risk in nurses from Northeastern Ontario, Canada.

PURPOSE: Previously published findings have documented increased breast cancer risks associated with the nursing profession. The aim of the present study was to assess whether an increased risk of breast cancer was associated with nursing in a population-based case-control breast cancer study of women in Northeastern Ontario, Canada. METHODS: A total of 1519 women (1380 never-nurses: 716 controls and 664 cases; 139 ever-nurses: 59 controls and 80 cases) were included in the present study. Study participants filled out a detailed questionnaire which included a history of smoking, general health information, breast cancer risk factors, and a detailed occupational history. RESULTS: Ever-nurses were at higher, but nonsignificant risk of breast cancer compared to never-nurses (adjusted OR 1.39, 95 % CI 0.93-2.07). Ever-nurses who worked for longer than 10 years were at a significantly increased risk of breast cancer compared to never-nurses (adjusted OR 1.70, 95 % CI 1.04-2.79). A nonsignificant, but increased risk of breast cancer was observed in ever-nurses who worked full-time compared to never-nurses (OR 1.52, 95 % CI 0.92-2.52), while nurses who worked part-time, or both part-time and full-time were not at increased risk. Ever-nurses who worked in a hospital setting had a significantly increased risk of breast cancer (OR 1.65, 95 % CI 1.04-2.62) compared to never-nurses. CONCLUSIONS: The results indicate that the nurses in the present study population are at increased risk of breast cancer. A prolonged duration of nursing years and prolonged intensity (being a full-time nurse) are factors associated with this increased risk.

Ablation of Akt2 induces autophagy through cell cycle arrest, the downregulation of p70S6K, and the deregulation of mitochondria in MDA-MB231 cells.

BACKGROUND: Akt/PKB is a promising anticancer therapeutic target, since abnormally elevated Akt activity is directly correlated to tumor development, progression, poor prognosis and resistance to cancer therapies. Currently, the unique role of each Akt isoform and their relevance to human breast cancer are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: We previously found that Akt1, 2 and 3 are localized at specific subcellular compartments (the cytoplasm, mitochondria and nucleus, respectively), raising the possibility that each isoform may have unique functions and employ different regulation mechanisms. By systematically studying Akt-ablated MDA-MB231 breast cancer cells with isoform-specific siRNA, we here show that Akt2 is the most relevant isoform to cell proliferation and survival in our cancer model. Prolonged ablation of Akt2 with siRNA resulted in cell-cycle arrest in G0/G1 by downregulating Cdk2 and cyclin D, and upregulating p27. The analysis of the Akt downstream signaling pathways suggested that Akt2 specifically targets and activates the p70S6K signaling pathway. We also found that Akt2 ablation initially resulted in an increase in the mitochondrial volume concomitantly with the upregulation of PGC-1α, a regulator of mitochondrial biogenesis. Prolonged ablation of Akt2, but not Akt1 or Akt3, eventually led to cell death by autophagy of the mitochondria (i.e., mitophagy). CONCLUSIONS/SIGNIFICANCE: Collectively, our data demonstrates that Akt2 augments cell proliferation by facilitating cell cycle progression through the upregulation of the cell cycle engine, and protects a cell from pathological autophagy by modulating mitochondrial homeostasis. Our data, thus, raises the possibility that Akt2 can be an effective anticancer target for the control of (breast) cancer.

The Akt isoforms, their unique functions and potential as anticancer therapeutic targets.

Akt (also known as protein kinase B or PKB) is the major downstream nodal point of the PI3K signaling pathway. This pathway is a promising anticancer therapeutic target, because constitutive activation of the PI3K-Akt pathway is correlated with tumor development, progression, poor prognosis, and resistance to cancer therapies. The Akt serine/threonine kinase regulates diverse cellular functions including cell growth, proliferation, glucose metabolism, and survival. Although all three known Akt isoforms (Akt1-3) are encoded by separate genes, their amino acid sequences show a high degree of similarity. For this and other reasons, it has long been assumed that all three Akt isoforms are activated in the same way, and their functions largely overlap. However, accumulating lines of evidence now suggest that the three Akt isoforms might have unique modes of activation and many distinct functions. In particular, it has recently been found that the Akt isoforms are localized at different subcellular compartments in both adipocytes and cancer cells. In this review, we highlight the unique roles of each Akt isoform by introducing published data obtained from both in vitro and in vivo studies. We also discuss the significant potential of the Akt isoforms as effective anticancer therapeutic targets.

The Akt isoforms are present at distinct subcellular locations.

Akt is involved in the regulation of diverse cellular functions such as cell proliferation, energy metabolism, and apoptosis. Although three Akt isoforms are known, the function of each isoform is poorly understood. To gain a better understanding of each Akt isoform, we examined the subcellular localization and expression of each isoform in transformed and nontransformed cells. Akt1 was localized in the cytoplasm, which is in agreement with the currently accepted model that cytoplasmic Akt is translocated and activated at the inner leaflet of the plasma membrane. Interestingly, HEK-293 and HEK-293T cells contained Akt1 in the nucleus and cytoplasm, respectively, suggesting that SV40 T-antigen plays a crucial role in the cytoplasmic localization and activation of Akt1 in HEK-293T. Akt2 was colocalized with the mitochondria, while Akt3 was localized in both the nucleus and nuclear membrane. The subcellular localization of the Akt isoforms was not substantially altered in response to ionizing radiation or EGF. Furthermore, the ablation of one Akt isoform by small interfering RNA (siRNA) did not alter the subcellular location of the remaining isoforms, suggesting that the major function of one isoform is not compensated for by other isoforms. Together, our data support the notion that Akt2 and Akt3 are regulated at the mitochondrial and nuclear membranes, respectively. The mitochondrial localization of Akt2 raises the possibility that this isoform may be involved in both glucose-based energy metabolism and suppression of apoptosis, two Akt functions previously identified with anti-pan-Akt antibodies.

Chloroquine-mediated radiosensitization is due to the destabilization of the lysosomal membrane and subsequent induction of cell death by necrosis.

The anti-malarial drug chloroquine (CQ) is also thought to be a potential radiation sensitizer. To gain a better understanding of how the lysomotropic CQ can potentiate the effects of ionizing radiation, we investigated the effects of CQ on lysosomal and mitochondrial membrane stability, the subcellular localization of ceramide, plasma membrane permeability, and the mode of cell death in response to irradiation. We found that CQ accumulated in the lysosomes and thus lysosomal volumes increased. As a result, both the lysosomal and plasma membranes were destabilized. After 7 Gy irradiation, most ceramide was associated with the lysosomes in the cells treated with CQ but not in the CQ-untreated control. The elevated levels of ceramide in the lysosomes of the CQ-treated cells appeared to further destabilize the lysosomal and plasma membranes of the cell. Both CQ-treated and -untreated cells had approximately the same rate of cell death by apoptosis after 7 Gy irradiation (P > 0.05, ns). However, in contrast to the CQ-untreated control, the CQ-treated cells underwent massive cell death by necrosis at 24-48 h after irradiation (P < 0.05). Taken together, our data support the idea that the increase in cytotoxic effects by the combination of CQ and radiation is due to radiation-mediated apoptosis and CQ-mediated necrosis.