Global Burden of Neuroendocrine Tumors and Changing Incidence in Kentucky

Background: Neuroendocrine tumors (NETs) have a low incidence but relatively high prevalence. Over the last three decades, the incidence of NETs has risen 6-fold in the United States. We conducted an observational study to compare the incidence of NETs reported to the Kentucky Cancer Registry (KCR) versus that reported to Surveillance, Epidemiology, and End Results Program (SEER). We also provide a systematic review of the state of neuroendocrine tumors worldwide, and compare the available global and local published data. Methods: KCR and SEER databases were queried for NET cases between 1995 and 2015. A detailed literature review of epidemiological data for various nations worldwide summarize epidemiological data from various countries. Results: KCR recorded 6179 individuals with newly diagnosed NETs between 1995 and 2015. Between 1995-2012, the incidence of NETs in KCR increased from 3.1 to 7.1 per 100,000 cases, while it increased from 3.96 to 6.61 in the SEER database. The incidence rates in both KCR and SEER databases were linear. 90.57% were Caucasians with 54.74% females. 27.67% of the Kentucky population was from the Appalachian region. Patients aged 50-64 years had the highest prevalence (38%). Lung NET (30.60%) formed the bulk of cases, followed by small intestine (16.82%), rectum/anus (11.35%) and colon (9.71%). Conclusions: NETs incidence between 1995 and 2015 show a linear increase in both KCR and SEER databases. Because of this increased incidence it is imperative for community oncologists to familiarize themselves with this entity, which until recently was under-studied and with few viable treatment options

Capecitabine and Temozolomide in Neuroendocrine Tumor of Unknown Primary

Incidence of low grade well-differentiated neuroendocrine tumors (NET) is on the rise. The North American Neuroendocrine Tumor Society estimates that the United States has more than 150,000 gastroenteropancreatic NET patients. About 10% of metastatic NETs can be unknown primary, and due to their rarity, dedicated treatment algorithms and regimens are not defined. Combination of capecitabine and temozolomide (CAPTEM) is one of the systemic treatments used in gastroenteropancreatic NETs. We explored clinical activity of CAPTEM in NET of unknown primary. Methods. Retrospective review of NET of unknown primary managed at the University of Kentucky over the past five years (2012–2016). Result. 56 patients with NET of unknown primary were identified; 12 patients were treated with CAPTEM. Median progression-free survival on CAPTEM in grade II and grade III NET of unknown primary was 10.8 and 7 months, respectively. Six patients showed reduction in metastatic tumor volume at three-month CT scan. Three patients had stable disease and three patients showed disease progression at the first surveillance scan. Common side-effects were as follows: four patients developed grade II thrombocytopenia, three patients developed grade I lymphocytopenia, and two patients developed hand foot syndrome (grades I and III). Six patients developed grade I fatigue. Conclusion. CAPTEM should be considered for grades I and II NET of unknown primary, especially in the case of visceral crisis or bulky disease

Negative Poisson’s ratio polyethylene matrix and 0.5BaCa0.8Zr0.2O3-0.5Ba0.7Ca0.3TiO3 based piezocomposite for sensing and energy harvesting applications

Abstract Finite element studies were conducted on 0.5Ba(Zr0.2 Ti0.8) O3–0.5(Ba0.7 Ca0.3)TiO3 (BCZT) piezoelectric particles embedded in polyethylene matrix to create a piezocomposite having a positive and negative Poisson's ratio of −0.32 and 0.2. Polyethylene with a positive Poisson's ratio is referred to as non-auxetic while those with negative Poisson's ratio are referred to as auxetic or inherently auxetic. The effective elastic and piezoelectric properties were calculated at volume fractions of (4%, 8% to 24%) to study their sensing and harvesting performance. This study compared lead-free auxetic 0–3 piezocomposite for sensing and energy harvesting with non-auxetic one. Inherently auxetic piezocomposites have been studied for their elastic and piezoelectric properties and improved mechanical coupling, but their sensing and energy harvesting capabilities and behavior patterns have not been explored in previous literatures. The effect of Poisson's ratio ranging between −0.9 to 0.4 on the sensing and energy harvesting performance of an inherently auxetic lead free piezocomposite composite with BCZT inclusions has also not been studied before, motivating the author to conduct the present study. Auxetic piezocomposite demonstrated an overall improvement in performance in terms of higher sensing voltage and harvested power. The study was repeated at a constant volume fraction of 24% for a range of Poisson's ratio varied between −0.9 to 0.4. Enhanced performance was observed at the extreme negative end of the Poisson's ratio spectrum. This paper demonstrates the potential improvements by exploiting auxetic matrices in future piezocomposite sensors and energy harvesters

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Negative Poisson’s ratio polyethylene matrix and 0.5BaCa0.8Zr0.2O3-0.5Ba0.7Ca0.3TiO3 based piezocomposite for sensing and energy harvesting applications

Finite element studies were conducted on 0.5Ba(Zr0.2 Ti0.8) O3-0.5(Ba0.7 Ca0.3)TiO3 (BCZT) piezoelectric particles embedded in polyethylene matrix to create a piezocomposite having a positive and negative Poisson's ratio of -0.32 and 0.2. Polyethylene with a positive Poisson's ratio is referred to as non-auxetic while those with negative Poisson's ratio are referred to as auxetic or inherently auxetic. The effective elastic and piezoelectric properties were calculated at volume fractions of (4%, 8% to 24%) to study their sensing and harvesting performance. This study compared lead-free auxetic 0-3 piezocomposite for sensing and energy harvesting with non-auxetic one. Inherently auxetic piezocomposites have been studied for their elastic and piezoelectric properties and improved mechanical coupling, but their sensing and energy harvesting capabilities and behavior patterns have not been explored in previous literatures. The effect of Poisson's ratio ranging between -0.9 to 0.4 on the sensing and energy harvesting performance of an inherently auxetic lead free piezocomposite composite with BCZT inclusions has also not been studied before, motivating the author to conduct the present study. Auxetic piezocomposite demonstrated an overall improvement in performance in terms of higher sensing voltage and harvested power. The study was repeated at a constant volume fraction of 24% for a range of Poisson's ratio varied between -0.9 to 0.4. Enhanced performance was observed at the extreme negative end of the Poisson's ratio spectrum. This paper demonstrates the potential improvements by exploiting auxetic matrices in future piezocomposite sensors and energy harvesters.<br/

Effect of Poling on Multicatalytic Performance of 0.5Ba(Zr_0.2Ti_0.8)O₃-0.5(Ba_0.7Sr_0.3)TiO₃ Ferroelectric Ceramic for Dye Degradation

Ferroelectric materials with a spontaneous polarization are proven to be potential multicatalysts in water remediation applications. The composition of 0.5Ba(Zr0.2Ti0.8)O3-0.5(Ba0.7Sr0.3)TiO3 (BST-BZT) was examined for photocatalysis, piezocatalysis, and piezo-photocatalysis processes by degrading an azo dye named methylene blue (MB). Generally, dis-aligned dipoles restrict the catalytic activities due to which the BST-BZT powder sample was poled by the corona poling technique. Coupled piezocatalysis and photocatalysis process, i.e., the piezo-photocatalysis process has shown maximum dye degradation. There was a significant improvement in degradation efficiency by using a poled BST-BZT sample compared to the unpoled sample in all processes, thus the results suggest an extensive scope of poled ferroelectric ceramic powder in the catalysis field

Capecitabine and Temozolomide in Neuroendocrine Tumor of Unknown Primary

Incidence of low grade well-differentiated neuroendocrine tumors (NET) is on the rise. The North American Neuroendocrine Tumor Society estimates that the United States has more than 150,000 gastroenteropancreatic NET patients. About 10% of metastatic NETs can be unknown primary, and due to their rarity, dedicated treatment algorithms and regimens are not defined. Combination of capecitabine and temozolomide (CAPTEM) is one of the systemic treatments used in gastroenteropancreatic NETs. We explored clinical activity of CAPTEM in NET of unknown primary. Methods. Retrospective review of NET of unknown primary managed at the University of Kentucky over the past five years (2012–2016). Result. 56 patients with NET of unknown primary were identified; 12 patients were treated with CAPTEM. Median progression-free survival on CAPTEM in grade II and grade III NET of unknown primary was 10.8 and 7 months, respectively. Six patients showed reduction in metastatic tumor volume at three-month CT scan. Three patients had stable disease and three patients showed disease progression at the first surveillance scan. Common side-effects were as follows: four patients developed grade II thrombocytopenia, three patients developed grade I lymphocytopenia, and two patients developed hand foot syndrome (grades I and III). Six patients developed grade I fatigue. Conclusion. CAPTEM should be considered for grades I and II NET of unknown primary, especially in the case of visceral crisis or bulky disease