Study investigating the impact of pharmacist involvement on the outcomes of diabetes medication therapy adherence program Malaysia.

Involvement of pharmacists in improving medication adherence among diabetic patients is recognized globally. In Malaysian healthcare system, pharmacists are also operating health services i.e. Diabetes Medication Therapy Adherence Clinic (DMTAC). This study aimed to assess the clinical outcomes of patients managed by pharmacists (DMTAC), in a Malaysian hospital setting. This was an open labelled randomised study. Type 2 diabetes patients with HbA1c ≥8% were recruited and arbitrarily divided into the intervention group (usual care plus DMTAC) and the non-intervention group (usual care only). Those enrolled in the intervention group were scheduled for follow-up for eight consecutive visits. Improvements in lab results were compared longitudinally (pre and post analysis) between the groups. Data analysis was done using PASW 18® version. A total of 76 patients were enrolled, with 39 patients in the intervention group and 37 patients in the non-intervention group. Mean HbA1c (-0.90% vs. -0.08%, p=0.011) and fasting blood glucose levels (-3.45 mmol.l vs. +0.79 mmol/l, p=0.002) reduced significantly between the intervention group vs. non-intervention group. Total cholesterol and low-density lipoprotein cholesterol (LDL-C) were also significantly reduced in the intervention group (TC -0.34 mmol/l, p=0.018) (LDL -0.45 mmol/l, p=0.001). In conclusion, pharmacists managed DMTAC significantly improved glycaemic control and lipid profile of diabetic patients.

Squamous cell carcinoma of the ear arising in patients after radiotherapy for nasopharyngeal carcinoma.

Radiation-induced malignancies are a rare but serious complication arising in patients receiving radiotherapy for nasopharyngeal carcinoma (NPC). To characterize patients who develop post-irradiation squamous cell carcinoma (PISCC) of the ear after radiotherapy for NPC and to compare their outcomes with patients who have de novo squamous cell carcinoma (SCC) of the ear. Clinical and pathological characteristics and their outcomes were analysed and compared between post-irradiation and de novo SCC cases. From 2002 to 2011, 25 patients were treated at our institution for SCC of the ear, of which 8 (32%) occurred after prior irradiation. There were no significant differences between the two groups with regards to age, gender, race, smoking status, tumour size, grade, stage and differentiation. Patients in the PISCC group appeared to have inferior overall survival (median survival 71.2 vs. 85.6 months; p = 0.292) and disease-specific survival (mean 59.6 vs. 71.5 months; p = 0.441). PISSC of the ear in long-standing survivors of NPC has a poor prognosis despite advances in medical care. Surgical resection with clear margins seems to offer the best outcomes.

Repurposing FDA-approved compounds to target JAK2 for colon cancer treatment.

Colorectal cancer is one of the common cancers worldwide and the second leading cause of cancer-related death. The current treatment has the inherent drawbacks and there is a need of developing a new treatment. Interleukin-6 a pleiotropic cytokine involved in immune regulation and activation of JAK2/STAT3 pathway in colorectal cancer. JAK2/STAT3 signaling pathway functions as a critical regulator of cell growth, differentiation, and immune expression. The abnormality in the JAK2/STAT3 pathway is involved in the tumorigenesis of colon cancer including apoptosis. In this study, we identified novel inhibitors for JAK2 protein by performing virtual screening against FDA-approved compounds. To address the selectivity issue, we implemented cross-docking method followed by DFT calculations to understand the chemical reactivity of the identified compounds. Additionally, molecular dynamics (MD) simulations were performed for the top FDA compounds against JAK2 to understand the molecular interactions and structural stability of the complex over a period of 200 ns. Our results indicated that ergotamine, entrectinib, exatecan, dihydroergotamine, and paritaprevir can be used as alternative drugs for colon cancer. In addition, ergotamine was found to efficiently lower the cell viability with IC50 values of 100 µM on colon cancer cell lines. The long-term inhibitory effect of the ergotamine led to a decrease in colony size, and the toxicity properties were studied using hemolysis assay. Our study shows the potential of targeting JAK2 as a novel approach to colon cancer treatment, and demonstrate that ergotamine as a promising effects as an anti-cancer drug.

Outcomes and prognostic factors of post-irradiation and de novo sarcomas of the head and neck: a histologically matched case-control study.

BACKGROUND: This study was designed to compare post-irradiation sarcomas (PIS) and de novo sarcomas (DN) of the head and neck in terms of tumor characteristics, prognostic factors, and survival outcomes. METHODS: All (N=83) head and neck sarcoma patients treated at National Cancer Centre, Singapore (Feb 2002-May 2011) were included: DN (N=60; 72%); PIS (N=23; 28%). Clinicopathologic features and outcomes of all patients and histologically matched pairs were compared. Prognostic factors were identified using univariate and multivariate analyses. RESULTS: Median age, gender, smoking status, and tumor size were not significantly different. Significant differences were seen in histology (most prevalent: PIS-sarcoma-NOS; DN-angiosarcoma) and tumor subsite (most prevalent: PIS-nasal cavity and sinuses; DN-skin). Median latency of PIS development was 16.7 years. PIS patients had shorter overall survival (OS) and disease-specific survival (DSS) compared with DN patients, most clearly seen on histologically matched pair analysis: 2-year OS (PIS: 54%; DN: 83%; P=0.028). Multivariate analyses showed that age>50 years (hazard ratio (HR)=3.68; P=0.007), ever-smokers (HR=2.79; P=0.017), and larger tumor-size (cm) (HR=1.12; P=0.045) were associated with worse OS, and age at >50 years (HR=2.77; P=0.04) and ever-smokers (HR=2.94; P=0.021) were associated with worse DSS. When treated with curative intent, no significant survival difference was noted between DN and PIS patients. CONCLUSIONS: In our cohort, PIS constituted 28% of head and neck sarcomas. Poorer prognosis traditionally associated with PIS compared with DN was not seen amongst patients treated with curative intent.

The profile of headaches and migraine amongst medical students and its association to stress level, disability and self-management practices.

Introduction: Migraine is the most common headache affecting young people that impairs their functional ability. This study aimed to determine the frequency of migraines among Malaysian medical students, the association between migraines, stress level, and functional disability among these students, and describe their self-management practices. Methods: A cross-sectional study was conducted among medical students in a private medical school in Penang state. All medical students in the study site were screened for the presence of headache symptoms and the diagnosis of migraine using a self-administered questionnaire comprising International Headache Society (IHS) diagnostic criteria. Other domains that were assessed were perceived stress level and functional disability, which were measured using the Perceived Stress Scale and the Headache Impact Test-6 (HIT-6), respectively. The students' selfmanagement practices for their headaches were determined using a descriptive survey. Results: A total of 374 medical students participated in this study and 157 (42%) students reported experiencing headaches. More than half (n=97, 61.8%) of those with headaches fulfilled the IHS criteria for migraines. Migraines were significantly associated with functional disability compared with non-migraine headaches (p<0.001); however, no significant difference in stress levels were reported between the two groups. During migraine attacks, sleep (n=73, 60.33%) and self-medication (n=56, 69.14%) were the most common self-management practices. Only 11.46% of the 157 students with headaches consulted a doctor. Conclusion: A high proportion of medical students suffered from headaches and more than half of them had migraines. Migraine headaches were associated with significant functional disability. Very few students sought medical consultation and most students chose to self-manage their headaches.

In-vitro 3D modelling for charged particle therapy - Uncertainties and opportunities.

Radiation therapy is a critical component of oncologic management, with more than half of all cancer patients requiring radiotherapy at some point during their disease course. Over the last decade, there has been increasing interest in charged particle therapy due to its advantageous physical and radiobiologic properties, with the therapeutic use of proton beam therapy (PBT) expanding worldwide. However, there remain large gaps in our knowledge of the radiobiologic mechanisms that underlie key aspects of PBT, such as variations in relative biologic effectiveness (RBE), radioresistance, DNA damage response and repair pathways, as well as immunologic effects. In addition, while the emerging technique of ultra-high dose rate or FLASH radiotherapy, with its potential to further reduce normal tissue toxicities, is an exciting development, in-depth study is needed into the postulated biochemical mechanisms that underpin the FLASH effect such as the oxygen depletion hypothesis as well as the relative contributions of immune responses and the tumor microenvironment. Further investigation is also required to ensure that the FLASH effect is not diminished or lost in PBT. Current methods to evaluate the biologic effects of charged particle therapy rely heavily on 2D cell culture systems and/or animal models. However, both of these methods have well-recognized limitations which limit translatability of findings from bench to bedside. The advent of novel three-dimensional in-vitro tumor models offers a more physiologically relevant and high throughput in-vitro system for the study of tumor development as well as novel therapeutic approaches such as PBT. Advances in 3D cell culture methods, together with knowledge of disease mechanism, biomarkers, and genomic data, can be used to design personalized 3D models that most closely recapitulate tumor microenvironmental factors promoting a particular disease phenotype, moving 3D models and PBT into the age of precision medicine.

Genomics of radiation sensitivity in squamous cell carcinomas.

Radiotherapy is an important modality in the management of squamous cell cancers with 50% of patients receiving radiotherapy at some point. Despite technological advances, the risk of severe toxicity in a proportion of radiosensitive patients limits radiation doses that can be safely prescribed affecting the potential for cure. While comorbidities, lifestyle and treatment factors can influence interindividual variations, genetic factors are thought to play a major role, accounting for approximately 80% of the variance observed. Over the last decade, substantial progress has been made in the field of radiogenomics, with compelling associations for SNPs identified in genes involved in DNA-damage response, cell-cycle control, apoptosis, antioxidant defenses and cytokine production. Future research efforts should be collaborative, focused on validating and broadening their clinical applicability. Numerous obstacles exist to the clinical application of this knowledge, which need to be overcome before personalized radiation therapy becomes a routine component of oncologic care.

Are heart doses associated with survival in patients with non-small cell lung cancer who received post-operative thoracic radiotherapy?: A national population-based study.

The aim of this retrospective national cohort study is to assess the association between various radiation heart dosimetric parameters (RHDPs), acute myocardial infarct (AMI) and overall survival (OS) outcomes in non-small cell lung cancer (NSCLC) patients treated with post-operative thoracic radiotherapy (PORT) using contemporary radiation techniques.We identified patients with stage I to III NSCLC treated with PORT at the 2 national cancer institutions from 2007 to 2014. We linked their electronic medical records to the national AMI and death registries. Univariable Cox regression was performed to assess the association between various RHDPs, AMI, and OS.We included 43 eligible patients with median follow-up of 36.6 months. Median age was 64 years. Majority of the patients had pathological stage III disease (72%). Median prescription dose was 60Gy. Median mean heart dose (MHD) was 9.4Gy. There were no AMI events. The 5-year OS was 34%. Univariable Cox regression showed that age was significantly associated with OS (hazard ratio, 1.06; 95% confidence interval, 1.01 to 1.10; P = .008). Radiation heart doses, including MHD, volume of heart receiving at least 5, 25, 30, 40, 50Gy and dose to 30% of heart volume, were not significantly associated with OS.There is insufficient evidence to conclude that RHDPs are associated with OS for patients with NSCLC treated with PORT in this study. Studies with larger sample size and longer term follow-up are needed to assess AMI outcome.

Craniospinal dissemination in teratocarcinosarcoma.

There have been fewer than 60 cases of malignant teratocarcinosarcoma (TCS) described in the literature, usually arising in the nose and paranasal sinuses. The authors report on a patient who presented with neurological symptoms caused by a frontal lobe TCS, and in whom widespread spinal tumor dissemination developed. In rare cases, TCSs can occur with a predominantly cranial and neurological presentation and spread to the spinal canal.

Radiobiology and radiotherapy of brain metastases.

Brain metastases are the most common intracranial tumors in adults, accounting for more than 50% of all such cases. The approach to and management of brain metastases have evolved significantly in recent years due to several reasons. These include advances in neurosurgical and radiotherapeutic techniques, improved systemic therapy options offering better systemic and intracranial disease control and prolongation of survival as a result of these improvements, making side-effects of proposed therapies (e.g. neurocognitive decline from whole brain radiotherapy) an important consideration. In this article, we review the the primary therapeutic approaches to the management of brain metastases, namely, surgery, stereotactic radiosurgery, and whole brain radiation therapy and the primary factors dictating choice.

Sequential external beam radiotherapy and high-dose-rate intracavitary brachytherapy in T1 and T2 nasopharyngeal carcinoma: an evaluation of long-term outcome.

OBJECTIVES/HYPOTHESIS: The standard treatment for nonmetastatic nasopharyngeal carcinoma (NPC) is external beam radiotherapy (EBRT), with or without chemotherapy. Because local control in NPC is an independent prognostic factor for distant metastases and survival, various dose-escalation strategies have been used to reduce recurrences at the primary site. The objective of this report was to evaluate the outcome of adjuvant high-dose-rate intracavitary brachytherapy (HDRIB) in patients with T1 and T2 NPC. STUDY DESIGN AND METHODS: Thirty-three consecutive patients with T1 and T2 NPC were treated prospectively according to a standardized institutional protocol between March 1999 and July 2001. Seventeen patients with stage I/II disease were treated with EBRT to 66 Gy followed by HDRIB (10 Gy in 2 weekly 5 Gy fractions). The remaining 16 patients with Stage III to IVb disease received chemotherapy in addition to radiation. All patients were assessed for treatment response, local control, survival, and toxicity. RESULTS: Median follow-up for all surviving patients was 67 (range 52-76) months. Local failure occurred in two patients; both subsequently underwent successful salvage treatments. Three patients died of metastatic disease, whereas two died of unrelated causes. Five year local control, overall survival, and disease-free survival rates were 93.8%, 83.9% and 78.4%, respectively. All patients experienced acute or late radiotherapy-related sequelae. However, no grade 4/5 toxicities were reported. Specifically, toxicities that could be attributed to brachytherapy were not seen, except for in one patient who developed severe choanal stenosis. CONCLUSIONS: EBRT supplemented by HDRIB produced superior local control rates for T1 and T2 NPC at 5 years of follow-up, with acceptable rates of acute and late toxicities.

Radiation-induced sarcomas of the head and neck.

With improved outcomes associated with radiotherapy, radiation-induced sarcomas (RIS) are increasingly seen in long-term survivors of head and neck cancers, with an estimated risk of up to 0.3%. They exhibit no subsite predilection within the head and neck and can arise in any irradiated tissue of mesenchymal origin. Common histologic subtypes of RIS parallel their de novo counterparts and include osteosarcoma, chondrosarcoma, malignant fibrous histiocytoma/sarcoma nitricoxide synthase, and fibrosarcoma. While imaging features of RIS are not pathognomonic, large size, extensive local invasion with bony destruction, marked enhancement within a prior radiotherapy field, and an appropriate latency period are suggestive of a diagnosis of RIS. RIS development may be influenced by factors such as radiation dose, age at initial exposure, exposure to chemotherapeutic agents and genetic tendency. Precise pathogenetic mechanisms of RIS are poorly understood and both directly mutagenizing effects of radiotherapy as well as changes in microenvironments are thought to play a role. Management of RIS is challenging, entailing surgery in irradiated tissue and a limited scope for further radiotherapy and chemotherapy. RIS is associated with significantly poorer outcomes than stage-matched sarcomas that arise independent of irradiation and surgical resection with clear margins seems to offer the best chance for cure.

Insufficiency fractures of the sacrum following stereotactic body radiotherapy for sacral tumors.

INTRODUCTION: There is little data on sacral insufficiency fracture(SIF) incidence following pelvic radiotherapy, with existing studies based on conventional fractionation. Stereotactic body radiotherapy (SBRT), characterized by dose escalation with hypofractionation, may pose even greater risks to sacral integrity. This study aims to define SIF incidence and risk factors following SBRT. METHODS: Records of 43 consecutive patients who underwent sacral SBRT from September 2005-May 2009 were reviewed. Baseline patient information (age, gender, menopausal status, body mass index, use of bone-thinning agents, presence of osteoporosis), tumor characteristics (histology, lesion appearance and extent) and treatment parameters (dose/fractionation, prior radiation/surgery) were documented. Primary end-point was development of new fractures or progression of pre-existing fractures. Secondary end-points included pain scores, analgesic use, functional ability, and local tumor control. RESULTS: Median follow-up was 17months. Common histologies included sarcoma, renal cell, and prostate carcinoma; 47% of lesions were lytic, 37% sclerotic and the remainder mixed. Doses ranged from 18-24Gy/1fraction to 30Gy/5fractions with 45% receiving single fractions.14% had prior radiation (median dose: 30Gy/10fractions).Five patients developed SIF. In four, fractures occurred in the context of controlled local disease. Median time to SIF was 8.2months. Symptoms varied from minimal pain requiring no intervention to severe pain impacting on function. Two patients underwent sacroplasty due to intractable pain, with both obtaining good analgesia. Low event numbers precluded meaningful univariate/multivariate analyses. One-year local tumor control rates were excellent (91.7%). CONCLUSION: In this study, actuarial SIF incidence at one year was 8.2%, suggesting that SIF risk from sacral SBRT is low. However, larger prospective studies with longer follow-up are needed. In addition, novel therapies such as sacroplasty need further study to determine safety, efficacy and indications for use.

Target volume delineation in oropharyngeal cancer: impact of PET, MRI, and physical examination.

INTRODUCTION: Sole utilization of computed tomography (CT) scans in gross tumor volume (GTV) delineation for head-and-neck cancers is subject to inaccuracies. This study aims to evaluate contributions of magnetic resonance imaging (MRI), positron emission tomography (PET), and physical examination (PE) to GTV delineation in oropharyngeal cancer (OPC). METHODS: Forty-one patients with OPC were studied. All underwent contrast-enhanced CT simulation scans (CECTs) that were registered with pretreatment PETs and MRIs. For each patient, three sets of primary and nodal GTV were contoured. First, reference GTVs (GTVref) were contoured by the treating radiation oncologist (RO) using CT, MRI, PET, and PE findings. Additional GTVs were created using fused CT/PET scans (GTVctpet) and CT/MRI scans (GTVctmr) by two other ROs blinded to GTVref. To compare GTVs, concordance indices (CI) were calculated by dividing the respective overlap volumes by overall volumes. To evaluate the contribution of PE, composite GTVs derived from CT, MRI, and PET (GTVctpetmr) were compared with GTVref. RESULTS: For primary tumors, GTVref was significantly larger than GTVctpet and GTVctmr (p < 0.001). Although no significant difference in size was noted between GTVctpet and GTVctmr (p = 0.39), there was poor concordance between them (CI = 0.62). In addition, although CI (ctpetmr vs. ref) was low, it was significantly higher than CI (ctpet vs. ref) and CI (ctmr vs. ref) (p < 0.001), suggesting that neither modality should be used alone. Qualitative analyses to explain the low CI (ctpetmr vs. ref) revealed underestimation of mucosal disease when GTV was contoured without knowledge of PE findings. Similar trends were observed for nodal GTVs. However, CI (ctpet vs. ref), CI (ctmr vs. ref), and CI (ctpetmr vs. ref) were high (>0.75), indicating that although the modalities were complementary, the added benefit was small in the context of CECTs. In addition, PE did not aid greatly in nodal GTV delineation. CONCLUSION: PET and MRI are complementary and combined use is ideal. However, the low CI (ctpetmr vs. ref) particularly for primary tumors underscores the limitations of defining GTVs using imaging alone. PE is invaluable and must be incorporated.

Feasibility of reirradiation of recurrent sinonasal carcinoma in the periorbital region using hypofractionated image-guided intensity-modulated radiation therapy.

BACKGROUND: Recurrent periorbital tumors pose management challenges because they are often unresectable and chemorefractory. Proximity to critical structures renders reirradiation difficult. With image-guided intensity-modulated radiation therapy (IG-IMRT), real-time corrections to patient setup are possible, enabling significant shrinkage of planning target volume margins and safe dose escalation with hypofractionation. Here, we present our experience with hypofractionated IG-IMRT in a patient with multiply recurrent sinonasal carcinomas in the periorbital region. METHODS: The patient is a 67-year-old woman with sinonasal carcinoma, treated with surgery and 2 prior courses of high-dose radiotherapy. She developed a second tumor recurrence in the right lateral orbit, which was reirradiated using hypofractionated IG-IMRT (24 Gy in 3 fractions). RESULTS: Near-complete resolution of her ocular symptoms was observed at 4 months. Progress scans demonstrated a decrease in size of the orbital lesion. CONCLUSION: Preliminary results of reirradiation using hypofractionated IG-IMRT suggest that it is safe and effective.

Development of a spreadsheet for the calculation of new tools to improve the reporting of the results of medical research.

PRIMARY OBJECTIVE: Confidence levels, clinical significance curves and risk - benefit contours have recently been developed with the aim of improving the interpretation of clinical studies. It has been suggested that their use may complement traditional methods of result reporting (i.e. p values and 95% confidence intervals), and subsequently improve medical decision-making. These new methods have been used to report study results; however, widespread use may be hampered by the lack of available computer software. Our objective was to design user-friendly software to enable researchers to use these statistical methods. RESEARCH DESIGN: A spreadsheet was designed to calculate these statistics for the assessment of two arm medical studies. The spreadsheet was tested using a wide range of input data and operating systems. User-friendliness was tested by researchers who had no background in statistics. MAIN OUTCOMES AND RESULTS: The confidence calculator was successfully designed, and found to be user-friendly. The spreadsheet is MS Excel-based to allow wide usage. The spreadsheet is freely available from the author and from the web site http://www.primercollaboration.com/Tools/tools.html. CONCLUSIONS: We have successfully designed a spreadsheet that is simple to use and freely accessible for researchers. This is the first such software that calculates confidence levels, clinical significance curves, and risk - benefit contours.

Evaluation of the quality of radiotherapy randomized trials for painful bone metastases.

BACKGROUND: The quality of randomized radiotherapy studies investigating the palliation of painful bone metastases has been questioned, with some authors recognizing the potential impact of bias on result interpretation. However, there has been no published comprehensive evaluation of quality assessment. The goals of the current study were to evaluate the quality of randomized studies using a validated checklist and to discuss implications and future directions. METHODS: The authors performed a search for studies that could be reliably assessed using the validated quality assessment instrument. Independent assessors scored study quality using the instrument. RESULTS: The median quality score of the 17 identified randomized studies was 1 of 5 (range, 0-3). The majority (71%) of points were awarded for the authors describing the study as "randomized." The method of randomization and description of withdrawals and dropouts were scored poorly for most studies. None of the studies were awarded points for allocation concealment (blinding). The overall quality was deemed poor (a score of 0-2) for 16 of 17 (94%) studies. CONCLUSIONS: The quality of published randomized evidence comparing efficacy of fractionation schedules for the palliation of bone metastases was suboptimal. As a result of the potential biases present, subjective end points (e.g., retreatment rates) cannot be reliably evaluated. Greater efforts are required by radiation oncology trial groups to improve quality, with a particular focus on developing methods of allocation concealment and comprehensively reporting results.