bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of multi-parametric ultrasound in transient perivascular inflammation of the carotid artery syndrome
Authors: Rafailidis Vasileios , Chryssogonidis Ioannis , Tegos Thomas , Partovi Sasan , Charitanti-Kouridou Afroditi , Staub Daniel
Published: January 2019

Introduction

The term “carotidynia” has been used to describe a symptom or a nosologic entity characterized by pain in the lateral neck region and over the carotid bifurcation. Recent advances in diagnostic imaging and the introduction of diagnostic criteria have led to the adoption of term “Transient perivascular inflammation of the carotid artery” (TIPIC) syndrome.

Method

A retrospective analysis of the Radiology Department’s database was performed to identify cases with the diagnosis of TIPIC syndrome. The purpose was to identify ultrasound images including B-mode technique, colour, power Doppler technique and contrast-enhanced ultrasound (CEUS).

Findings

In total, five patients with the diagnosis of TIPIC syndrome are presented in this review. TIPIC syndrome is a clinic-radiologic entity characterized by pain over the carotid area, a symptom referring to a wide differential diagnosis where imaging plays a crucial role for proper diagnosis and treatment. Characteristic imaging findings on conventional ultrasound and CEUS are presented in this review.

Discussion

TIPIC syndrome can be investigated with virtually any imaging modality. Ultrasound typically reveals perivascular infiltration and a hypoechoic intimal plaque, while no significant luminal narrowing is appreciated. Computed tomography angiography and magnetic resonance angiography also demonstrate these vascular wall changes primarily affecting the distal common carotid artery, the carotid bulb and possibly the internal carotid artery proximal part. Contrast enhancement is a very characteristic and constant finding of TIPIC lesions, suggestive of the inflammatory nature of the disease and can be appreciated on computed tomography angiography and magnetic resonance angiography. CEUS has been recently used and successfully observed contrast enhancement of the lesions, similar to computed tomography angiography and magnetic resonance angiography.

Conclusion

Ultrasound remains the first-line modality for the evaluation of TIPIC syndrome, capable of providing all the information needed, especially if supplemented with the administration of microbubbles so that the enhancement of lesions can be evaluated.
Participation can make a difference to be competitive in sports: A systematic review on the relation between complex motor development and self-controlled learning settings
Authors: Jaitner David , Mess Filip
Published: January 2019

The purpose of the study was to provide an empirically based argument that grounds the relation between potentials of athletic performance and participatory settings within the autonomous inner logic of competitive sports. Therefore, the present paper systematically reviewed the empirical evidence of the association between complex motor learning and performance, and self-controlled practice conditions. Six electronic databases, reference lists and citations of full-text articles were searched for English and German language peer-reviewed articles. The search string multiply combined different terms relating to motor learning AND self-control. Two reviewers evaluated the full-text articles and critically appraised the included studies. Thirty-one studies with 1273 participants met the inclusion criteria. The vast majority of the studies reported significant learning advantages for experimental groups under self-controlled practice conditions compared to experimenter-imposed yoked groups. No study showed adverse effects. Thereby, the effects of self-controlled practice conditions have been shown to be relatively generalised to a variety of participatory variables and target groups. Advantages in accuracy, form and performance were more frequently reported than advantages in consistency. Despite increasing research efforts, the explanatory underpinnings behind the learning benefits remain debatable. The evidence indicates that complex motor learning and motor performance are typically enhanced when learners are given the opportunity to take part in decisions and therefore presents profitable implications for coaches and anyone responsible in competitive sports. However, in order to become a professional effective argument, the social context and the status of reasoning in changing habits need to be considered.
From the ‘What’ and ‘How’ to the ‘Where’: Class Distinction as a Matter of Place
Authors: Koehrsen Jens
Published: January 2019

Research on the symbolic boundary work of upper- and middle-class actors has placed a greater emphasis on the ‘what’ and ‘how’ of cultural consumption than on the ‘where’. However, the spaces where actors move are important: the ‘what’ and ‘how’ of marking distinction vary according to national class cultures and cultural fields. This article focuses on the ‘where’ arguing that interaction settings shape actors’ boundary work. Based upon research on Argentinean Pentecostalism, the study shows that middle-class Pentecostals switch between distinction-marking and ‘omnivorous’ performances of Pentecostalism depending on the social permeability of the spaces where they move. These insights suggest that the contextual conditions in which actors present themselves as ‘omnivores’ or ‘snobs’ deserve more attention.
Golimumab in the treatment of ulcerative colitis
Authors: Cunningham Georgina , Samaan Mark A. , Irving Peter M.
Published: January 2019

Golimumab was approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of moderate-to-severe ulcerative colitis in 2013 and was the third antitumour-necrosis-factor therapy after adalimumab and infliximab licensed for this indication. However, given it is the most recent of these drugs to become available, evidence regarding its optimal use and its positioning in relation to other biological therapies is only now emerging. In this article, we review the efficacy, effectiveness and safety of golimumab both in the setting of clinical trials and in ‘real world’ observational studies. We also explore the limited data available regarding the possible role of therapeutic-drug monitoring and dose flexibility.
Improving patient self-care using diabetes technologies
Authors: Alcántara-Aragón Valeria
Published: January 2019

Diabetes technologies are an unstoppable phenomenon. They offer opportunities to improve patient self-care through empowerment. However, they can be a challenge for both patients and clinicians. Thus, the use of technology may empower or burden. To understand and benefit from the use of diabetes technologies, one must understand the currently unmet needs in diabetes management. These unmet needs call for perspectives beyond glycated hemoglobin and an evaluation of technology solutions. Optimal use of these technologies is necessary to obtain benefits and achieve cost-effectiveness; this process depends on diabetes education and training. This review evaluates clinician and patient perspectives regarding diabetes technologies, followed by an evaluation of technology solutions. Diabetes technology solutions are evaluated according to available results about their effectiveness and their potential to empower people living with diabetes.
PTSD: Catastrophizing in Combat as Risk and Protection
Authors: Seligman Martin E. P. , Allen Andrew R. , Vie Loryana L. , Ho Tiffany E. , Scheier Lawrence M. , Cornum Rhonda , Lester Paul B.
Published: January 2019

We used the Army Person-Event Data Environment to explore risk and protective factors for diagnosed posttraumatic stress disorder (PTSD). We examined the entire eligible cohort of 79,438 active duty soldiers who deployed to Iraq or Afghanistan between 2009 and 2013, an unusually large and complete cohort. Soldiers highest on catastrophic thinking were 29% more likely to develop PTSD than soldiers with average catastrophic thinking, whereas soldiers lowest on catastrophic thinking were 25% less likely to develop PTSD, adjusting for demographic characteristics; psychological (including baseline depression), behavioral, and physical health; and military characteristics. Soldiers who faced four or more combat stressors were 120% more likely to develop PTSD than soldiers who experienced two combat stressors. Additionally, soldiers higher in catastrophic thinking and experiencing higher combat intensity were 274% more likely to develop PTSD than those low on both. The Army might consider interventions to reduce catastrophic thinking prior to combat to lower PTSD casualties.
Nonsuicidal Self-Injury and Suicidal Behaviors in Girls: The Case for Targeted Prevention in Preadolescence
Authors: Beauchaine Theodore P. , Hinshaw Stephen P. , Bridge Jeffrey A.
Published: January 2019

Nonsuicidal self-injury (NSSI) affects 15% to 20% of adolescents—disproportionately girls—and is a strong predictor of eventual suicide attempts and suicide. Many girls now initiate NSSI before age 10. These early starters exhibit greater frequency of NSSI, use more diverse methods, and are hospitalized more often than later starters, yet there are no empirically supported prevention programs for preadolescents. Obstacles to prevention include ascertaining who is sufficiently vulnerable and specifying mechanistic intervention targets. Recent research indicates that (a) preadolescent girls with ADHD who are also maltreated are at alarming risk for NSSI and suicide attempts by adolescence and (b) the conjoint effects of these vulnerabilities are sufficiently potent for targeted prevention. Research also indicates that existing interventions are effective in altering child- and family-level mechanisms of NSSI. These interventions alter neurobiological markers of vulnerability, which can be used as proximal efficacy signals of prevention response without waiting for NSSI and suicide attempts to emerge.
HIV Viral Dynamics of Lopinavir/Ritonavir Monotherapy as Second-Line Treatment: A Prospective, Single-Arm Trial
Authors: Claassen Cassidy W. , Keckich David , Nwizu Chidi , Abimiku Alash’le , Salami Donald , Obiefune Michael , Gilliam Bruce L. , Amoroso Anthony
Published: January 2019

Background:

Characterizing viral response to lopinavir/ritonavir (LPV/r) monotherapy as second-line treatment may guide recommendations for resource-limited settings (RLS).

Methods:

We conducted a 48-week prospective, single-arm study of LPV/r monotherapy in patients failing first-line therapy in Nigeria. The primary outcome was sustained HIV-1 viral load (VL) <400 copies/mL at 48 weeks.

Results:

Of 30 enrolled patients, 28 (93%) achieved viral suppression on LPV/r, while 29 (96%) experienced low-level viremia. At 48 weeks, 9 (30%) met the primary outcome of sustained viral suppression; 14 (47%) patients were suppressed on LPV/r in a snapshot analysis. Detectable VLs at 12 and 24 weeks were strongly associated with treatment failure at 48 weeks. New resistance mutations were not detected. The trial was stopped early due to treatment failure.

Conclusion:

In this study, the rate of virologic failure among patients on a second-line lopinavir monotherapy regimen was relatively high and predicted by early detectable viremia. However, no LPV/r-associated resistance mutations were detected despite fluctuating low-level viremia, demonstrating the high genetic barrier to resistance of the protease inhibitor class which could be useful in RLS.
New insights on scleromyxedema
Authors: Atzori Laura , Ferreli Caterina , Rongioletti Franco
Published: January 2019

Scleromyxedema is a rare fibromucinous disorders, with several clinical and pathological overlaps with scleroderma and scleredema. Etiopathogenesis remains uncovered, and no explanation has been provided either for the origin of mucin deposition or for the paraprotein role. The disease does not show gender predilection and affects mainly middle-age adults. The course is unpredictable, and prognosis remains guarded for renal, cardiac, and neurologic complications, especially in the setting of dermato-neuro syndrome. A valuable recent progress is the consensus definition of diagnostic criteria and lines of treatment, which hold the promise to improve the early recognition and management of this rare condition worldwide. High-dose intravenous immunoglobulin has been suggested as the first-line treatment either alone or associated with systemic steroids and/or thalidomide. In very recalcitrant cases, adjunctive bortezomib and/or autologous stem cell transplant might be considered. Melphalan treatment was associated with very toxic side effects and actually is no longer recommended.
A phase 1 trial of ibrutinib plus palbociclib in previously treated mantle cell lymphoma
Authors: Martin Peter , Bartlett Nancy L. , Blum Kristie A. , Park Steven , Maddocks Kami , Ruan Jia , Ridling LeAnn , Dittus Christopher , Chen Zhengming , Huang Xiangao , Inghirami Giorgio , DiLiberto Maurizio , Chen-Kiang Selina , Leonard John P.
Published: January 2019

Single-agent ibrutinib is active in patients with previously treated mantle cell lymphoma (MCL); however, nearly half of all patients experience treatment failure during the first year. We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human MCL cells and MCL cell lines expressing wild-type Bruton’s tyrosine kinase (BTK). Therefore, we conducted a phase 1 trial to evaluate the dosing, safety, and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. From August 2014 to June 2016, a total of 27 patients (21 men, 6 women) were enrolled. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1 to 21 of each 28-day cycle. The dose-limiting toxicity was grade 3 rash. The most common grade 3 to 4 toxicities included neutropenia (41%), thrombocytopenia (30%), hypertension (15%), febrile neutropenia (15%), and lung infection (11%). The overall and complete response rates were 67% and 37%, and with a median follow-up of 25.6 months, the 2-year progression-free survival was 59.4% and the 2-year response duration was 69.8%. A phase 2 multicenter clinical trial to further characterize efficacy is now ongoing. The current trial was registered at www.clinicaltrials.gov as #NCT02159755.
Distinguishing suicides of people reported missing from those not reported missing: retrospective Scottish cohort study
Authors: Woolnough Penny , Magar Emily , Gibb Graham
Published: January 2019

Background

Understanding what distinguishes the suicide of individuals reported missing (missing-suicides) from those of individuals not reported missing (other-suicides) may have preventative and/or operational utility and inform our knowledge of suicide.

Aims

To assess whether specific epidemiological, sociodemographic or circumstantial characteristics differ between individuals reported missing and those not reported missing who take their own life.

Method

Content analysis of Scottish Police Death Reports, detailing 160 suicides/undetermined deaths over a 3-year period in the North-East of Scotland.

Results

Those in the missing-suicide group were more likely to be older but did not differ from the other-suicide group on any other epidemiological or sociodemographic characteristics. Individuals in the other-suicide group were more likely to be found inadvertently by people known to them. The missing-suicide group took longer to find and were more likely to be located in natural outdoor locations by police/searchers or members of the public.

Conclusions

Individuals who die by suicide and who are reported as a missing person differ from those not reported as missing in terms of factors relating to location and how they are found but not epidemiological or sociodemographic characteristics.

Declaration of interest

None.
Tislelizumab in combination with chemotherapy in Chinese patients with advanced gastric or gastroesophageal junction (G/GEJ) cancer: Results from one cohort of an ongoing phase 2 study.
Authors: Bai Yu-Xian , Li En Xiao , Wang Buhai , Yuan Xianglin , Xu Nong , Chen Yunxin , Li Xiang , Wang Huanli , Xu Jianming
Published: January 2019

11

Background: Tislelizumab, a humanized IgG4 mAb with high affinity and specificity for PD-1, was specifically engineered to minimize FcγR binding on macrophages, thus abrogating antibody-dependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy. This phase 2 study (NCT03469557) evaluated safety, tolerability, and antitumor activity of first-line tislelizumab plus chemotherapy in Chinese pts with advanced G/GEJ or esophageal cancer; data from the G/GEJ cohort are presented here. Methods: Adult pts with histologically or cytologically confirmed HER2 negative G/GEJ were treated with tislelizumab (200 mg IV Q3W) + oxaliplatin (130 mg/m² IV Q3W for up to 6 cycles) + capecitabine (1000 mg/m² BID, Days 1–14 Q3W). AEs were assessed per CTCAE v4.03; tumor responses were assessed every 9 wks. Results: As of 13 June 2018, 15 G/GEJ pts (median age, 59 yr; M/F, 11/4) were enrolled; median treatment duration was 171 days (range 21-251). AEs in > 2 pts considered related to chemotherapy and/or tislelizumab are detailed in the Table. No fatal AEs occurred. Three pts discontinued treatment due to ascites or increased ALT, AST, or total bilirubin. With a median follow up of 181 days, 46.7% (n = 7) had confirmed PR, 20% (n = 3) had SD, 13.3% (n = 2) with non-target disease only at baseline had non-CR/non-PD, 6.7% (n = 1) had PD, and 13.3% (n = 2) did not have evaluable disease. ORR and DCR were 46.7% (n = 7/15) and 80% (n = 12/15), respectively. Conclusions: First-line tislelizumab plus chemotherapy was generally well tolerated and antitumor activity was observed in pts with advanced G/GEJ cancer. Clinical trial information: NCT03469557. [Table: see text]
The hyperprogressive disease during nivolumab treatment or irinotecan treatment in patients with advanced gastric cancer.
Authors: Aoki Masahiko , Shoji Hirokazu , Imazeki Hiroshi , Miyamoto Takahiro , Hirano Hidekazu , Honma Yoshitaka , Iwasa Satoru , Okita Natsuko , Takashima Atsuo , Kato Ken , Boku Narikazu
Published: January 2019

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Background: Nivolumab has demonstrated a survival benefit as a single agent in patients with advanced gastric cancer (AGC) refractory to, or intolerant of, two or more previous regimens in phase III study (ATTRACTION-2). However, an acceleration of tumor growth during immunotherapy, (hyperprogressive disease: HPD), was reported in advanced cancers treated with immunotherapy. The frequency and outcome of HPD in AGC comparing between immunotherapy and cytotoxic agents are little known. The aim of this study was to clarify the prevalence and background of HPD in patients treated with nivolumab or irinotecan. Methods: The subjects of this retrospective study were AGC patients with measurable disease defined by RECIST version 1.1 who were treated with nivolumab or irinotecan at our institution between June 2009 and September 2018, and whose tumors were assessed at least 3 times (during prior therapy, immediately before and after initiating nivolumab or irinotecan). The tumor growth rates (TGR) both before and after nivolumab or irinotecan were calculated as reported (Stéphane Champiat, Clin Cancer Res 2017). HPD was defined as an increase in the TGR exceeding 50% after nivolumab or irinotecan compared with prior therapy. Results: 32 and 66 patients received nivolumab and irinotecan (20 patients received both irinotecan and nivolumab). There were more prior chemotherapy before nivolumab than irinotecan (median: 3 vs 2). The median overall survival (MST) was 4.1 months (95%CI; 4.6-9.3 months) after nivolumab, and 7.0 months (95%CI; 6.3-9.3 months) after irinotecan. There were 9 patients showing HPD (28.1%) after initiating nivolumab and 9 patients (13.5%) after irinotecan (p = 0.0824). There were no differences in background between patients with and without HPD either after nivolumab or irinotecan. 9 patients with HPD showed shorter survival than those without HPD after nivolumab (median: 1.9 vs 6.4 months, p = 0.0007) while there was no such difference after irinotecan (median: 7.3 vs 7.0 months, p = 0.3345). Conclusions: HPD was observed more frequently after initiating nivolumab compared with irinotecan, and was associated with a poor prognosis after nivolumab but not after irinotecan.
Gastric cancer liver metastasis: Optimal management for oligo-metastatic disease.
Authors: Ito Hiromichi , Takemura Nobuyuki , Ono Yoshihiro , Sato Takafumi , Mise Yoshihiro , Inoue Yosuke , Takahashi Yu , Saiura Akio
Published: January 2019

136

Background: The role of surgery for gastric cancer liver metastasis (GCLM) has not been established and particularly, the optimal management for liver-isolated, oligo-GCLMs remains controversial. The aims of this study were to review the outcomes for our patients with GCLM who underwent liver resection and to define the optimal selection criteria for resection. Methods: The medical records of patients who underwent liver resection for GCLMs with curative intent at our institution from 1993 through 2018 were reviewed. Our criteria for liver resection included absence of extrahepatic disease, and the limited number of liver metastasis (often 3 or less). Results: Total 101 patients with GCLM (77 men [76%], median age 66 years) were included. Forty-seven patients (46%) had synchronous metastasis and all underwent simultaneous resection with the primary disease. Those with synchronous disease received neoadjuvant therapy more often than those with metachronous disease (63% vs 37%, p = 0.021). Median RFS and OS for the entire cohort were 11 months and 39 months, respectively, and 5-year-OS rate was 41%. Of note, 25 patients achieved survival longer than 5 years without any recurrence thereafter with median follow-up of 137 months. In the multivariate analyses, elevated CEA 50 ng/ml or greater and nodal status of the primary were associated with shorter RFS, while primary T4 disease, liver tumor 5cm or great and elevated CEA were associated with shorter OS (Table 1). Conclusions: For well selected patients with GCLM, liver resection is an effective therapy not only to prolong disease-free time, but also to achieve cure. CEA is useful to select patients with GCLM who unlikely benefit from aggressive surgery. [Table: see text]
Predictors of lymphopenia in esophageal cancer patients receiving photon or proton radiation therapy: A dosimetric analysis.
Authors: Routman David M. , Whitaker Thomas J , Day Courtney N. , Harmsen William S. , Neben-Wittich Michelle A. , Haddock Michael G. , Hallemeier Christopher Leigh , Merrell Kenneth
Published: January 2019

147

Background: Lymphopenia during radiation therapy (RT) has been associated with worse oncologic outcomes in a number of malignancies, including esophageal cancer (EC). No studies to date have investigated specific dosimetric parameters associated with this lymphopenia in EC. We performed an analysis of RT dose to multiple organs at risk (OARs) to investigate associations with grade 4 lymphopenia (G4L). Methods: Consecutive EC patients receiving curative intent chemoradiotherapy +/- surgery between July of 2015 and December of 2017 were included. Lymphocyte nadir was defined as the lowest lymphocyte count during RT. G4L was defined as absolute lymphocyte count <200/mm3. Dose to OARs including aorta, body, bone marrow, heart, liver, lung, and spleen were calculated. Univariate logistic regression analyses were performed for each OAR at the 1, 5, 10, 15, 20, 30, 35, 40, and 50 Gy levels with volume receiving dose ‘x’(VxGy) analyzed as a continuous variable per 10% increase. Clinical tumor volume (CTV) and RT modality (photon vs. proton) as well clinical factors including sex, stage (I/II vs. III/IV), age (per 10 year increase), and BMI (per 5 unit increase) were also analyzed. Results: One hundred forty-four pts were identified for inclusion. Seventy-nine pts received photon RT and 65 proton RT. Chemotherapy was weekly carbotaxol (99%). G4L at nadir was 40% overall (56% photon, 22% proton). By organ, body V1-V30Gy (OR 1.45-8.18, p<0.01), heart V1-V30Gy (OR 1.24-1.49, p<0.01), liver V1-V35Gy (OR 1.23-2.75, p<0.01), lung V1-V30Gy (OR 1.26-5.73 p<0.01), and spleen V1-V40Gy (OR 1.26-1.49 p<0.01) were highly associated with G4L whereas dose to aorta and bone marrow were not. Advanced stage (OR, 3.92 p<0.01), photon vs. proton (OR 4.58 p<0.01), and CTV (per 100 cc’s (OR=1.21, p<0.01)) were also associated with G4L. Sex, age, and BMI were not associated with G4L. Conclusions: Low to intermediate dose volumes to OARs including body, spleen, liver, lungs, and heart were associated with G4L. These findings provide rational for the differences seen in rates of G4L for photon versus proton RT.
Outcomes in pancreatic adenocarcinoma (PDA) patients (pts) with genetic alterations in DNA damage repair (DDR) pathways: Results from the Know Your Tumor (KYT) program.
Authors: Pishvaian Michael J. , Blais Edik Matthew , Brody Jonathan Robert , Sohal Davendra , Hendifar Andrew Eugene , Chung Vincent , Mikhail Sameh , Rahib Lola , Lyons Emily , Tibbetts Lisa , Madhavan Subha , Matrisian Lynn McCormick , Petricoin Emanuel
Published: January 2019

191

Background: Up to 17% of PDAs harbor mutations in the DDR pathway. However, the purely prognostic relevance of these mutations is unclear. Furthermore, outcomes in response to platinum-based therapies in PDA pts harboring mutations in a broad range of DDR genes, particularly beyond BRCA1/2 and PALB2, remain unexplored. Methods: We evaluated PDA pts enrolled in the KYT registry for whom we collected cancer related exome sequencing and clinical outcomes. Pts were categorized as resected and advanced (LAPC and metastatic pts), and tumor genomic profiles were categorized as DDR mutated (DDRmut) based on the presence of pathogenic alterations in BRCA1/2, PALB2 (Group 1), ATM, ATR, ATRX (Group 2), or BAP1, BARD1, BRIP1, CHEK1/2, RAD50/51/51B, or FANCA/C/D2/E/F/G/L (Group 3). Tumors harboring no DDR mutations were labelled DDR proficient (pDDR). Median overall survival (OS) was measured from the date of diagnosis until death. Results: The OS was similar in all resected pts, irrespective of exposure to platinum therapy (see Table). However, for the pts with advanced disease, OS was significantly longer for DDRmut vs. pDDR pts, particularly in the platinum-treated group; but no such difference was identified in the platinum-naïve pts. Detailed outcomes for the 3 Groups will be presented, but in general the OS in pts with mutations in all 3 DDRmut Groups was greater than for the pDDR pts; but again this difference was lost in the platinum-naïve pts. Conclusions: Advanced DDRmut pts have an improved OS when treated with platinums, compared to pDDR pts. But, in the absence of platinum-based therapy, there is no OS difference observed in DDRmut vs. pDDR pts, suggesting that DDR status has no pure prognostic value. These findings support the need to test all pts with advanced PDA, to ensure that DDRmut pts are treated with platinum-based therapy. [Table: see text]
Immune checkpoint inhibition (ICI) in combination with SBRT in patients with advanced pancreatic adenocarcinoma (aPDAC).
Authors: Brar Gagandeep , Xie Changqing , Floudas Charalampos S. , Morelli M. Pia , Fioravanti Suzanne , Walker Melissa , Mabry-Hrones Donna , Jones Jennifer C , Greten Tim F.
Published: January 2019

192

Background: Chemotherapy in aPDAC has resulted in only modest improvements in outcome. The effectiveness of ICI monotherapy is also limited in PDAC, suggesting an immunogenic inert tumor microenvironment. SBRT is safe and effective in locally advanced PDAC and exhibits enhanced antitumor immunity. We hypothesize that ICI plus SBRT will improves immunomodulatory effects of ICI in patients with aPDAC resulting in a greater clinical benefit. Methods: Eligible patients with aPDAC were enrolled to four different treatment cohorts. Cohort 1: Durvalumab (Durva) 1500 mg every 4 weeks + SBRT 1 fraction x 8Gy on day 1. Cohort 2: SBRT 5 fractions x 5Gy followed by Durva. Cohort 3: Durva + Tremelimumab (Treme) 75 mg every 4 weeks + SBRT 1 fraction x 8Gy on day 1. Cohort 4: SBRT 5 fractions x 5Gy followed by Durva + Treme. This was continued until unacceptable toxicity or progression of disease. A biopsy was performed at baseline and pre-cycle 2 of treatment for exploratory correlative analysis. The primary objective was to evaluate the safety and feasibility of combining ICI and SBRT to enhance the efficacy of ICI. Results: 51 patients with aPDAC were enrolled and 31 patients were evaluable for the efficacy. The most commonly TRAEs were lymphopenia. Grade 3-4 AEs were lymphopenia and anemia. No dose limiting toxicities were seen. Out of total 31 evaluable patients, 1 patient achieved a confirmed partial response seen in Cohort 1 and 2 patients in Cohort 4, and 7 stable disease across the 4 treatment arms. Median PFS and OS was 1.7 months (95% CI 0.7-2.8 months) and 3.4 months (95% CI 0.9-11.4 months) in cohort 1; 2.6 months (95% CI 2.1-4.7 months) and 9.1 months (95% CI 3.4-18.7 months)in cohort 2; 1.6 months (95% CI 0.5-4.0 months) and 3.0 months (95% CI 0.7-6.6 months) in cohort 3; and 3.2 months (95% CI 1.5-16.5months) and 6.4 months (95% CI 1.5-17.6 months) in cohort 4. Conclusions: The combination of ICI and SBRT is safe and well tolerated in patients with aPDAC. The overall response rate of 9.6% including 2 patients who achieved a durable partial response lasting over 12 months, suggests meaningful clinical activity. This signifies that ICI and SBRT is a potential new treatment for aPDAC. Clinical trial information: NCT02311361.
Quality-adjusted life years assessment using cabozantinib for patients with advanced hepatocellular carcinoma (aHCC) in the CELESTIAL trial.
Authors: Abou-Alfa Ghassan K. , Mollon Patrick , Meyer Tim , Cheng Ann-Lii , El-Khoueiry Anthony B. , Kelley Robin Kate , Baron Ari David , Benzaghou Fawzi , Valcheva Velichka Valerieva , Hazra Saswati , Mangeshkar Milan , Freemantle Nicholas
Published: January 2019

207

Background: In patients previously treated for aHCC, cabozantinib (cabo) led to longer overall survival and progression-free survival vs placebo (pbo) in the randomized, phase 3 CELESTIAL trial (NCT01908426; N = 707). CELESTIAL was stopped early for benefit at the second interim analysis. This post hoc analysis estimated the incremental quality-adjusted life years (QALYs) accrued in CELESTIAL. Methods: Health utility was elicited at each study visit using the EQ-5D-5L quality of life questionnaire. (completed by 82–100% of patients overall). UK crosswalk tariffs were applied for health states. Cumulative QALYs by patient were calculated by linear interpolation; for patients who were censored (31% of patients; including 9% within 100 days of randomization), the last observed utility value was carried forward to study end. The difference in restricted mean QALYs was calculated using generalized linear models, accounting for baseline utility, and with 0.06–0.08 QALYs considered the minimal important difference. Results: At day 50 after randomization (acute treatment phase), cabo was associated with a small reduction in mean total QALYs vs pbo (difference −0.003; 95% CI −0.005 to −0.002; p ≤ 0.001; n = 601 [cabo, n = 389; pbo, n = 212]). At day 100, there was a numerical benefit in mean total QALYs for cabo (difference +0.007; 95% CI −0.001 to 0.015; p = 0.103; n = 627 [cabo, n = 410; pbo, n = 217]), and at day 150 the difference was +0.032 QALYs (95% CI 0.017 to 0.047; p ≤ 0.001; n = 629 [cabo, n = 412; pbo, n = 217]) in favor of cabo. Over the entire follow-up, patients randomized to cabo accrued a mean of +0.092 (95% CI 0.016 to 0.169; p = 0.018; n = 700 [cabo, n = 465; pbo, n = 235]) additional QALYs compared with those receiving pbo. Using alternative Devlin weights for health states, the mean accrued QALYs with cabo was +0.115 vs pbo (95% CI 0.032 to 0.198; p = 0.007). Conclusions: Cabo was associated with an initial, small reduction in health utility. However, with continued treatment, health utility increased and at the end of the study there was a clinically and statistically significant benefit in mean QALYs in favor of cabo. Clinical trial information: NCT01908426.
Prevalence and molecular etiology of mismatch repair deficiency among gastrointestinal cancers.
Authors: Shukla Navika , Abrha Aser , Longacre Teri A. , Koff Rachel , Ford James M. , Fisher George A. , Haraldsdottir Sigurdis
Published: January 2019

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Background: In light of recent FDA approval of anti-PD-1 therapy for microsatellite unstable (MSI-H) or mismatch repair deficient (dMMR) solid tumors, identifying patients with dMMR tumors has become increasingly important. While screening for dMMR and MSI-H in colorectal cancer (CRC) is recommended, this screening is less commonly done for extracolonic gastrointestinal (GI) tumors. At Stanford Comprehensive Cancer Institute (SCCI), all GI cancer patients have been universally screened for dMMR via immunohistochemistry since January 2016. Methods: In this study, we undertook a retrospective review of all GI cancer patients screened for dMMR between January 2016 to December 2017. Data on patient characteristics, germline and tumor sequencing, and tumor characteristics were collected and reported. Results: A total of 1543 GI malignancies were screened for dMMR at SCCI during the study period. Colorectal (n = 711), pancreatic (n = 264), gastric (n = 159), and gastro-esophageal (n = 137) cancer were amongst the most frequently screened tumors. dMMR was detected in 7.1% of all GI malignancies. We detected the highest prevalence of dMMR in colorectal (69/711, 9.7%), followed by gastric (15/159, 9.4%), pancreatic (18/264, 6.8%), and gastro-esophageal cancer (6/137, 4.4%). Lynch syndrome was the most common etiology for dMMR in CRC patients (39.4%), double somatic (confirmed or possibly) mutations were most common in pancreatic cancer (44.4%), and somatic MLH1 hypermethylation was the most common etiology in gastric (73.3%) and gastro-esophageal cancer (100%). Conclusions: Given the relatively high incidence of dMMR in GI malignancies, we strongly recommend screening all GI malignancies. Of note, we found higher than previously reported rates of dMMR within pancreatic cancer. Our results also suggest that while rare, double somatic mismatch repair mutations may be a significant pathway causing dMMR in pancreatic cancer.
Plasma GH as a diagnostic and prognostic biomarker in HCC without cirrhosis.
Authors: Carmagnani Pestana Roberto , Hassan Manal , Abdel-Wahab Reham , Abugabal Yehia I. , Girard Lauren , Hatia Rikita , Nguyen Van , Raghav Kanwal Pratap Singh , Morris Jeffrey , Rashid Asif , Wolff Robert A. , Amin Hesham M. , Kaseb Ahmed Omar
Published: January 2019

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Background: The association between the GH/IGF-1 axis and HCC was reported in patients (pt) with underlying cirrhosis. However, there is limited information among HCC pt without (w/o) cirrhosis. We herein investigated the role of GH as a circulating biomarker for HCC diagnosis and prognosis in pt w/o cirrhosis. Methods: Under IRB approval, we prospectively enrolled 1267 newly-diagnosed HCC pt in a case control study at the MD Anderson Cancer Center (2000-2015). Controls were healthy individuals (n = 1104). Plasma GH and AFP were measured 274 HCC pt w/o cirrhosis 200 healthy controls. IGF-1 was measured in 133 and 82 pt, respectively. We classified HCC pt into higher and lower GH values (cutoff for women, 3.7 µg/L; men, > 0.9 µg/L). Results: Most pt (74%) were male, with advanced BCLC staging (C-D, 74%) and 61% were older than 60y. Baseline GH was higher in HCC w/o cirrhosis (mean 3.3 µg/L) than controls (mean 0.4 µg/) (p < .001). ROC curve was plotted to assess diagnostic role. The AUC for AFP was 82.9 (p < .001); for GH 78.2 (p < .001). When only non-cirrhotic HCC pt with early stage (CLIP 0-2) and AFP < 20 ng/m were compared to controls, the GH/IGF-1 ratio had high prediction of early stage HCC - AUC 83 (95% CI 78-89%) (p < .0001). At a specificity of 90%, sensitivity of GH/IGF ratio was 67%. In addition, among HCC w/o cirrhosis, higher GH levels correlated with presence of vascular invasion (p < .001) and thrombosis (p = .004), tumor involvement of > 50% liver (p = .003), and more advanced BCLC (p < .001) and TNM staging (p < .001). Median overall survival (months) of HCC pt w/o cirrhosis with high GH levels was 13.1 (10.8-15.4) compared to 37.4 (19.8-55.1) of pt with lower plasma GH (p < .001). Multivariate cox-regression analysis identified high GH as an independent risk factor for mortality (HR = 1.8; 95% CI, 1.3-2.4; p < .001). Conclusions: Our study demonstrates the diagnostic and prognostic role of plasma GH in non-cirrhotic HCC and identifies the GH/IGF-1 ratio as a promising diagnostic marker for early stage HCC w/o cirrhosis and low AFP; this analysis excludes the confounding effect hepatocyte impaired function by presence of cirrhosis. Further studies are warranted to assess the causes of the observed differences.
Landscape of germline mutations in hepatobiliary carcinoma: Unrealized risk, untapped clinical trial opportunities.
Authors: Samadder Jewel , Rupp Margaret , Yang Shan , Michalski Scott T. , Lincoln Stephen E , Nussbaum Robert L. , Borad Mitesh J. , Esplin Edward D.
Published: January 2019

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Background: Hepatobiliary cancer (HBC), including cholangiocarcinoma, affects over 40,000 people in the U.S. each year, and results in over 30,000 cancer deaths annually. Despite continuing advances in next-generation sequencing (NGS), the understanding of germline genetic risk as it relates to these malignancies remains limited, and guidelines for the germline testing of these patients are lacking. We report the spectrum of pathogenic/likely pathogenic (P/LP) germline genetic variants observed in patients with HBC, and the clinical utility related to germline genetic test results. Methods: We retrospectively studied a consecutive series of 267 patients referred to Invitae for germline genetic testing based on a personal history of HBC, per an IRB approved protocol. Patients were evaluated with a multigene panel of up to 135 genes chosen by the ordering providers. De-identified clinical and family history information were reviewed as provided by clinicians. Results: Among 267 HBC patients 15% (n = 41) had P/LP variants identified in genes including MUTYH, ATM, CHEK2, BAP1, BRCA1, MLH1, BRCA2, PALB2, TP53, APC, CDH1, MSH6, and PMS2 (12% excluding MUTYH heterozygotes). Amongst patients with a family history (FH) of HBC, P/LP rate was 13%; for patients with a FH of cancers other than HBC, P/LP rate was 16%; for patients with no reported FH, P/LP rate was 13%. Conclusions: In this study, 15% of HBC patients had P/LP variants in cancer-risk genes. The clinical utility of these germline P/LP variants includes 32% of patients who were eligible for ongoing clinical treatment trials based on their germline test results (NCT02286687), 60% with clinical management recommendations per current NCCN guidelines, and cascade testing of at risk family members. These data justify comprehensive germline multigene panel testing in all HBC patients, in view of the potential impact on clinical management for a substantial fraction of positive patients as well as facilitating cascade testing for risk assessment of family members.
A phase Ib dose escalation study of vantictumab (VAN) in combination with nab-paclitaxel (Nab-P) and gemcitabine (G) in patients with previously untreated stage IV pancreatic cancer.
Authors: Davis S. Lindsey , Cardin Dana Backlund , Shahda Safi , Lenz Heinz-Josef , Dotan Efrat , O'Neil Bert , Kapoun Ann M. , Stagg Robert J. , Berlin Jordan , Messersmith Wells A. , Cohen Steven J.
Published: January 2019

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Background: Vantictumab is a fully human monoclonal antibody that inhibits Wnt pathway signaling through binding FZD1, 2, 5, 7, and 8 receptors. A phase Ib study of VAN in combination with Nab-P and G was performed in patients with untreated stage IV pancreatic adenocarcinoma. Methods: Patients received VAN at escalating doses (3-7 mg/kg) in combination with standard dosing of Nab-P and G according to a 3+3 design. Due to fragility fractures occurring in this and other related clinical trials, dosing on an every 2 week schedule in cohorts 1 and 2 was transitioned to every 4 week dosing for cohorts 3 through 5. In these later cohorts, a minimum of six patients were treated at each dose level and additional criteria for maximum tolerated dose (MTD) integrating bone safety parameters were added. The bone safety plan was also revised for these cohorts. Sequential dosing of VAN followed by Nab-P and G was explored in cohort 5. Results: Thirty-one patients (52% male, 48% female) were enrolled and treated in 5 dosing cohorts. Median age was 66. Most common study-treatment related adverse events were nausea (68%) and fatigue (52%). One dose limiting toxicity (DLT) event occurred in the study population—grade 3 dehydration in 1 of 9 patients in cohort 4 (5 mg/kg q4w). Fragility fractures attributed to VAN occurred in two patients in cohort 2 (7 mg/kg q2w). Once the dosing schedule was revised to every 4 weeks, the maximum administered VAN dose was 5 mg/kg. No fragility fractures attributed to VAN occurred in these cohorts; pathologic fracture not attributed to VAN was documented in 2 patients. The study was terminated due to lack of an acceptable therapeutic index. Partial response was documented in 13 patients (42%) and stable disease in 11 (36%). Conclusions: The MTD of VAN plus Nab-P and G was not determined, but the maximum administered dose (MAD) of VAN, 7 mg/kg every 2 weeks, was considered unsafe related to bone toxicity, a known effect of WNT inhibition. After the study was revised, the MAD was 5 mg/kg every 4 weeks, with no protocol-specified bone toxicity observed (n = 16). Clinical trial information: NCT02005315.
Comprehensive genomic analysis of metastatic pancreatic ductal adenocarcinoma (mPDAC) reveals a significant proportion of clinical actionable aberrations.
Authors: Lee Michael , Jones Martin R , Williamson Laura , Topham James Thomas , Addison Sean , Wong Hui-Li , Denroche Rob , Jang Gun Ho , Karasinska Joanna , McGhie John Paul , Gill Sharlene , Lim Howard John , Yip Stephen , Knox Jennifer J. , Gallinger Steven , Laskin Janessa J. , Marra Marco A. , Jones Steven J. M. , Sschaeffer David F , Renouf Daniel John ,   POG PDAC
Published: January 2019

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Background: Substantial progress has been made in the understanding of the genomic landscape of PDAC, but the clinical utility of these data remains uncertain. Methods: As part of the BC Cancer Personalized Oncogenomics (POG) and PanGen studies, whole genome analysis and transcriptome sequencing were performed on fresh biopsy and blood sample from 47 mPDAC patients. Genomic findings informed therapy choices including potential eligibility for the CCTG PM.1 molecular basket trial. Results: Cohort consists of 53% male, average age 57.8, 34/47 had ≥2 lines of treatment. 37/47 biopsies were from liver and 26/47 were collected pre-treatment. 8/47 (17%) patients had aberrations with strong evidence of clinical actionability. These include 2 germline BRCA2, 1 germline BRCA1, 1 somatic XRCC2 homozygous deletion with strong COSMIC signature 3, all predictive of platinum sensitivity. Patients with XRCC2 deletion and BRCA1 had over 2 years on FOLFIRINOX. Fusions affecting the NRG1 gene were identified in 3 patients, all with KRAS wildtype tumours, which may confer ERRB inhibitor sensitivity. 1/3 NRG1 fusion patients had thus far been treated with the ERBB inhibitor afatinib, with reduction of CA19-9 from >120,000 to 7246 and dramatic response noted on PET CT imaging one month post treatment. One patient had mismatch repair deficiency, and a high mutational burden, suggestive of immune checkpoint inhibitor sensitivity. In total 85% (40/47) sequenced mPDAC patients had potentially actionable mutations which includes CCTG PM.1 trial eligibility: 24/47 with cell cycle dysregulation (CDK4/6 inhibitor arm), 4/47 with high homologous recombination defects (PARP inhibitor arm), 1/47 ERBB2 amplification (anti-HER2 arm), 2/47 high expression of FGFR1 (Sunitinib arm) and 1/47 with high FLT4 and IGF1R expression (Axitinib arm). Conclusions: More routine use of comprehensive genomic analysis should be considered in mPDAC given finding of high degree of actionability. Importantly, a significant proportion (17%) had findings with strong evidence of clinical impact.(NCT02155621, NCT02869802, NCT03297606)
Disparities associated with the receipt of palliative care in patients with metastatic gastric cancer.
Authors: Paul Subhadeep , Hester Caitlin , Wang Sam C. , Polanco Patricio , Yopp Adam Charles , Augustine Mathew M , Mansour John C. , Zeh Herbert , Porembka Matthew R.
Published: January 2019

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Background: Metastatic gastric adenocarcinoma (mGA) is frequently associated with debilitating symptoms that negatively impact quality of life. We aim to determine the rate of palliative care (PC) use in mGA and the factors which are associated with receipt of PC. Methods: Using the National Cancer Database, mGA patients were selected. Receipt of PC as defined by the NCDB participant use file was correlated to demographic and clinicopathologic factors. As defined according to NCDB, PC treatment included surgery, radiation, systemic therapy, and pain management to alleviate symptoms. Logistic regression was performed to assess the impact of factors on the likelihood of receiving PC. Overall survival was estimated using the Kaplan-Meier method and compared using log-rank tests. Results: Between 2004 and 2013, 45519 patients with mGA and reported PC status were identified. Median age was 66 years (IQR: 55-76 years) and 64% were male. 7365 (16.2%) patients received PC. PC utilization increased over time (2004-6 13.4%, 2007-10 15.8%, 2011-13 19.1%; p < 0.001). Factors associated with PC on univariate analysis included insurance status, education level, income, sex, race, Charlson/Deyo comorbidity score, and year of diagnosis (all p < 0.001). On multivariate analysis, female sex (0.87, 95%CI: 0.83-0.92) and minority race were associated with less receipt of PC (Hispanic 0.73, 95%CI: 0.66-0.80, Black 0.87, 95%CI: 0.80-0.95, Asian 0.89, 95%CI: 0.77-0.98 compared to non-Hispanic White patients). Higher education level was associated with greater receipt of PC (1.46, 95%CI: 1.31-1.62). Receipt of PC was associated with decreased overall survival (PC 4.8 months vs no PC 6.0 months; p < 0.001). Conclusions: Although use of PC has increased over time, PC is underutilized in mGA. Disparities exist in receipt of PC in regard to race, gender, and education. Additional research is necessary to better optimize PC use in mGA and mitigate potential disparities.