The impact of peer review on the radiotherapy treatment planning process in the treatment of lung cancer

Background:
Advanced radiotherapy techniques permit accurate delivery of radiotherapy to lung tumours. Improved accuracy increases the possibility of radiotherapy field geographic miss of the tumour. One source of error is the accuracy of target volume (TV) delineation by the clinical oncologist. Colleague peer review of all curative intent lung cancer plans has been mandatory in our institution since May 2013. At least 2 clinical oncologists review plans checking treatment paradigm, TV delineated, dose to tumour and dose to critical organs. We report the impact of peer review on the radiotherapy planning process for lung cancer.

Methods:
The radiotherapy treatment plans of all patients receiving radical radiotherapy were presented at weekly peer review meetings after their TVs volumes were provisionally signed off by the treating consultant or post-fellowship registrar. All cases and any resultant change to the treatment plan were recorded in our prospective peer review database. We present the summary of changes agreed following the peer review process for a 6 month period.

Results:
Fifteen peer review sessions, including 46 patients (36 NSCLC, 10 SCLC) were analysed. An average of 3 cases were discussed per meeting (range 1 5). 24% of treatment courses were changed. In 4% there was a complete change in paradigm
of treatment (1 patient proceeded to induction chemotherapy, 1 patient had high dose palliative radiotherapy). In 16% there was a change in TV delineated and in 9% a change in dose (2 dose reductions and 2 alterations to post-operative dose fractionations).

Conclusions:
Consultant led peer review resulted in a change in a component of the treatment plan for 28% of patients that would not otherwise have taken place. Given this impact, consultant led peer review should be considered as an essential component in the radiotherapy planning process for all patients treated with curative radiotherapy.

Pre-operative fasting for intravenous conscious sedation used in dental treatment: are conclusions based on relative risk management or evidence?

Intravenous sedation is a widely used pharmacological method of patient management commonly used in dental surgery for the treatment of anxious patients. Variety exists in fasting regimes between different centres offering dental sedation, with some advocating starvation in line with general anaesthesia protocols and others not enforcing starvation at all. The currently available guidelines on fasting protocols are ambiguous and open to interpretation partly because they are based on expert opinion rather than evidence-based research. This article reviews the available evidence on the subject of pre-operative fasting and discusses current guidelines.

Nanoparticle technology: future opportunities in cancer treatment

Gold nanoparticles are emerging as promising agents for cancer therapy and are being investigated as vehicles for drug delivery, agents for photothermal therapy, image contrast and radiosensitisation. This review introduces the field of nanotechnology with a focus on recent gold nanoparticle research which has led to early phase clinical trials. In particular the increasing preclinical evidence for gold nanoparticles as sensitizers with ionizing radiation in vitro and in vivo is discussed.

Molecular markers in the treatment of metastatic colorectal cancer

Although significant progress has been made in colorectal cancer (CRC) treatment within the last decade with the approval of multiple new agents, the prognosis for patients with metastatic CRC remains poor with 5-year survival rates of approximately 8%. Resistance to chemotherapy remains a major obstacle in effective CRC treatment and many patients do not receive any clinical benefit from chemotherapy. In addition, other patients will experience adverse reactions to treatment resulting in dose modifications or treatment withdrawal, which can severely reduce treatment efficacy. Currently, significant research efforts are attempting to identify reliable and validated biomarkers with which will guide clinicians to make more informed treatment decisions. Specifically, the use of molecular profiling has the potential to assist the clinician in administering the correct drug, dose, or intervention for the patient before the onset of therapy thereby selecting a treatment strategy likely to have the greatest clinical outcome while minimizing adverse events. However, until recently, personalized medicine is a paradigm that has existed more in conceptual terms than in reality with very few validated biomarkers used routinely in metastatic CRC treatment. Rapid advances in genomic, transcriptomic and proteomic technologies continues to improve our understanding of tumor biology, but the search for reliable biomarkers has turned out to be more challenging than previously anticipated with significant disparity in published literature and limited translation into routine clinical practice. Recent progress with the identification and validation of biomarkers to the anti-epidermal growth factor receptor monoclonal antibodies including KRAS and possibly BRAF provide optimism that the goal of individualized treatment is within reach. This review will highlight and discuss current progress in the search for biomarkers, the challenges this emerging field presents, and the future role of biomarkers in advancing CRC treatment.

Heller's myotomy and pneumatic dilatation in the treatment of achalasia: a population-based case–control study assessing long-term quality of life

Long-term health-related quality-of-life (HRQL) outcomes have not been widely reported in the
treatment of achalasia. The aims of this study were to examine long-term disease-specific and general HRQL in
achalasia patients using a population-based case–control method, and to assess HRQL between treatment interventions.
Manometrically diagnosed achalasia cases (n = 120) were identified and matched with controls (n = 115)
using a population-based approach. Participants completed general (SF-12) and disease-specific (Achalasia Severity
Questionnaire [ASQ]) HRQL questionnaires, as appropriate, in a structured interview. Mean composite scores
for SF-12 (Mental Component Summary score [MCS-12] and Physical Component Summary score [PCS-12]) and
ASQ were compared between cases and controls, or between intervention groups, using an independent t-test.
Adjusted mean differences in HRQL scores were evaluated using a linear regression model. Achalasia cases were
treated with a Heller’s myotomy (n = 43), pneumatic dilatation (n = 44), or both modalities (n = 33). The median
time from last treatment to HRQL assessment was 5.7 years (interquartile range 2.4–11.5). Comparing achalasia
patients with controls, PCS-12 was significantly worse (40.9 vs. 44.2, P = 0.01), but MCS-12 was similar. However,
both PCS-12 (39.9 vs. 44.2, P = 0.03) and MCS-12 (46.7 vs. 53.5, P = 0.004) were significantly impaired in those
requiring dual treatment compared with controls. Overall however, there was no difference in adjusted HRQL
between patients treated with Heller’s myotomy, pneumatic dilatation or both treatment modalities. In summary,
despite treatment achalasia patients have significantly worse long-term physical HRQL compared with population
controls. No HRQL differences were observed between the treatment modalities to suggest a benefit of one
treatment over another.

The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label, phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis

BACKGROUND: Anemia is considered a negative prognostic risk factor for survival in patients with myelofibrosis. Most patients with myelofibrosis are anemic, and 35-54 % present with anemia at diagnosis. Ruxolitinib, a potent inhibitor of Janus kinase (JAK) 1 and JAK2, was associated with an overall survival benefit and improvements in splenomegaly and patient-reported outcomes in patients with myelofibrosis in the two phase 3 COMFORT studies. Consistent with the ruxolitinib mechanism of action, anemia was a frequently reported adverse event. In clinical practice, anemia is sometimes managed with erythropoiesis-stimulating agents (ESAs). This post hoc analysis evaluated the safety and efficacy of concomitant ruxolitinib and ESA administration in patients enrolled in COMFORT-II, an open-label, phase 3 study comparing the efficacy and safety of ruxolitinib with best available therapy for treatment of myelofibrosis. Patients were randomized (2:1) to receive ruxolitinib 15 or 20 mg twice daily or best available therapy. Spleen volume was assessed by magnetic resonance imaging or computed tomography scan.

RESULTS: Thirteen of 146 ruxolitinib-treated patients had concomitant ESA administration (+ESA). The median exposure to ruxolitinib was 114 weeks in the +ESA group and 111 weeks in the overall ruxolitinib arm; the median ruxolitinib dose intensity was 33 mg/day for each group. Six weeks before the first ESA administration, 10 of the 13 patients had grade 3/4 hemoglobin abnormalities. These had improved to grade 2 in 7 of the 13 patients by 6 weeks after the first ESA administration. The rate of packed red blood cell transfusions per month within 12 weeks before and after first ESA administration remained the same in 1 patient, decreased in 2 patients, and increased in 3 patients; 7 patients remained transfusion independent. Reductions in splenomegaly were observed in 69 % of evaluable patients (9/13) following first ESA administration.

CONCLUSIONS: Concomitant use of an ESA with ruxolitinib was well tolerated and did not affect the efficacy of ruxolitinib. Further investigations evaluating the effects of ESAs to alleviate anemia in ruxolitinib-treated patients are warranted (ClinicalTrials.gov identifier, NCT00934544; July 6, 2009).

Drug repurposing in the treatment of Melanoma Brain Metastasis

Dissertação de Mestrado, Biologia Molecular e Microbiana, Faculdade de Ciências e Tecnologia, Universidade do Algarve, 2015

Evaluation of quinazolin-4-piperidine sulfamides as inhibitors of human NPP1: relevance in the treatment of pathologic mineralization of valve interstitial cells

Le rétrécissement valvulaire aortique calcifié (RAC) est le trouble valvulaire le plus fréquent chez les personnes âgées des pays développés. La seule option de traitement possible le remplacement de la valve aortique. L’identification du rôle de l’enzyme ecto-nucleotidase NPP1 dans le processus de calcification suggère que cette enzyme pourrait être une cible potentielle pour le développement d’un inhibiteur pharmacologique contre la calcification de la valve aortique. Jusqu’à présent, les composés qui ont été développés en tant qu’inhibiteurs de NPP1 manquent de puissance et de spécificité. Dans la présente étude, nous avons démontré que les dérivés de sulfonamides quinazolin-4-pipéridine sont des inhibiteurs puissants, spécifiques, et non-compétitifs de NPP1. In vitro, dans des cellules isolées de valve aortique nous avons fourni des preuves que l’inhibition de NPP1 par ces dérivés bloque la minéralisation, l’apoptose et la transition ostéogénique des cellules interstitielles de valve aortique.

Akt/PKB activation and insulin signaling: a novel insulin signaling pathway in the treatment of type 2 diabetes

Type 2 diabetes is a metabolic disease categorized primarily by reduced insulin sensitivity, β-cell dysfunction, and elevated hepatic glucose production. Treatments reducing hyperglycemia and the secondary complications that result from these dysfunctions are being sought after. Two distinct pathways encourage glucose transport activity in skeletal muscle, ie, the contraction-stimulated pathway reliant on Ca2+/5′-monophosphate-activated protein kinase (AMPK)-dependent mechanisms and an insulin-dependent pathway activated via upregulation of serine/threonine protein kinase Akt/PKB. Metformin is an established treatment for type 2 diabetes due to its ability to increase peripheral glucose uptake while reducing hepatic glucose production in an AMPK-dependent manner. Peripheral insulin action is reduced in type 2 diabetics whereas AMPK signaling remains largely intact. This paper firstly reviews AMPK and its role in glucose uptake and then focuses on a novel mechanism known to operate via an insulin-dependent pathway. Inositol hexakisphosphate (IP6) kinase 1 (IP6K1) produces a pyrophosphate group at the position of IP6 to generate a further inositol pyrophosphate, ie, diphosphoinositol pentakisphosphate (IP7). IP7 binds with Akt/PKB at its pleckstrin homology domain, preventing interaction with phosphatidylinositol 3,4,5-trisphosphate, and therefore reducing Akt/PKB membrane translocation and insulin-stimulated glucose uptake. Novel evidence suggesting a reduction in IP7 production via IP6K1 inhibition represents an exciting therapeutic avenue in the treatment of insulin resistance. Metformin-induced activation of AMPK is a key current intervention in the management of type 2 diabetes. However, this treatment does not seem to improve peripheral insulin resistance. In light of this evidence, we suggest that inhibition of IP6K1 may increase insulin sensitivity and provide a novel research direction in the treatment of insulin resistance.

Mapping non-suicidal self-injury in adolescence: Development and confirmatory factor analysis of the impulse, self-harm and sucidal ideation questionnaire for adolescents (ISSIQ-A)

Non-suicidal self-injury (NSSI) is the deliberate, self-inflicted destruction of body tissue without suicidal intent and an important clinical phenomenon. Rates of NSSI appear to be disproportionately high in adolescents and young adults, and is a risk factor for suicidal ideation and behavior. The present study reports the psychometric properties of the Impulse, Self-harm and Suicide Ideation Questionnaire for Adolescents (ISSIQ-A), a measure designed to comprehensively assess the impulsivity, NSSI behaviors and suicide ideation. An additional module of this questionnaire assesses the functions of NSSI. Results of Confirmatory Factor Analysis (CFA) of the scale on 1722 youths showed items' suitability and confirmed a model of four different dimensions (Impulse, Self-harm, Risk-behavior and Suicide ideation) with good fit and validity. Further analysis showed that youth׳s engagement in self-harm may exert two different functions: to create or alleviate emotional states, and to influence social relationships. Our findings contribute to research and assessment on non-suicidal self-injury, suggesting that the ISSIQ-A is a valid and reliable measure to assess impulse, self-harm and suicidal thoughts, in adolescence.