Targeted Therapy and Immunotherapy Response Assessment with F-18 Fluorothymidine Positron-Emission Tomography/Magnetic Resonance Imaging in Melanoma Brain Metastasis: A Pilot Study.

INTRODUCTION: This pilot study aimed at exploring the utility of the proliferation tracer F-18 fluorothymidine (FLT) and positron-emission tomography (PET)/magnetic resonance imaging (MRI) (FLT-PET/MRI) for early treatment monitoring in patients with melanoma brain metastasis (MBM) who undergo targeted therapy or immunotherapy. MATERIAL AND METHODS: Patients with newly diagnosed MBM underwent baseline and follow-up FLT-PET/MRI scans at 3-4 weeks of targeted therapy or immunotherapy. Up to six measurable brain lesions ≥1.0 cm per subject, as identified on T1-weighted post-gadolinium images, were included for quantitative analyses. The maximum SUV of each lesion was divided by the mean SUV of the pons to obtain the SUV ratio (SUVR). RESULTS: Five enrolled subjects underwent the baseline FLT-PET/MRI study in which the MBM showed a median size of 1.7 cm (range 1.0-2.9) and increased metabolic activity with SUVR of 9.9 (range 3.2-18.4). However, only two subjects (cases #1 and #2) returned for a follow-up scan. At baseline, a total of 22 lesions were analyzed in all five subjects, which showed a median size of 1.7 cm (range 1.0-2.9) and median SUVR of 9.9 (range 3.2-18.4). At follow-up, case #1 was a 55-year-old man who received targeted BRAF inhibitor and MEK inhibitor therapy with dabrafenib and trametinib. Fused PET/MRI data of six measured lesions demonstrated a significant reduction in MBM proliferative activity (median -68%; range -38 to -77%) and size (median -23%; range -4 to -55%) at three weeks of therapy. Nevertheless, the subject eventually progressed and died 13 months after therapy initiation. Case #2 was a 36-year-old man who received immunotherapy with nivolumab and ipilimumab. The five measured MBM lesions showed a mixed response at both proliferative and morphologic imaging at 1-month follow-up. Some lesions demonstrated interval decrease while others interval increase in proliferative activity with a median -44% (range -77 to +68%). On MRI, the size change was +7% (range -64 to +50%). The therapy was switched to dabrafenib and trametinib, which led to a partial response. The patient is still alive 16 months following therapy initiation. CONCLUSION: The five cases presented show the potential benefit of hybrid FLT-PET/MRI for the diagnosis of MBM and treatment monitoring of targeted therapy and immunotherapy. However, further studies are required to assess their complementary role in distinguishing true progression from pseudoprogression.

Symptom incidence, distress, cancer-related distress, and adherence to chemotherapy among African American women with breast cancer.

BACKGROUND: There is a persistent racial survival disparity between African American (AA) and white women with breast cancer. There is evidence that symptom incidence, associated distress, and overall cancer-related distress may be unexplored, important contributing factors. The purpose of the current study was to: 1) describe and compare the number of chemotherapy-related symptoms and associated distress among AA women with breast cancer over the course of chemotherapy at 3 time points (at baseline before initiating chemotherapy, midpoint, and at the completion of chemotherapy); and 2) to describe the relationship between the number of chemotherapy-related symptoms and overall cancer distress compared with the ability to receive at least 85% of the prescribed chemotherapy within the prescribed timeframe. METHODS: Descriptive, comparative, and correlational analyses of symptom incidence, symptom distress, cancer-related distress, and prescribed chemotherapy dose received among a cohort of AA women receiving chemotherapy for breast cancer were performed. RESULTS: AA women (121 women) experienced worsening symptoms from baseline to midpoint in chemotherapy and then stabilized for the duration of therapy. The inability to receive 85% of the prescribed chemotherapy within a prescribed time point was found to be significantly correlated with midpoint symptom distress. CONCLUSIONS: The main findings of the current study were that AA women experience a deterioration in symptom distress over the course of chemotherapy from baseline (before chemotherapy) to the midpoint, which was found to be associated with less adherence to chemotherapy overall. Thus, the incidence and management of physical and emotional symptoms, as measured through a multidimensional symptom measurement tool, may be contributing to breast cancer dose disparity and should be explored further. Cancer 2017;123:2061-2069. © 2017 American Cancer Society.

Why do general practitioners prescribe antibiotics for upper respiratory tract infections to meet patient expectations: a mixed methods study.

OBJECTIVES: To describe the role patient expectations play in general practitioners (GPs) antibiotic prescribing for upper respiratory tract infections (URTI). METHODS: Concurrent explanatory mixed methods approach using a cross-sectional survey and semistructured interviews. SETTINGS: Primary care GPs in Australia. PARTICIPANTS: 584 GPs (response rate of 23.6%) completed the cross-sectional survey. 32 GPs were interviewed individually. OUTCOME MEASURE: Prescribing of antibiotics for URTI. RESULTS: More than half the GP respondents to the survey in Australia self-reported that they would prescribe antibiotics for an URTI to meet patient expectations. Our qualitative findings suggest that 'patient expectations' may be the main reason given for inappropriate prescribing, but it is an all-encompassing phrase that includes other reasons. These include limited time, poor doctor-patient communication and diagnostic uncertainty. We have identified three role archetypes to explain the behaviour of GPs in reference to antibiotic prescribing for URTIs. The main themes emerging from the qualitative component was that many GPs did not think that antibiotic prescribing in primary care was responsible for the development of antibiotic resistance nor that their individual prescribing would make any difference in light of other bigger issues like hospital prescribing or veterinary use. For them, there were negligible negative consequences from their inappropriate prescribing. CONCLUSIONS: There is a need to increase awareness of the scope and magnitude of antibiotic resistance and the role primary care prescribing plays, and of the contribution of individual prescribing decisions to the problem of antibiotic resistance.

A mixed methods study to understand patient expectations for antibiotics for an upper respiratory tract infection.

BACKGROUND: Antimicrobial resistance is a public health challenge supplemented by inappropriate prescribing, especially for an upper respiratory tract infection in primary care. Patient/carer expectations have been identified as one of the main drivers for inappropriate antibiotics prescribing by primary care physicians. The aim of this study was to understand who is more likely to expect an antibiotic for an upper respiratory tract infection from their doctor and the reasons underlying it. METHODS: This study used a sequential mixed methods approach: a nationally representative cross sectional survey (n = 1509) and four focus groups. The outcome of interest was expectation and demand for an antibiotic from a doctor when presenting with a cold or flu. RESULTS: The study found 19.5 % of survey respondents reported that they would expect the doctor to prescribe antibiotics for a cold or flu. People younger than 65 years of age, those who never attended university and those speaking a language other than English at home were more likely to expect or demand antibiotics for a cold or flu. People who knew that 'antibiotics don't kill viruses' and agreed that 'taking an antibiotic when one is not needed means they won't work in the future' were less likely to expect or demand antibiotics. The main reasons for expecting antibiotics were believing that antibiotics are an effective treatment for a cold or flu and that they shortened the duration and potential deterioration of their illness. The secondary reason centered around the value or return on investment for visiting a doctor when feeling unwell. CONCLUSION: Our study found that patients do not appear to feel they have a sufficiently strong incentive to consider the impact of their immediate use of antibiotics on antimicrobial resistance. The issue of antibiotic resistance needs to be explained and reframed as a more immediate health issue with dire consequences to ensure the success of future health campaigns.

How do GPs want to learn in the digital era?

BACKGROUND: Various continuing medical education (CME) options are available for general practitioners (GPs). These options differ in their clinical effectiveness and GPs' preferences for learning format. We report on a national survey, conducted by NPS MedicineWise, identifying Australian GPs' preferences for CME. METHODS: A stratified random sample of 2500 GPs in Australia participated in the survey in 2012. Reponses to the questions on GPs' preferences for CME activities and motivation for choice were analysed. RESULTS: Most GPs (95%) preferred learning in a group rather than on their own. Specifically, 83% preferred face-to-face lecture-based formats; 70% preferred interactive group discussions; 66% preferred one-to-one learning with an expert; and 55% preferred online self-education. Relevance to clinical practice was the key motivation for participation (80%). DISCUSSION: Although GPs are increasingly using online learning, conventional face-to-face activities with peers and experts remain popular. Lecture-based CME continues to be preferred, despite evidence suggesting other modalities may be more effective. CME activities delivered through a combination of methods are likely to appeal to the wide range of GP preferences while optimising clinical outcomes.

The degree of segmental aneuploidy measured by total copy number abnormalities predicts survival and recurrence in superficial gastroesophageal adenocarcinoma.

BACKGROUND: Prognostic biomarkers are needed for superficial gastroesophageal adenocarcinoma (EAC) to predict clinical outcomes and select therapy. Although recurrent mutations have been characterized in EAC, little is known about their clinical and prognostic significance. Aneuploidy is predictive of clinical outcome in many malignancies but has not been evaluated in superficial EAC. METHODS: We quantified copy number changes in 41 superficial EAC using Affymetrix SNP 6.0 arrays. We identified recurrent chromosomal gains and losses and calculated the total copy number abnormality (CNA) count for each tumor as a measure of aneuploidy. We correlated CNA count with overall survival and time to first recurrence in univariate and multivariate analyses. RESULTS: Recurrent segmental gains and losses involved multiple genes, including: HER2, EGFR, MET, CDK6, KRAS (recurrent gains); and FHIT, WWOX, CDKN2A/B, SMAD4, RUNX1 (recurrent losses). There was a 40-fold variation in CNA count across all cases. Tumors with the lowest and highest quartile CNA count had significantly better overall survival (p = 0.032) and time to first recurrence (p = 0.010) compared to those with intermediate CNA counts. These associations persisted when controlling for other prognostic variables. SIGNIFICANCE: SNP arrays facilitate the assessment of recurrent chromosomal gain and loss and allow high resolution, quantitative assessment of segmental aneuploidy (total CNA count). The non-monotonic association of segmental aneuploidy with survival has been described in other tumors. The degree of aneuploidy is a promising prognostic biomarker in a potentially curable form of EAC.

A long-term siRNA strategy regulates fibronectin overexpression and improves vascular lesions in retinas of diabetic rats.

PURPOSE: A sustained gene modulatory strategy is necessary for regulating abnormal gene expression in diabetic retinopathy, a long-term complication. We investigated the efficacy of a small interference RNA (siRNA) strategy in mediating the long-term downregulatory effect of fibronectin (FN) overexpression in vivo. METHODS: Streptozotocin-induced diabetic rats were intravitreally injected with 3 µM of FN-siRNA at six week intervals over a period of 4.5 months. Retinal FN protein expression, vascular basement membrane (BM) thickness, and retinal vascular cell loss were assessed by western blot, electron microscopy, and retinal trypsin digest, respectively. RESULTS: Retinal FN expression and BM thickness were significantly increased in diabetic rat retinas compared to those in non-diabetic control rats (188±14.2% of control versus 100±7.4% of control, p<0.002; 72.5±5.0 nm versus 51.5±4.8 nm, p<0.001, respectively). FN-siRNA treatment reduced FN overexpression and BM thickening (145±19.9% of control and 56.4±2.8 nm, respectively) and significantly reduced the number of acellular capillaries (35%) and pericyte loss (55%) compared to those of untreated diabetic eyes. CONCLUSIONS: These findings suggest that BM thickening is an important target for preventing vascular cell loss in a diabetic retina, and that the siRNA approach could be useful for long-term gene modulation in diabetic retinopathy.

Vertigo secondary to isolated PICA insufficiency: successful treatment with balloon angioplasty.

BACKGROUND: The posterior inferior cerebellar arteries (PICA) arise from the intracranial segments of the vertebral artery (VA). We report a case where a nondominant isolated vertebral artery, which terminated in PICA, was stenotic. This resulted in brainstem-lower cerebellar ischemia, corrected with balloon angioplasty. CASE DESCRIPTION: A 62-year-old male presented primarily with transient vertigo, syncope, and dizziness and was diagnosed with transient ischemic attack. Angiography of the left vertebral artery (VA) demonstrated a small-caliber vessel terminating in PICA with a 90% stenosis at the C6 level. Angioplasty of the left VA was performed with excellent resolution of the stenosis. CONCLUSIONS: This case illustrates cerebellar insufficiency in a unique case where the PICA was isolated, supplied by a small- caliber VA. Correction of the stenosis improved the patient's symptomatology and prevented an inferior brainstem-cerebellar infarction.