bluuebunny/crossref_metadata_2025 huggingface dataset:
Dendritic Cell/Cytokine-Induced Killer Cell Immunotherapy Combined with S-1 in Patients with Advanced Pancreatic Cancer: A Prospective Study
Authors: Jiang Ni , Qiao Guoliang , Wang Xiaoli , Morse Michael A. , Gwin William R. , Zhou Lei , Song Yuguang , Zhao Yanjie , Chen Feng , Zhou Xinna , Huang Lefu , Hobeika Amy , Yi Xin , Xia Xuefeng , Guan Yanfang , Song Jin , Ren Jun , Lyerly H. Kim
Published: June 2017

Purpose: Advanced pancreatic cancer has remained challenging to treat effectively. This study aimed to investigate the clinical effects and safety of immunotherapy with dendritic cells and cytokine-induced killer cells (DC-CIK) administered with the chemotherapy (CT) S-1 in this malignancy.

Experimental Design: Consecutive patients (n = 47) with advanced pancreatic cancer were treated with either DC-CIK + S-1, DC-CIK alone, S-1 alone, or best supportive care.

Results: DC-CIK plus S-1 produced significantly longer median OS and PFS (212 and 136 days) compared with DC-CIK (128 and 85 days), CT (141 and 92 days), or supportive care only (52 and 43 days; P < 0.001). After adjusting for competing risk factors, DC-CIK combined with S-1 and receipt of 2 or more cycles of DC-CIK treatment remained independent predictors of disease-free and overall survival (P < 0.05). Phenotypic analysis of PBMCs demonstrated that the CD3+, CD3+/CD4+, and CD8+/CD28+ T-cell subsets were elevated (P < 0.05), while the CD3+/CD8+, CD3+/CD16+/CD56+ and CD4+/CD25+ cell subsets were significantly decreased after DC-CIK cell therapy (P < 0.05). There were no grade 3 or 4 toxicities. In addition, the mutational frequency in cell-free tumor DNA (cfDNA) declined in 4 of 14 patients who received DC-CIK, and was associated with a more favorable survival.

Conclusions: Treatment of advanced pancreatic cancer with combined DC-CIK infusions and S-1 was safe, resulted in favorable PFS and OS, and modulated the peripheral blood immune repertoire. Clin Cancer Res; 23(17); 5066–73. ©2017 AACR.
U.S. Food and Drug Administration Approval Summary: Atezolizumab for Metastatic Non–Small Cell Lung Cancer
Authors: Weinstock Chana , Khozin Sean , Suzman Daniel , Zhang Lijun , Tang Shenghui , Wahby Sakar , Goldberg Kirsten B. , Kim Geoffrey , Pazdur Richard
Published: June 2017

On October 18, 2016, the FDA approved atezolizumab (TECENTRIQ; Genentech, Inc.) for treatment of patients with metastatic non–small cell lung cancer (mNSCLC) whose disease progressed during or following platinum-containing chemotherapy. Approval was based on demonstration of clinically meaningful improvements in overall survival (OS) and an acceptable safety profile in two randomized clinical trials (OAK and POPLAR). Median OS in OAK, a phase III trial, was 13.8 months [95% confidence interval (CI), 11.8–15.7] in the atezolizumab arm compared with 9.6 months (95% CI, 8.6–11.2) in the docetaxel arm [hazard ratio (HR) = 0.74; 95% CI, 0.63–0.87; P = 0.0004]. Median OS in POPLAR, a phase II trial, was 12.6 months (95% CI, 9.7–16.0) and 9.7 months (95% CI, 8.6–12.0; HR = 0.69; 95% CI, 0.52–0.92) for the atezolizumab and docetaxel arms, respectively. In patients treated with atezolizumab, the most common (≥20%) adverse reactions were fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation; the most common (≥2%) grade 3 to 4 adverse events were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, aspartate aminotransferase increase, alanine aminotransferase increase, dysphagia, and arthralgia. Clinically significant immune-related adverse events for patients receiving atezolizumab included 1.4% incidence each of grade 3 to 4 pneumonitis, hepatitis, colitis, and thyroid disease. Clin Cancer Res; 23(16); 4534–9. ©2017 AACR.
An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer
Authors: Ashenden Matthew , van Weverwijk Antoinette , Murugaesu Nirupa , Fearns Antony , Campbell James , Gao Qiong , Iravani Marjan , Isacke Clare M.
Published: June 2017

Chemotherapy remains the mainstay of treatment for advanced breast cancer; however, resistance is an inevitable event for the majority of patients with metastatic disease. Moreover, there is little information available to guide stratification of first-line chemotherapy, crucial given the common development of multidrug resistance. Here, we describe an in vivo screen to interrogate the response to anthracycline-based chemotherapy in a syngeneic metastatic breast cancer model and identify JNK signaling as a key modulator of chemotherapy response. Combining in vitro and in vivo functional analyses, we demonstrate that JNK inhibition both promotes tumor cell cytostasis and blocks activation of the proapoptotic protein Bax, thereby antagonizing chemotherapy-mediated cytotoxicity. To investigate the clinical relevance of this dual role of JNK signaling, we developed a proliferation-independent JNK activity signature and demonstrate high JNK activity to be enriched in triple-negative and basal-like breast cancer subtypes. Consistent with the dual role of JNK signaling in vitro, high-level JNK pathway activation in triple-negative breast cancers is associated both with poor patient outcome in the absence of chemotherapy treatment and, in neoadjuvant clinical studies, is predictive of enhanced chemotherapy response. These data highlight the potential of monitoring JNK activity as early biomarker of response to chemotherapy and emphasize the importance of rational treatment regimes, particularly when combining cytostatic and chemotherapeutic agents. Mol Cancer Ther; 16(9); 1967–78. ©2017 AACR.
The DNA-Binding Polyamine Moiety in the Vectorized DNA Topoisomerase II Inhibitor F14512 Alters Reparability of the Consequent Enzyme-Linked DNA Double-Strand Breaks
Authors: Bombarde Oriane , Larminat Florence , Gomez Dennis , Frit Philippe , Racca Carine , Gomes Bruno , Guilbaud Nicolas , Calsou Patrick
Published: June 2017

Poisons of topoisomerase II (TOP2) kill cancer cells by preventing religation of intermediate DNA breaks during the enzymatic process and thus by accumulating enzyme–drug–DNA complexes called TOP2 cleavage-complex (TOP2cc). F14512 is a highly cytotoxic polyamine-vectorized TOP2 inhibitor derived from etoposide and currently in clinical trials. It was shown in vitro that F14512 has acquired DNA-binding properties and that the stability of TOP2cc was strongly increased. Paradoxically, at equitoxic concentrations in cells, F14512 induced less DNA breaks than etoposide. Here, we directly compared etoposide and F14512 for their rates of TOP2cc production and resolution in human cells. We report that targeting of TOP2α and not TOP2β impacts cell killing by F14512, contrary to etoposide that kills cells through targeting both isoforms. Then, we show that despite being more cytotoxic, F14512 is less efficient than etoposide at producing TOP2α cleavage-complex (TOP2αcc) in cells. Finally, we report that compared with TOP2αcc mediated by etoposide, those generated by F14512 persist longer in the genome, are not dependent on TDP2 for cleaning break ends from TOP2α, are channeled to a larger extent to resection-based repair processes relying on CtIP and BRCA1 and promote RAD51 recruitment to damaged chromatin. In addition to the addressing of F14512 to the polyamine transport system, the properties uncovered here would be particularly valuable for a therapeutic usage of this new anticancer compound. More generally, the concept of increasing drug cytotoxicity by switching the repair mode of the induced DNA lesions via addition of a DNA-binding moiety deserves further developments. Mol Cancer Ther; 16(10); 2166–77. ©2017 AACR.
IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma
Authors: Long Kristen B. , Tooker Graham , Tooker Evan , Luque Santiago Lombo , Lee Jae W. , Pan Xiaoqing , Beatty Gregory L.
Published: June 2017

Inflammation mediated by activation of JAK/STAT signaling is a major cause of chemotherapy resistance in cancer. We studied the impact of selectively blocking the IL6 receptor (IL6R) as a strategy to inhibit IL6-induced STAT activation and to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). To do this, STAT activation was investigated in tumors arising spontaneously in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1Cre (KPC) mice. Plasma from patients with PDAC was assessed for its ability to activate STAT3/SOCS3 in human monocytes using immunofluorescence microscopy and quantitative gene expression assays. KPC mice and syngeneic mice (wild type and IL6−/−) implanted with KPC-derived cell lines were treated with an IL6R-blocking antibody (anti-IL6R). The impact of treatment on tumor growth in KPC mice and mice with KPC-derived tumor implants was monitored using ultrasonography and calipers, respectively. Tumors were analyzed by IHC to detect changes in STAT activation, tumor viability, and proliferation. We found that STAT3 was the most activated STAT protein in PDAC tumors from KPC mice. Plasma from patients with advanced PDAC stimulated STAT3/SOCS3 activation in human monocytes. In mice, anti-IL6R antibodies targeted Ly6Chi monocytes, inhibited STAT3 activation in tumor cells, and decreased tumor cell proliferation in vivo. IL6R blockade in combination with chemotherapy induced tumor cell apoptosis, tumor regressions, and improved overall survival. Overall, we show that IL6 signaling drives STAT3 activation in tumor cells and mediates chemoresistance in PDAC. Thus, disrupting IL6 signaling using anti-IL6R antibodies holds promise for improving chemotherapy efficacy in PDAC. Mol Cancer Ther; 16(9); 1898–908. ©2017 AACR.
Chemoprevention Uptake among Women with Atypical Hyperplasia and Lobular and Ductal Carcinoma In Situ
Authors: Trivedi Meghna S. , Coe Austin M. , Vanegas Alejandro , Kukafka Rita , Crew Katherine D.
Published: June 2017

Women with atypical hyperplasia and lobular or ductal carcinoma in situ (LCIS/DCIS) are at increased risk of developing invasive breast cancer. Chemoprevention with selective estrogen receptor modulators or aromatase inhibitors can reduce breast cancer risk; however, uptake is estimated to be less than 15% in these populations. We sought to determine which factors are associated with chemoprevention uptake in a population of women with atypical hyperplasia, LCIS, and DCIS. Women diagnosed with atypical hyperplasia/LCIS/DCIS between 2007 and 2015 without a history of invasive breast cancer were identified (N = 1,719). A subset of women (n = 73) completed questionnaires on breast cancer and chemoprevention knowledge, risk perception, and behavioral intentions. Descriptive statistics were generated and univariate and multivariable log-binomial regression were used to estimate the association between sociodemographic and clinical factors and chemoprevention uptake. In our sample, 29.3% had atypical hyperplasia, 23.3% had LCIS, and 47.4% had DCIS; 29.4% used chemoprevention. Compared with women with atypical hyperplasia, LCIS [RR, 1.43; 95% confidence interval (CI), 1.16–1.76] and DCIS (RR, 1.54; 95% CI, 1.28–1.86) were significantly associated with chemoprevention uptake, as was medical oncology referral (RR, 5.79; 95% CI, 4.80–6.98). Younger women were less likely to take chemoprevention (RR, 0.61; 95% CI, 0.42–0.87), and there was a trend toward increased uptake in Hispanic compared with non-Hispanic white women. The survey data revealed a strong interest in learning about chemoprevention, but there were misperceptions in personal breast cancer risk and side effects of chemoprevention. Improving communication about breast cancer risk and chemoprevention may allow clinicians to facilitate informed decision-making about preventative therapy. Cancer Prev Res; 10(8); 434–41. ©2017 AACR.
Resistance of Enteric Viruses on Fomites
Authors: Alidjinou Enagnon Kazali , Sane Famara , Firquet Swan , Lobert Pierre-Emmanuel , Hober Didier
Published: June 2017

Human enteric viruses are associated with several clinical features, especially gastroenteritis. Large amounts of these viruses can be released in the environment and spread to people. Enteric viruses are nonenveloped viruses and have displayed good survival in the environment. They can be significantly resistant in food and water but also on fomites, and this is thought to play a role in transmission, leading to sporadic cases or outbreaks. The survival of enteric viruses on fomites relies on many factors including the virus itself, fomite properties, and extrinsic environmental factors such as temperature or relative humidity. Several reports in the literature have found an association with gastroenteritis cases or outbreaks and fomites naturally contaminated by enteric viruses. However, the study of virus survival following natural contamination is challenging, and most published studies are laboratory based, using experimental contamination. In addition, recent and detailed data on the resistance of each of the main enteric viruses on fomites are scarce. Many approaches, both physical and chemical, can be used to inactivate enteric viruses, the efficacy of which depends on the virus and the disinfection conditions.
Polycystic Kidney Disease and the Vasopressin Pathway
Authors: van Gastel Maatje D.A. , Torres Vicente E.
Published: June 2017

Vasopressin, also known as arginine vasopressin or antidiuretic hormone, plays a pivotal role in maintaining body homeostasis. Increased vasopressin concentrations, measured by its surrogate copeptin, have been associated with disease severity as well as disease progression in polycystic kidney disease (PKD), and in experimental studies vasopressin has been shown to directly regulate cyst growth. Blocking vasopressin effects on the kidney via the vasopressin V2-receptor and lower circulating vasopressin concentration are potential treatment opportunities that have been the subject of study in PKD in recent years. Treatment with vasopressin V2-receptor antagonist tolvaptan has been shown to inhibit disease progression in experimental studies, as well as in a large randomized controlled trial involving 1,445 patients with autosomal dominant PKD, lowering total kidney volume growth from 5.5 to 2.8%, and the slope of the reciprocal of the serum creatinine level from -3.81 to -2.61 mg per mL-1/year. Alternatively, lowering circulating vasopressin could delay disease progression. Vasopressin is secreted in response to an increased plasma osmolality, which in turn is caused by a low fluid or high osmolar intake. Other lifestyle factors, like smoking, increase vasopressin concentration. Here, we provide a comprehensive review of the physiology as well as pathophysiology of vasopressin in PKD, the promising effects of tolvaptan treatment, and potential synergistic or additive treatments in combination with tolvaptan. In this study, we also review current evidence regarding the effect of influencing disease progression in PKD by lifestyle changes, especially by fluid intake.
Under What Conditions do Water-Intervention Studies Significantly Improve Child Body Weight?
Authors: Stookey Jodi D.
Published: June 2017

There are particular conditions that may optimize the effects of drinking-water interventions on body weight change and risk of obesity. Strategic planning to create and sustain conditions for optimal effects of drinking water may maximize the impact of school-based interventions to reduce childhood obesity. This paper proposes questions about the target population, type of diet and activity level that will be maintained during the intervention, and planned intervention message(s). The proposed questions are motivated by conditions associated with significant effects of drinking water in randomized controlled trials. They are discussed in relation to conditions underlying the recently successful school-based drinking-water intervention in New York City. If conditions allow, school-based drinking-water interventions have the potential to efficiently benefit millions of children worldwide, who are at risk of becoming obese.
Relationship between Sodium Intake and Water Intake: The False and the True
Authors: Bankir Lise , Perucca Julie , Norsk Peter , Bouby Nadine , Damgaard Morten
Published: June 2017

Background: Generally, eating salty food items increases thirst. Thirst is also stimulated by the experimental infusion of hypertonic saline. But, in steady state, does the kidney need a higher amount of water to excrete sodium on a high than on a low sodium intake? This issue is still controversial. The purpose of this review is to provide examples of how the kidney handles water in relation to salt intake/output. It is based on re-analysis of previously published studies in which salt intake was adjusted to several different levels in the same subjects, and in databases of epidemiologic studies in populations on an ad libitum diet. Summary and Key Messages: These re-analyses allow us to draw the following conclusions: (1) In a steady state situation, the urine volume (and thus the fluid intake) remains unchanged over a large range of sodium intakes. The adaptation to a higher sodium excretion rests only on changes in urinary sodium concentration. However, above a certain limit, this concentration cannot increase further and the urine volume may then increase. (2) In population studies, it is not legitimate to assume that sodium is responsible for changes in urine volume, since people who eat more sodium also eat more of other nutrients leading to an increase in the excretion of potassium, urea and other solutes, besides sodium. (3) After an abrupt increase in sodium intake, fluid intake is increased in the first few days, but urine volume does not change. The extra fluid drunk is responsible for an increase in body weight.
A Case of T Cell Lymphoma Treated by Korean Medicine Therapy Alone
Authors: Jung Jun-Suk , Lee Dong-Hyun , Seong Shin , Kim Sung Su
Published: June 2017

This case report is aimed to investigate the effects of Korean medicine therapy (KMT) alone including oral herbal medicine on treating a patient with atypical peripheral CD4 T cell lymphoma. The oral medicine used is Hyunamdan made of heat-processed ginseng and Hangamdan S. An 87-year-old man who was diagnosed as having atypical peripheral CD4 T cell lymphoma on November 30, 2015 was treated with KMT from December 23, 2015 until October 22, 2016. The effectiveness of therapies was evaluated with PET-CT scan as well as the change of the main sign of lymphoma. The sizes of the right axillar and right external iliac lymph nodes decreased. These results suggest that KMT can be an effective method to treat atypical peripheral CD4 T cell lymphoma.
Trichoscopic Findings of Erosive Pustular Dermatosis of the Scalp Associated with Gefitinib
Authors: Fukui Tomohisa , Kitamura Hideo , Harada Ken , Nakano Hajime , Sawamura Daisuke
Published: June 2017

Alopecia associated with epidermal growth factor receptor (EGFR) inhibitor therapy is a rare cutaneous side effect with the potential to progress to scarring alopecia. Thus, dermatologists should make an early diagnosis. We present the case of a 57-year-old Japanese female with scarring alopecia associated with gefitinib, which is an EGFR inhibitor, including trichoscopic findings. The patient treated with gefitinib for non-small cell lung cancer experienced skin rash and hair loss of the scalp. The scalp lesions appeared similar to erosive pustular dermatosis of the scalp. Trichoscopic examination showed follicular keratotic plugging, milky red areas, white patches, hair shaft disorder, tapering hair, and absence of follicular opening. Histological examination showed ruptured hair follicles with a perifollicular infiltration of plasma cells, lymphocytes, and histiocytes. Oral minocycline and topical steroid treatment produced no improvement. With a reduction in the gefitinib dosage, alopecia gradually improved, although scarring remained. We consider these trichoscopic findings and suspect that follicular keratotic plugging might be a finding associated with scarring alopecia due to EGFR inhibitor therapy.
A Complicated Thread: Abdominal Actinomycosis in a Young Woman with Crohn Disease
Authors: Nahum Ari , Filice Gregory , Malhotra Ashish
Published: June 2017

Crohn disease is a chronic inflammatory condition that primarily affects the gastrointestinal tract. Typical manifestations include fever, weight loss, fatigue, and abdominal pain, and abdominal abscesses and fistulae are frequent complications. Abdominal actinomycosis is a subacute or indolent disease associated with Actinomyces spp. Symptoms can be very similar to those of Crohn disease, and fistulae are also common. Since ulcerations in the intestinal tract are thought to be caused by Actinomyces escaping from the gut lumen and establishing intra-abdominal infection, it seems likely that abdominal actinomycosis may occur in patients with inflammatory bowel disease. We report a case of abdominal actinomycosis in a woman with active Crohn disease.
Thyroid-Stimulating Hormone, Degree of Obesity, and Metabolic Risk Markers in a Cohort of Swedish Children with Obesity
Authors: Lundbäck Veroniqa , Ekbom Kerstin , Hagman Emilia , Dahlman Ingrid , Marcus Claude
Published: June 2017

Background/Aims: Thyroid-stimulating hormone (TSH) is affected in obesity and might influence metabolic risk. It is unclear what mechanisms cause elevated TSH in obesity. We aimed to investigate TSH status within the normal range and the association of TSH with degree of obesity and metabolic parameters in children with obesity. Methods: A total of 3,459 children, aged 3.0–17.9 years, were identified in the Swedish Childhood Obesity Treatment Registry, BORIS. Age, gender, TSH, free triiodothyronine (fT3), free thyroxine (fT4), body mass index standard deviation scores (BMI SDS), as well as variables of lipid and glucose metabolism were examined. Results: Children with high-normal TSH (>3.0 mU/L) (28.8%) had higher BMI SDS compared to children with low-normal TSH (<3.0 mU/L) (p < 0.001). Multivariable regression analysis adjusted for age and gender showed that TSH levels were associated with BMI SDS (β: 0.21, 95% CI: 0.14–0.28, p < 0.001). Associations of thyroid hormones with markers of lipid and glucose metabolism were observed, where TSH was associated with fasting insulin, HOMA (homeostatic model assessment of insulin resistance), total cholesterol, and triglycerides. Conclusions: A positive association between TSH levels and BMI SDS was seen in children with obesity. Associations of TSH and free thyroid hormones with glucose metabolism indicated that TSH might be one of several factors acting to determine body weight and obesity co-morbidities, although the underlying mechanism remains unclear.
Use of the Myocardial Performance Index in Decreased Fetal Movement Assessment: A Case-Control Study
Authors: Ho Daphne , Wang Jingjing , Homann Yvette , Alphonse Jennifer , Beirne Geraldene , Welsh Alec W. , Henry Amanda
Published: June 2017

Objectives: To determine whether there are any fetal cardiac function changes, as measured by the myocardial performance index (MPI), in pregnancies complicated by decreased fetal movement (DFM). Methods: We performed a prospective cross-sectional case-control study of 50 DFM and 50 uncomplicated third-trimester pregnancies matched within 2 gestational weeks. Routine ultrasound growth and well-being parameters as well as MPI were measured. Average MPI measurements and its component values were compared between the DFM and the control group, as were demographics, other ultrasound data, and perinatal outcomes. Results: Average left MPI (LMPI) and right MPI (RMPI) was similar between groups (LMPI: 0.54 ± 0.08 [DFM], 0.53 ± 0.08 [controls], p = 0.76; RMPI: 0.60 ± 0.12 (DFM), 0.59 ± 0.11 [controls], p = 0.79). However, subgroup analysis of DFM fetuses with (n = 20) or without (n = 30) any adverse perinatal outcome demonstrated modestly higher average RMPI and LMPI in the adverse perinatal outcome group (RMPI: 0.64 ± 0.08 vs. 0.57 ± 0.13, p = 0.02; LMPI: 0.56 ± 0.07 vs. 0.52 ± 0.07, p = 0.052). Conclusion: The MPI did not demonstrate clinically usable differences between the overall DFM population and controls. However, higher LMPI and RMPI values in the exploratory subgroup of DFM fetuses with adverse perinatal outcomes may warrant further exploration of the MPI in DFM.
Fluoropyrimidine-Associated Toxicity in Two Gastrointestinal Cancer Patients: Potential Role of Common DPYD Polymorphisms
Authors: Falvella Felicia Stefania , Luoni Marco , Cheli Stefania , Fava Sergio , Cergnul Massimiliano
Published: June 2017

While the majority of patients can be treated safely with fluoropyrimidine, some experience severe fluoropyrimidine-associated toxicity. The frequency and severity of these adverse events vary from patient to patient and are partially explained by genetic polymorphism into the dihydropyrimidine dehydrogenase (DPYD) gene. Carriers of the rare allelic variants DPYD*2A, DPYD*13, and DPYD D949V are more likely to experience severe adverse reactions during fluoropyrimidine-based therapy. However, these 3 genetic variants explain only a small percentage of the overall drug toxicity, and more frequent ones such as homozygous or compound heterozygous DPYD V732I can play a key role.
Erdheim-Chester Disease: Case Report with Aggressive Multisystem Manifestations and Review of the Literature
Authors: Alotaibi Sultan , Alhafi Osama , Nasr Hatem , Eltayeb Khalid , Elyamany Ghaleb
Published: June 2017

Erdheim-Chester disease (ECD) is an extremely rare and aggressive form of non-Langerhans cell histiocytosis. ECD usually presents with bone pain in adults aged 40–60. Its etiology is unknown but it is thought to be either a reactive or neoplastic disorder. Recently, mutation of the proto-oncogene BRAF (BRAFV600E) has been found in more than 50% of cases. The multisystemic form of ECD is associated with significant morbidity, which may arise due to histiocytic infiltration of critical organ systems. The common sites of involvement are the skeleton, central nervous system, cardiovascular system, lungs, retroperitoneum, and skin. Current available treatment is interferon alpha as the first line of treatment. Treatment with other agents is based on anecdotal case reports. Cladribine, anakinra, and vemurafenib (BRAF inhibitor) are currently advocated as promising second-line treatments for patients whose response to interferon alpha is unsatisfactory. Herein, we are reporting a middle-aged Saudi male patient with an aggressive type of ECD and highlighting the clinical, radiological, and pathological manifestations associated with ECD and the various treatment options and patient follow-up.
Interstitial Pneumonitis Secondary to Trastuzumab: A Case Report and Literature Review
Authors: Costa Ricardo , Costa-Filho Rubens B. , Talamantes Sarah M. , Queiroga Jr Fernando , Campello Emmanuel C. , Cartaxo Henrique , Costa Rubens B.
Published: June 2017

Interstitial lung disease is a rare complication of trastuzumab-based breast cancer treatment with few case reports published. Herein, we report the case of a 67-year-old female with early-stage HER2-postitive breast cancer who developed interstitial pneumonitis during cycle 5 of treatment with trastuzumab combined with carboplatin and docetaxel. After supportive care and treatment with prednisone, the patient showed rapid improvement of respiratory symptoms. Retreatment with trastuzumab as a single agent led to worsening of symptoms and required a second course of treatment with prednisone combined with cyclophosphamide, which was followed by improvement of symptoms. In conclusion, interstitial pneumonitis is a rare but life-threatening adverse event from trastuzumab breast cancer treatment.
Visual Evaluation of Medial Temporal Lobe Atrophy as a Clinical Marker of Conversion from Mild Cognitive Impairment to Dementia and for Predicting Progression in Patients with Mild Cognitive Impairment and Mild Alzheimer's Disease
Authors: Persson Karin , Barca Maria Lage , Eldholm Rannveig Sakshaug , Cavallin Lena , Šaltytė Benth Jūratė , Selbæk Geir , Brækhus Anne , Saltvedt Ingvild , Engedal Knut
Published: June 2017

Background/Aims: To evaluate whether visual assessment of medial temporal lobe atrophy (vaMTA) can predict 2-year conversion from mild cognitive impairment (MCI) to dementia and progression of MCI and Alzheimer's disease dementia as measured by the Clinical Dementia Rating Scale Sum of Boxes score (CDR-SB). Methods: vaMTA was performed in 94 patients with MCI according to the Winblad criteria and in 124 patients with AD according to ICD-10 and NINCDS-ADRDA criteria. Demographic data, the Consortium to Establish a Registry for Alzheimer's Disease 10-word delayed recall, APOE ɛ4 status, Cornell Scale for Depression in Dementia, and comorbid hypertension were used as covariates. Results: vaMTA was associated with MCI conversion in an unadjusted model but not in an adjusted model (p = 0.075), where delayed recall and APOE ɛ4 status were significant predictors. With CDR-SB change as the outcome, an interaction between vaMTA and diagnosis was found, but in the adjusted model only delayed recall and age were significant predictors. For vaMTA below 2, the association between vaMTA and CDR-SB change differed between diagnostic groups. Similar results were found based on a trajectory analysis. Conclusion: In adjusted models, memory function, APOE ɛ4 status and age were significant predictors of disease progression, not vaMTA. The association between vaMTA and CDR-SB change was different in patients with MCI and Alzheimer's disease dementia.
Erythema Gyratum Repens-Like Purpura in a Patient with Sjögren Syndrome
Authors: Fukunaga Miyuki , Harada Kazutoshi , Mae Kenichiro , Wakamatsu Kanae , Kiriyama Noriko , Tsuboi Ryoji , Okubo Yukari
Published: June 2017

The etiology of purpura in Sjögren syndrome (SS) includes cryoglobulinemia, hypergammaglobulinemia, and leukocytoclastic vasculitis (LCV). The clinical symptoms of LCV associated with SS comprise palpable or nonpalpable purpura and urticarial vasculitis. Here, we report a case of LCV presenting as erythema gyratum repens (EGR)-like purpura in a 62-year-old woman with rheumatoid arthritis and SS. EGR-like skin lesions, characterized by annular lesions with expanding concentric pattern and coalescing to form a zebra-like pattern or grain of wood pattern, can appear in various autoimmune conditions; however, EGR-like eruption in SS is extremely rare. On the basis of the expansion pattern, we considered that the EGR-like purpura in this case was elicited by urticarial vasculitis accompanied by SS.
Optimizing Quality of Life in Patients with Hormone Receptor-Positive Metastatic Breast Cancer: Treatment Options and Considerations
Authors: Chalasani Pavani
Published: June 2017

The treatment landscape for hormone receptor-positive metastatic breast cancer continues to evolve as the molecular mechanisms of this heterogeneous disease are better understood and targeted treatment strategies are developed. Patients are now living for extended periods of time with this disease as they progress through sequential lines of treatment. With a rapidly expanding therapeutic armamentarium, the prevalence of metastatic breast cancer patients with prolonged survival is expected to increase, as is the duration of survival. Practice guidelines recommend endocrine therapy alone as first-line therapy for the majority of patients with metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. The approval of new agents and expanded combination options has extended their use beyond first line, but endocrine therapy is not used as widely in clinical practice as recommended. As all treatments are palliative, even as survival is prolonged, optimizing and maintaining patient quality of life is crucial. This article surveys data relevant to the use of endocrine therapy in the setting of hormone receptor-positive metastatic breast cancer, including key clinical evidence regarding approved therapies and the impact of these therapies on patient quality of life.
Primary Type3 (Non-ABC, Non-GCB) Subtype of Extranodal Diffuse Large B-Cell Lymphoma of the Thyroid Bearing No MYD88 Mutation by Padlock Probe Hybridization
Authors: Nishi Yukiko , Kitazawa Riko , Haraguchi Ryuma , Ouchi Ayaka , Ueda Yasuo , Kamaoka Yuri , Yamamoto Ken , Todo Yasuhiko , Miyaoka Hiroaki , Kitazawa Sohei
Published: June 2017

Primary extranodal malignant lymphoma of the thyroid is a rare entity composed of mostly neoplastic transformation of germinal center-like B cells (GCB) or memory B cells. Other B-cell-type malignancies arising primarily in the thyroid have rarely been described. Immunohistochemical examination of autopsied primary malignant lymphoma of the thyroid in an 83-year-old Japanese female revealed the presence of a non-GCB subtype of diffuse large B-cell lymphoma (DLBCL) without the typical codon 206 or 265 missense mutation of MYD88. The lack of the highly oncogenic MYD88 gene mutation, frequently observed in DLBCL of the activated B-cell (ABC) subtype, and the detection of an extremely aggressive yet local clinical phenotype demonstrated that the present case was an exceptional entity of the type3 (non-GCB and non-ABC) subtype.
Pulmonary Vein Isolation Alone Versus Additional Linear Ablation in Patients With Persistent Atrial Fibrillation Converted to Paroxysmal Type With Antiarrhythmic Drug Therapy
Authors: Yu Hee Tae , Shim Jaemin , Park Junbeom , Kim In-Soo , Kim Tae-Hoon , Uhm Jae-Sun , Joung Boyoung , Lee Moon-Hyoung , Kim Young-Hoon , Pak Hui-Nam
Published: June 2017

Background—

Atrial fibrillation (AF) type can vary depending on condition and timing, and some patients who initially present with persistent AF may be changed to paroxysmal AF after antiarrhythmic drug medication and cardioversion. We investigated whether circumferential pulmonary vein isolation (CPVI) alone is an effective rhythm control strategy in patients with persistent AF to paroxysmal AF.

Methods and Results—

We enrolled 113 patients with persistent AF to paroxysmal AF (male 75%, 60.4±10.1 years old) who underwent catheter ablation for nonvalvular AF at 3 tertiary hospitals. The participants were randomly assigned to 2 groups: CPVI alone (n=59) or CPVI plus linear ablation (CPVI+Line; posterior box+anterior line, n=54). Compared with the CPVI+Line, CPVI alone required shorter procedure (187.2±58.0 versus 211.2±63.9 min;
P
=0.043) and ablation times (4922.1±1110.5 versus 6205.7±1425.2 s;
P
<0.001) without difference in procedure-related major complication (3% versus 2%;
P
=0.611). Antiarrhythmic drug utility rates after ablation were not different between the 2 groups (22% versus 30%;
P
=0.356). Overall, AF-free survival (log-rank;
P
=0.206) and AF and antiarrhythmic drug–free survival (log-rank;
P
=0.321) were not different between groups.

Conclusions—

CPVI alone is an effective rhythm control strategy with a shorter procedure time in persistent AF patients converted to paroxysmal AF compared with CPVI with linear ablation.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02176616.
Whole Exome Sequencing Identifies Truncating Variants in Nuclear Envelope Genes in Patients With Cardiovascular Disease
Authors: Haskell Gloria T. , Jensen Brian C. , Samsa Leigh Ann , Marchuk Daniel , Huang Wei , Skrzynia Cecile , Tilley Christian , Seifert Bryce A. , Rivera-Muñoz Edgar A. , Koller Beverly , Wilhelmsen Kirk C. , Liu Jiandong , Alhosaini Hassan , Weck Karen E. , Evans James P. , Berg Jonathan S.
Published: June 2017

Background—

The genetic variation underlying many heritable forms of cardiovascular disease is incompletely understood, even in patients with strong family history or early age at onset.

Methods and Results—

We used whole exome sequencing to detect pathogenic variants in 55 patients with suspected monogenic forms of cardiovascular disease. Diagnostic analysis of established disease genes identified pathogenic variants in 21.8% of cases and variants of uncertain significance in 34.5% of cases. Three patients harbored heterozygous nonsense or splice-site variants in the nucleoporin genes
NUP37
,
NUP43
, and
NUP188
, which have not been implicated previously in cardiac disease. We also identified a heterozygous splice site variant in the nuclear envelope gene
SYNE1
in a child with severe dilated cardiomyopathy that underwent transplant, as well as in his affected father. To confirm a cardiovascular role for these candidate genes in vivo, we used morpholinos to reduce
SYNE1, NUP37,
and
NUP43
gene expression in zebrafish. Morphant embryos displayed cardiac abnormalities, including pericardial edema and heart failure. Furthermore, lymphoblasts from the patient carrying a
SYNE1
splice-site variant displayed changes in nuclear morphology and protein localization that are consistent with disruption of the nuclear envelope.

Conclusions—

These data expand the repertoire of pathogenic variants associated with cardiovascular disease and validate the diagnostic and research use of whole exome sequencing. We identify
NUP37
,
NUP43
, and
NUP188
as novel candidate genes for cardiovascular disease, and suggest that dysfunction of the nuclear envelope may be an under-recognized component of inherited cardiac disease in some cases.
Association Between Mutation Size and Cardiac Involvement in Myotonic Dystrophy Type 1
Authors: Chong-Nguyen Caroline , Wahbi Karim , Algalarrondo Vincent , Bécane Henri Marc , Radvanyi-Hoffman Hélène , Arnaud Pauline , Furling Denis , Lazarus Arnaud , Bassez Guillaume , Béhin Anthony , Fayssoil Abdallah , Laforêt Pascal , Stojkovic Tanya , Eymard Bruno , Duboc Denis
Published: June 2017

Background—

In myotonic dystrophy type 1, the association between mutation size (CTG expansion) and the severity of cardiac involvement is controversial.

Methods and Results—

We selected 855 patients with myotonic dystrophy type 1 (women, 51%; median age, 37 years), with genetic testing performed at the moment of their initial cardiac evaluation, out of 1014 patients included in the Myotonic Dystrophy Type 1-Heart Registry between January 2000 and December 2015. We studied the association between CTG expansion size and other baseline characteristics and (1) cardiac involvement at baseline and (2) the incidence of death, sudden death, and other cardiac adverse events. At initial presentation, the median CTG expansion size was 530 (interquartile range, 300–830). In multivariate analysis, larger expansions were associated with the presence at baseline of conduction defects on the ECG and left ventricular systolic dysfunction. In a median 11.5 years of follow-up period, 210 patients died (25%), including 32 suddenly (4%). Supraventricular arrhythmias developed over lifetime in 166 patients (19%), sustained ventricular tachyarrhythmias in 17 (2%), and permanent pacemakers were implanted in 181 (21%). In Cox regression analyses, larger CTG expansions were significantly associated with (1) total death, sudden death, and pacemaker implantation in a model, including CTG expansion size, age, sex, diabetes mellitus, and (2) all end points except sudden death in a model including all baseline characteristics.

Conclusions—

The size of the CTG expansion in the blood of myotonic dystrophy type 1 patients is associated with total and sudden deaths, conduction defects, left ventricular dysfunction, and supraventricular arrhythmias.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique Identifier: NCT01136330
Genome-Wide Dynamics of Nascent Noncoding RNA Transcription in Porcine Heart After Myocardial Infarction
Authors: Kaikkonen Minna U. , Halonen Paavo , Liu Oscar Hsin-Fu , Turunen Tiia A. , Pajula Juho , Moreau Pierre , Selvarajan Ilakya , Tuomainen Tomi , Aavik Einari , Tavi Pasi , Ylä-Herttuala Seppo
Published: June 2017

Background—

Microarrays and RNA sequencing are widely used to profile transcriptome remodeling during myocardial ischemia. However, the steady-state RNA analysis lacks in sensitivity to detect all noncoding RNA species and does not provide separation between transcriptional and post-transcriptional regulations. Here, we provide the first comprehensive analysis of nascent RNA profiles of mRNAs, primary micro-RNAs, long noncoding RNAs, and enhancer RNAs in a large animal model of acute infarction.

Methods and Results—

Acute infarction was induced by cardiac catheterization of domestic swine. Nuclei isolated from healthy, border zone, and ischemic regions of the affected heart were subjected to global run-on sequencing. Global run-on sequencing analysis indicated that half of affected genes are regulated at the level of transcriptional pausing. A gradient of induction of inflammatory mediators and repression of peroxisome proliferator-activated receptor signaling and oxidative phosphorylation was detected when moving from healthy toward infarcted area. In addition, we interrogated the transcriptional regulation of primary micro-RNAs and provide evidence that several arrhythmia-related target genes exhibit repression at post-transcriptional level. We identified 450 long noncoding RNAs differently regulated by ischemia, including novel conserved long noncoding RNAs expressed in antisense orientation to myocardial transcription factors GATA-binding protein 4, GATA-binding protein 6, and Krüppel-like factor 6. Finally, characterization of enhancers exhibiting differential expression of enhancer RNAs pointed a central role for Krüppel-like factor, MEF2C, ETS, NFY, ATF, E2F2, and NRF1 transcription factors in determining transcriptional responses to ischemia.

Conclusions—

Global run-on sequencing allowed us to follow the gradient of gene expression occurring in the ischemic heart and identify novel noncoding RNAs regulated by oxygen deprivation. These findings highlight potential new targets for diagnosis and treatment of myocardial ischemia.
Sex Differences in Mortality Based on United Network for Organ Sharing Status While Awaiting Heart Transplantation
Authors: Hsich Eileen M. , Blackstone Eugene H. , Thuita Lucy , McNamara Dennis M. , Rogers Joseph G. , Ishwaran Hemant , Schold Jesse D.
Published: June 2017

Background—

There are sex differences in mortality while awaiting heart transplantation, and the reason remains unclear.

Methods and Results—

We included all adults in the Scientific Registry of Transplant Recipients placed on the heart transplant active waitlist from 2004 to 2015. The primary end point was all-cause mortality. Multivariable Cox proportional hazards models were performed to evaluate survival by United Network for Organ Sharing (UNOS) status at the time of listing. Random survival forest was used to identify sex interactions for the competing risk of death and transplantation. There were 33 069 patients (25% women) awaiting heart transplantation. This cohort included 7681 UNOS status 1A (26% women), 13 027 UNOS status 1B (25% women), and 12 361 UNOS status 2 (26% women). During a median follow-up of 4.3 months, 1351 women and 4052 men died. After adjusting for >20 risk factors, female sex was associated with a significant risk of death among UNOS status 1A (adjusted hazard ratio, 1.14; 95% confidence interval, 1.01–1.29) and UNOS status 1B (adjusted hazard ratio, 1.17; 95% confidence interval, 1.05–1.30). In contrast, female sex was significantly protective for time to death among UNOS status 2 (adjusted hazard ratio, 0.85; 95% confidence interval, 0.76–0.95). Sex differences in probability of transplantation were present for every UNOS status, and >20 sex interactions were identified for mortality and transplantation.

Conclusions—

When stratified by initial UNOS status, women had a higher mortality than men as UNOS status 1 and a lower mortality as UNOS status 2. With >20 sex interactions for mortality and transplantation, further evaluation is warranted to form a more equitable allocation system.
Design and Rationale of the Phase 3 ATTR-ACT Clinical Trial (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial)
Authors: Maurer Mathew S. , Elliott Perry , Merlini Giampaolo , Shah Sanjiv J. , Cruz Márcia Waddington , Flynn Alison , Gundapaneni Balarama , Hahn Carolyn , Riley Steven , Schwartz Jeffrey , Sultan Marla B. , Rapezzi Claudio
Published: June 2017

Transthyretin amyloidosis is a rare, life-threatening disease resulting from aggregation and deposition of transthyretin amyloid fibrils in various tissues. There are 2 predominate phenotypic presentations of the disease: transthyretin familial amyloid polyneuropathy, which primarily affects the peripheral nerves, and transthyretin cardiomyopathy (TTR-CM), which primarily affects the heart. However, there is a wide overlap with symptoms at presentation and disease course being highly variable and influenced by the underlying transthyretin mutation, age of the affected individual, sex, and geographic location. Treatment of transthyretin amyloidosis is typically focused on symptom management. Although tafamidis has been shown to delay neurologic progression of transthyretin familial amyloid polyneuropathy, there are no approved pharmacologic therapies shown to improve survival in TTR-CM. The natural history of TTR-CM is poorly characterized, which presents difficulties for the design of large-scale trials for new treatments. This review provides a brief overview of TTR-CM and the challenges of identifying clinically meaningful end points and study parameters to determine the efficacy of treatments for rare diseases. The design and rationale behind the ongoing phase 3 ATTR-ACT study (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), an international, multicenter, double-blind, placebo-controlled, randomized clinical trial, is also outlined. The ATTR-ACT study will provide important insight into the efficacy and safety of tafamidis for the treatment of TTR-CM.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01994889.
Pulmonary Hypertension Is Associated With a Higher Risk of Heart Failure Hospitalization and Mortality in Patients With Chronic Kidney Disease
Authors: Selvaraj Senthil , Shah Sanjiv J. , Ommerborn Mark J. , Clark Cheryl R. , Hall Michael E. , Mentz Robert J. , Qazi Saadia , Robbins Jeremy M. , Skelton Thomas N. , Chen Jiaying , Gaziano J. Michael , Djoussé Luc
Published: June 2017

Background—

African Americans develop chronic kidney disease and pulmonary hypertension (PH) at disproportionately high rates. Little is known whether PH heightens the risk of heart failure (HF) admission or mortality among chronic kidney disease patients, including patients with non–end-stage renal disease.

Methods and Results—

We analyzed African Americans participants with chronic kidney disease (estimated glomerular filtration rate <60 mL/min per 1.73 m
2
or urine albumin/creatinine >30 mg/g) and available echocardiogram-derived pulmonary artery systolic pressure (PASP) from the Jackson Heart Study (N=408). We used Cox models to assess whether PH (PASP>35 mm Hg) was associated with higher rates of HF hospitalization and mortality. In a secondary, cross-sectional analysis, we examined the relationship between cystatin C (a marker of renal function) and PASP and potential mediators, including BNP (B-type natriuretic peptide) and endothelin-1. In our cohort, the mean age was 63±13 years, 70% were female, 78% had hypertension, and 22% had PH. Eighty-five percent of the participants had an estimated glomerular filtration rate >30 mL/min per 1.73 m
2
. During follow-up, 13% were hospitalized for HF and 27% died. After adjusting for potential confounders, including BNP, PH was found to be associated with HF hospitalization (hazard ratio, 2.37; 95% confidence interval, 1.15–4.86) and the combined outcome of HF hospitalization or mortality (hazard ratio, 1.84; confidence interval, 1.09–3.10). Log cystatin C was directly associated with PASP (adjusted β =2.5 [95% confidence interval, 0.8–4.1] per standard deviation change in cystatin C). Mediation analysis showed that BNP and endothelin-1 explained 56% and 40%, respectively, of the indirect effects between cystatin C and PASP.

Conclusions—

Among African Americans with chronic kidney disease, PH, which is likely pulmonary venous hypertension, was associated with a higher risk of HF admission and mortality.