Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Superior Therapeutic Index in Lymphoma Therapy: CD30+ CD34+ Hematopoietic Stem Cells Resist a Chimeric Antigen Receptor T-cell Attack
Molecular Therapy 24, 1423 (August 2016). doi:10.1038/mt.2016.82
Authors: Andreas A Hombach, André Görgens, Markus Chmielewski, Florian Murke, Janine Kimpel, Bernd Giebel & Hinrich Abken
Call for papers: Nanoparticle Development and Applications in Cellular and Molecular Therapies
Molecular Therapy 24, 1334 (August 2016). doi:10.1038/mt.2016.164
Authors: Robert M. Frederickson, SM Moghimi, E Wagner & Seppo Yla-Herttuala
Corrigendum to "AAVR: A Multi-Serotype Receptor for AAV"
Molecular Therapy 24, 1502 (August 2016). doi:10.1038/mt.2016.113
In This Issue
Molecular Therapy 24, 1336 (August 2016). doi:10.1038/mt.2016.155
Safety and Immunogenicity of ChAd63 and MVA ME-TRAP in West African Children and Infants
Molecular Therapy 24, 1470 (August 2016). doi:10.1038/mt.2016.83
Authors: Muhammed O Afolabi, Alfred B Tiono, Uche J Adetifa, Jean Baptiste Yaro, Abdoulie Drammeh, Issa Nébié, Carly Bliss, Susanne H Hodgson, Nicholas A Anagnostou, Guillaume S Sanou, Ya Jankey Jagne, Oumarou Ouedraogo, Casimir Tamara, Nicolas Ouedraogo, Mirielle Ouedraogo, Jainaba Njie-Jobe, Amidou Diarra, Christopher JA Duncan, Riccardo Cortese, Alfredo Nicosia, Rachel Roberts, Nicola K Viebig, Odile Leroy, Alison M Lawrie, Katie L Flanagan, Beate Kampman, Philip Bejon, Egeruan B Imoukhuede, Katie J Ewer, Adrian VS Hill, Kalifa Bojang & Sodiomon B Sirima
Research Highlights
Molecular Therapy 24, 1337 (August 2016). doi:10.1038/mt.2016.156
Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics
Molecular Therapy 24, 1405 (August 2016). doi:10.1038/mt.2016.111
Authors: Jennifer CJ Chen, Oliver D King, Yuanfan Zhang, Nicholas P Clayton, Carrie Spencer, Bruce M Wentworth, Charles P Emerson & Kathryn R Wagner
Good Things Come in Threes: Genetically Engineered Neural Stem Cells Mitigate Chronic CNS Autoimmunity
Molecular Therapy 24, 1338 (August 2016). doi:10.1038/mt.2016.157
Author: David Pleasure
Intratumoral Infection with Murine Cytomegalovirus Synergizes with PD-L1 Blockade to Clear Melanoma Lesions and Induce Long-term Immunity
Molecular Therapy 24, 1444 (August 2016). doi:10.1038/mt.2016.121
Authors: Dan A Erkes, Guangwu Xu, Constantine Daskalakis, Katherine A Zurbach, Nicole A Wilski, Toktam Moghbeli, Ann B Hill & Christopher M Snyder
Like Angler Fish, CAARs Lure Their Prey
Molecular Therapy 24, 1339 (August 2016). doi:10.1038/mt.2016.165
Author: Anne Galy
A Phase l Study of a Tumor-targeted Systemic Nanodelivery System, SGT-94, in Genitourinary Cancers
Molecular Therapy 24, 1484 (August 2016). doi:10.1038/mt.2016.118
Authors: Arlene Siefker-Radtke, Xin-qiao Zhang, Charles C Guo, Yu Shen, Kathleen F Pirollo, Sharjeel Sabir, Chris Leung, Cindy Leong-Wu, Chi-Ming Ling, Esther H Chang, Randall E Millikan & William F Benedict
Oral Delivery of Protein Drugs Bioencapsulated in Plant Cells
Molecular Therapy 24, 1342 (August 2016). doi:10.1038/mt.2016.115
Authors: Kwang-Chul Kwon & Henry Daniell
Gene and Cell Therapies in Expansion Mode: ASGCT 2016
Molecular Therapy 24, 1333 (August 2016). doi:10.1038/mt.2016.154
Author: Cynthia E Dunbar
Long Non-coding RNA BGas Regulates the Cystic Fibrosis Transmembrane Conductance Regulator
Molecular Therapy 24, 1351 (August 2016). doi:10.1038/mt.2016.112
Authors: Sheena M Saayman, Amanda Ackley, Jon Burdach, Matthew Clemson, Dieter C Gruenert, Kiyoshi Tachikawa, Pad Chivukula, Marc S Weinberg & Kevin V Morris
Preclinical Justification of pbi-shRNA EWS/FLI1 Lipoplex (LPX) Treatment for Ewing's Sarcoma
Molecular Therapy 24, 1412 (August 2016). doi:10.1038/mt.2016.93
Authors: Donald D. Rao, Christopher Jay, Zhaohui Wang, Xiuquan Luo, Padmasini Kumar, Hilary Eysenbach, Maurizio Ghisoli, Neil Senzer & John Nemunaitis
Vastatin, an Endogenous Antiangiogenesis Polypeptide That Is Lost in Hepatocellular Carcinoma, Effectively Inhibits Tumor Metastasis
Molecular Therapy 24, 1358 (August 2016). doi:10.1038/mt.2016.56
Authors: Zan Shen, Chen Yao, Zifeng Wang, Lu Yue, Zheping Fang, Hong Yao, Feng Lin, Hui Zhao, Yuan-Jue Sun, Xiu-wu Bian, Wenqi Jiang, Xiaomei Wang, Yi Li, Gang Lu, Wai Sang Poon, Hsiang-Fu Kung & Marie Chia-mi Lin
Adenoviral Delivery of Tumor Necrosis Factor-α and Interleukin-2 Enables Successful Adoptive Cell Therapy of Immunosuppressive Melanoma
Molecular Therapy 24, 1435 (August 2016). doi:10.1038/mt.2016.137
Authors: Mikko Siurala, Riikka Havunen, Dipongkor Saha, Dave Lumen, Anu J. Airaksinen, Siri Tähtinen, Víctor Cervera-Carrascon, Simona Bramante, Suvi Parviainen, Markus Vähä-Koskela, Anna Kanerva & Akseli Hemminki
Structural Determinants of Sleeping Beauty Transposase Activity
Molecular Therapy 24, 1369 (August 2016). doi:10.1038/mt.2016.110
Authors: György Abrusán, Stephen R Yant, András Szilágyi, Joseph A Marsh, Lajos Mátés, Zsuzsanna Izsvák, Orsolya Barabás & Zoltán Ivics
Neural Stem Cells Engineered to Express Three Therapeutic Factors Mediate Recovery from Chronic Stage CNS Autoimmunity
Molecular Therapy 24, 1456 (August 2016). doi:10.1038/mt.2016.104
Authors: Xing Li, Yuan Zhang, Yaping Yan, Bogoljub Ciric, Cun-Gen Ma, Bruno Gran, Mark Curtis, Abdolmohamad Rostami & Guang-Xian Zhang
Genome Therapy of Myotonic Dystrophy Type 1 iPS Cells for Development of Autologous Stem Cell Therapy
Molecular Therapy 24, 1378 (August 2016). doi:10.1038/mt.2016.97
Authors: Yuanzheng Gao, Xiuming Guo, Katherine Santostefano, Yanlin Wang, Tammy Reid, Desmond Zeng, Naohiro Terada, Tetsuo Ashizawa & Guangbin Xia
Pectus excavatum results from dorsal deviation of the sternum causing narrowing of the anterior-posterior diameter of the chest. It can result in significant cosmetic deformities and cardiopulmonary compromise if severe. The Nuss procedure is a minimally invasive technique that involves placing a thin horizontally oriented metal bar below the dorsal sternal apex for correction of the pectus deformity.
To identify the frequency and types of Nuss bar migrations, to present a new categorization of bar migrations, and to present examples of true migrations and pseudomigrations.
We retrospectively reviewed the electronic medical records and all pertinent radiologic studies of 311 pediatric patients who underwent a Nuss procedure. We evaluated the frequency and type of bar migrations.
Bar migration was demonstrated in 23 of 311 patients (7%) and occurred within a mean period of 26 days after surgery. Bar migrations were subjectively defined as deviation of the bar from the position demonstrated on the immediate postoperative radiographs and categorized as superior, inferior, rotation, lateral or flipped using a new classification system. Sixteen of the 23 migrations required re-operation.
Nuss bar migration can be diagnosed with careful evaluation of serial radiographs. Nuss bar migration has a wide variety of appearances and requires exclusion of pseudomigration resulting from changes in patient positioning between radiologic examinations.
Monitoring the levels of malignant disease-causing cells in multiple myeloma, as opposed to the clinical symptoms alone, is an important move forward in the management of this disease. While current methods including multiparametric flow cytometry and PCR analysis of the clonal plasma cells can be used in a patient-specific manner, their use is limited and the fundamental malignant progenitor cell is not being monitored. The expression of cancer testis antigen MAGE C1 has been linked to the malignant stem cell in this disease, and thus, we investigated the use of both flow cytometric and qRTPCR approaches to monitor its expression as an alternative monitoring methodology in this pilot study.
We compared the levels of MAGE C1 in the peripheral blood to serum M protein and serum beta 2 microglobulin levels at 3-monthly intervals over a 2-year period, for 12 patients on chemotherapy regimens and 4 patients undergoing stem cell transplantation.
The analysis indicated that the novel flow cytometric analysis of MAGE C1 expression in the peripheral blood was extremely relevant as a potential minimal residual disease-monitoring tool. Expression of this cancer testis antigen was detectable in all patients throughout treatment, with comparable increases and decreases to serum M protein and/or serum beta 2 microglobulin, but with the advantage of being able to detect disease at a more sensitive level. Furthermore, due to the increased sensitivity, the ability to pre-empt disease relapse before clinical changes were evident, was preliminarily indicated. The qRTPCR approach showed potential as a monitoring tool in the chemotherapy patient cohort, with the mRNA MAGE C1 levels following a similar pattern of expression observed in the flow cytometry analysis.
African Americans have the highest incidence and mortality from colorectal cancer (CRC) of any US racial group. We recently described a panel of 15 genes that are statistically significantly more likely to be mutated in CRCs from African Americans than in Caucasians (AA-CRC genes). The current study investigated the outcomes associated with these mutations in African American CRCs (AA-CRCs). In a cohort of 66 patients with stage I-III CRCs, eight of 27 CRCs with AA-CRC gene mutations (Mut+) developed metastatic disease vs only four of 39 mutation-negative (Mut-) cases (P = .03, Cox regression model with two-sided Wald test). Moreover, among stage III cases (n = 33), Mut+ cancers were nearly three times more likely to relapse as Mut- cases (7 of 15 Mut+ vs 3 of 18 Mut-; P = .03, Cox regression model with two-sided Wald test). AA-CRC mutations may thus define a high-risk subset of CRCs that contributes to the overall disparity in CRC outcomes observed in African Americans.
Background: There is no validated, discriminating, and easy-to-apply tool for estimating risk of colorectal neoplasia. We studied whether the National Cancer Institute's (NCI's) Colorectal Cancer (CRC) Risk Assessment Tool, which estimates future CRC risk, could estimate current risk for advanced colorectal neoplasia among average-risk persons.
Methods: This cross-sectional study involved individuals age 50 to 80 years undergoing first-time screening colonoscopy. We measured medical and family history, lifestyle information, and physical measures and calculated each person's future CRC risk using the NCI tool's logistic regression equation. We related quintiles of future CRC risk to the current risk of advanced neoplasia (sessile serrated polyp or tubular adenoma ≥ 1 cm, a polyp with villous histology or high-grade dysplasia, or CRC). All statistical tests were two-sided.
Results: For 4457 (98.5%) with complete data (mean age = 57.2 years, SD = 6.6 years, 51.7% women), advanced neoplasia prevalence was 8.26%. Based on quintiles of five-year estimated absolute CRC risk, current risks of advanced neoplasia were 2.1% (95% confidence interval [CI] = 1.3% to 3.3%), 4.8% (95% CI = 3.5% to 6.4%), 6.4% (95% CI = 4.9% to 8.2%), 10.0% (95% CI = 8.1% to 12.1%), and 17.6% (95% CI = 15.5% to 20.6%; P < .001). For quintiles of estimated 10-year CRC risk, corresponding current risks for advanced neoplasia were 2.2% (95% CI = 1.4% to 3.5%), 4.8% (95% CI = 3.5% to 6.4%), 6.5% (95% CI = 5.0% to 8.3%), 9.3% (95% CI = 7.5% to 11.4%), and 18.4% (95% CI = 15.9% to 21.1%; P < .001). Among persons with an estimated five-year CRC risk above the median, current risk for advanced neoplasia was 12.8%, compared with 3.7% among those below the median (relative risk = 3.4, 95 CI = 2.7 to 4.4).
Conclusions: The NCI's Risk Assessment Tool, which estimates future CRC risk, may be used to estimate current risk for advanced neoplasia, making it potentially useful for tailoring and improving CRC screening efficiency among average-risk persons.
Gastric cancer ranks the fourth most prevalent malignancy yet it is the second leading cause of cancer-related death. Every year, gastric cancer adds nearly 1 million new cancer cases, and 723,000 or 10% of cancer deaths to the global cancer burden. Approximately, 405,000 or 43% of the new cases and 325,000 or 45% of the deaths are in China, making gastric cancer a particularly challenging malignancy. This thematic series discusses the molecular classifications of gastric cancer by the Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) as well as the implications in personalized therapeutic choices; discusses the evolution of gastric surgery and presents perspectives on surgical techniques in treating gastric cancer; and reviews current and emerging targeted agents as well as immunotherapies in treating gastric cancer. With these advancements in molecular characterization, surgical intervention, and targeted and immunotherapies, gastric cancer will enter a personalized medicine era in the next 5 years.
Gastric (including gastroesophageal junction) cancer is the third leading cause of cancer-related death in the world. In China, an estimated 420,000 patients were diagnosed with gastric cancer in 2011, ranking this malignancy the second most prevalent cancer type and resulting in near 300,000 deaths. The treatment landscape of gastric cancer has evolved in recent years. Although systemic chemotherapy is still the mainstay treatment of metastatic disease, the introduction of agents targeting human epidermal growth factor receptor 2 and vascular endothelial growth factor/vascular endothelia growth factor receptor has brought this disease into the molecular and personalized medicine era. The preliminary yet encouraging clinical efficacy observed with immune checkpoint inhibitors, e.g., anti-programmed cell death protein 1/programmed death-ligand 1, will further shape the treatment landscape for gastric cancer. Molecular characterization of patients will play a critical role in developing new agents, as well as in implementing new treatment options for this disease.
Many limited-resourced countries have either introduced cervical cancer screening programs or are contemplating to do so using visual inspection after acetic acid application (VIA) or human papillomavirus (HPV) detection tests. Both tests have high false-positivity and a suitable triaging strategy is required. Colposcopy triaging is not practicable in most resource-limited settings due to several reasons. We evaluated a portable, battery-operated, magnifying device (GynocularTM) to triage screen positive women in community setting in India.
Women positive on VIA or oncogenic HPV test were examined with Gynocular by clinicians in primary health clinics. Findings were documented using the International Federation for Cervical Pathology and Colposcopy (IFCPC) terminology. Swede score was also calculated. Biopsy was performed irrespective of Gynocular findings. The accuracy of Gynocular to detect high-grade lesions or cancer (HSIL+) was estimated. The suitability of Gynocular to correctly triage screen positive cases for immediate ablative treatment was also evaluated by creating simulated scenarios.
Sensitivity and specificity of Gynocular were 96.4 and 47.1 %, respectively, to detect HSIL + at the threshold of IFCPC grade 1 findings. Increasing threshold to grade 2 changed sensitivity and specificity to 92.9 and 94.1 %, respectively. Optimum combination of sensitivity and specificity as determined by the receiver operating curve analysis was at the cut-off Swede score of 5. Triaging of VIA/HPV positive women to treatment using grade 2 criteria would have resulted in modest overtreatment and missing of very few high-grade lesions.
Gynocular can be used as an effective triaging device for VIA/HPV positive women.
The objective of the study was to investigate hair trace elements content in children suffering from autism spectrum disorder (ASD). A total of 74 ASD children and 74 sex- and age-matched controls divided into two age groups (2–4 and 5–9 years) were investigated. Hair trace elements content was assessed using inductively coupled plasma mass spectrometry. A general cohort of ASD children was characterized by 29 %, 41 %, and 24 % lower hair levels of chromium (Cr), iodine (I), and vanadium (V), respectively, whereas the level of selenium (Se) exceeded the respective control values by 31 %. In ASD children aged 2–4 years hair Cr, I and V content was 68 %, 36 % and 41 % lower than in the controls. Older ASD children were characterized by 45 % increase in hair Se levels. In a general cohort of ASD children hair beryllium (Be) and tin (Sn) levels were 50 % and 34 % lower than the control values. In the first age group (2–4 years) of ASD children 34 %, 42 %, and 73 % lower levels of arsenic (As), boron (B), and Be were detected. In the second age group of ASD children only a nearly significant 25 % decrease in hair lead (Pb) was detected. Surprisingly, no significant group difference in hair mercury (Hg), zinc (Zn), and copper (Cu) content was detected. Generally, the results of the present study demonstrate that children with ASD are characterized by lower values in hair of not only essential but also toxic trace elements.
This retrospective study was undertaken to analyze the effectiveness and safety of surgery combined with postoperative 125I seed brachytherapy in the treatment of mucoepidermoid carcinoma (MEC) of the parotid gland with risk factors in pediatric patients.
From September 2002 to January 2012, 24 patients, ages 5–16 years (mean, 13.2 years; median, 12.3 years), with MEC of the parotid gland were included. Patients with high risk factors received 125I seed brachytherapy (median actuarial D90, 97 Gy) within 4 weeks following surgery. Radioactivity was 18.5–33.3 MBq per seed and the prescription dose was 60–120 Gy. Overall and disease-free survival rates, local control rate, and distant metastasis were recorded. Radiation-associated late side effects, including dermatitis, hearing loss, thyroid nodules, and secondary malignancy, were also evaluated.
During the follow-up period of 5–13.4 years (median, 7.2 years), the overall and disease-free survival rates were all 100%. No patients developed local recurrence, regional/distant metastasis, and no severe radiation-associated complications including the second malignancy were noted.
Surgery combined with postoperative 125I seed brachytherapy is effective and safe in the treatment of MEC of the parotid gland in pediatric patients, with no evidence of severe late radiation-related complications. More patients and longer follow-up data are still needed to prove the efficacy of 125I brachytherapy.
Ultrasound-guided (USG) cannulation of the brachiocephalic vein (BCV) is gaining worldwide consensus for central venous access in children. This study reports a 20-month experience with this approach in children.
All patients who underwent percutaneous USG central venous catheter (CVC) positioning in the BCV between August 2013 and March 2015 have been included. Devices inserted during this period were open-ended, either single or double-lumen tunneled CVC. Our series was divided into three consecutive study periods in order to determine the relative incidence of repositioning and complications.
During the study period, a total of 95 patients underwent 109 CVC insertions in the BCV. The median length of CVC duration was 230 days for a total of 23,212 catheter days. No major intraoperative complications occurred. Overall rate of CVC-related postoperative complications requiring repositioning or precocious removal was 0.90 per 1,000 catheter days and involved 21 CVC (19%, 95% confidence interval 13–28). These included 18 dislodgments, two infections, and one malfunction. Double-lumen CVCs represented the only significant risk factor for complications (52% complications—three per 1,000 catheter days).
USG supraclavicular cannulation of the BCV represents a safe approach for central line placement in children. It proved to be versatile, as it can be used in premature infants as well as in adolescents. Provided it is adopted by operators experienced in USG cannulation, we strongly suggest to resort to this approach as a first-line choice in children undergoing tunnelled central line placement for long-lasting therapy.
To study the prevalence of pediatric cancer patients who have underlying inherited bone marrow failure syndrome (IBMFS), we retrospectively reviewed the medical records of newly diagnosed pediatric cancer patients at The Hospital for Sick Children from June 2009 to May 2010, focusing on clinical, laboratory, and treatment-related findings which may indicate underlying IBMFS. We found five (1.8%) patients out of 276 who had two or more findings suggestive of IBMFS. We conclude that a small fraction of patients with cancer have clinical features that indicate investigations to rule out underlying IBMFSs. A prospective study is needed to determine their prevalence.
Iron overload is well documented in patients with β-thalassemia major, and patients who have undergone hematopoietic stem cell transplantation (HSCT) remain at risk as a result of pre- and immediate post-HSCT transfusions.
This is a prospective, randomized, 1-year clinical trial that compares the efficacy and safety of the once-daily oral iron chelator deferasirox versus phlebotomy for the treatment of iron overload in children with β-thalassemia major following HSCT.
Patients (aged 12.4 years) received deferasirox (n = 12, 10 mg/kg/day starting dose) or phlebotomy (n = 14, 6 ml/kg/2 weeks) for 1 year. In two and five patients, deferasirox dose was increased to 15 and 20 mg/kg/day, respectively. Magnetic resonance imaging (MRI)–assessed liver iron concentration (LIC) decreased with deferasirox (mean 12.5 ± 10.1 to 8.5 ± 9.3 mg Fe/g dry weight [dw]; P = 0.0005 vs. baseline) and phlebotomy (10.2 ± 6.8 to 8.3 ± 9.2 mg Fe/g dw; P = 0.05). LIC reductions were greater with deferasirox than with phlebotomy for patients with baseline serum ferritin 1,000 ng/ml or higher (–8.1 ± 1.5 vs. –3.5 ± 5.7 mg Fe/g dw; P = 0.048). Serum ferritin and non-transferrin-bound iron also decreased significantly. In two patients with severe cardiac siderosis, a clinically relevant improvement in myocardial T2* was seen, following phlebotomy and deferasirox therapy (n = 1 each). Adverse effects with deferasirox were skin rash, gastrointestinal upset, and increased liver function tests (all n = 1), while those for phlebotomy were difficulty with venous access (n = 4) and distress during procedure (n = 1). Parents of 13/14 children receiving phlebotomy wished to switch to deferasirox, with 1/14 being satisfied with phlebotomy.
Deferasirox treatment or phlebotomy reduces iron burden in pediatric patients with β- thalassemia major post-HSCT, with a manageable safety profile.
Nelarabine has been used for the treatment of T-cell malignancies including T-acute lymphoblastic leukemia (T-ALL)/T-lymphoblastic lymphoma. However, the mechanisms that underlie the susceptibility or resistance to nelarabine have not been fully elucidated. The aim of this study was to determine the significance of nelarabine transport and metabolism in the context of nelarabine cytotoxicity.
The expression profiles of six genes in the nelarabine pathway were analyzed in blast cells from six patients with T-ALL as well as in three T-ALL cell lines. In vitro cytotoxicity (LC50 of 9-β-d-arabinofuranosylguanine [ara-G]) was evaluated.
The mRNA expression of ENT1, DCK, CDA, NT5C2, RRM1, and RRM2 in patients showed inter-individual variability and was not correlated with the LC50 of ara-G. However, the ratio of (ENT1 × DCK)/(CDA × RRM1) expression was significantly correlated with LC50 (r = –0.831, P = 0.0405).
Chemosensitivity to nelarabine is influenced by the balance of the expression of these four genes, and the ratio of their expression predicts the response of T-cell malignancies to nelarabine.
Childhood cancer survivors (CCSs) are at high risk of morbidity and mortality from long-term complications of their cancer treatment. The Children's Oncology Group developed screening guidelines to enable the early identification of and intervention for late effects of cancer treatment. There is a paucity of data on the adherence of CCSs to screening recommendations.
A retrospective analysis of medical records to evaluate the rate of adherence of CCSs to the personalized, risk-based recommendations provided to them in the context of a structured long-term follow-up program over a 3-year period.
Two hundred eighty-six CCSs visited the survivorship clinic 542 times during the 3-year study period. The overall rate of adherence to recommended screening was 74.2%. Using a univariate model and greater age at diagnosis and at screening recommendation were associated with decreased screening adherence. Gender, cancer diagnosis, radiation therapy, anthracycline exposure, and hematopoietic stem cell transplant were not significantly associated with adherence. In a multivariate model, age over 18 years at the time of the visit was significantly associated with decreased adherence (P < 0.0329) (odds ratio: 1.53, 95% confidence interval: 1.04–2.25).
Adherence to recommended screening tests is suboptimal among CCSs, with lower rates of adherence in CCSs older than 18 years of age compared with those younger than 18 years of age. Given the morbidity and mortality from the late effects of therapy among young adult CCSs, it is critically important to identify and remove barriers to late-effects screening among CCSs.
Optimal cancer care requires a multidisciplinary approach. The purpose of the current study was to evaluate the impact of a multidisciplinary tumor board on the treatment plans of children with solid tumors.
The records of 158 consecutive patients discussed at a formal multidisciplinary pediatric tumor board between July 2012 and April 2014 were reviewed. Treatment plans were based on clinical practice guidelines and on current Children's Oncology Group protocols. Alterations in radiologic, pathologic, surgical, and medical interpretations were analyzed to determine the impact on changes in recommendations for clinical management.
Overall, 55 of 158 children (35%) had alterations in radiologic, pathologic, medical, or surgical interpretation of clinical data following multidisciplinary discussion. Of these, 64% had changes to the initial recommendation for clinical management. Review of imaging studies resulted in interpretation changes in 30 of 158 patients studied (19%), with 12 clinical management changes. Six of 158 patients (3.9%) had changes in pathologic interpretation, with four patients (2.5%) requiring treatment changes. In eight patients (5%), a change in medical management was recommended, while in 11 patients (7%) there were changes in surgical management that were based solely on discussion and not on interpretation of imaging or pathology.
Formal multidisciplinary review led to alterations in interpretation of clinical data in 35% of patients, and the majority led to changes in recommendations for treatment. Comprehensive multidisciplinary tumor board incorporated into the care of children with cancer provides additional perspectives for families and care providers when delineating optimal treatment plans.
Despite similarities in upfront treatment of childhood cancer, not every adult survivor of childhood cancer (CCS) has an impaired bone mineral density (BMD). No data are available on the role of genetic variation on impairment of BMD in CCS.
This cross-sectional single-center cohort study included 334 adult CCSs (median follow-up time after cessation of treatment: 15 years; median age at follow-up: 26 years). Total body BMD (BMDTB) and lumbar spine BMD (BMDLS) were measured by dual x-ray absorptiometry. We selected 12 candidate single-nucleotide polymorphisms (SNPs) in 11 genes (COL1A1, TNFSF11, TNFRSF11, TNRFSA11B, VDR, ESR1, WLS, LRP5, MTHFR, MTRR, IL-6).
Multivariate analyses revealed that lower BMD was associated with lower weight and height at follow-up, male sex, and previously administered radiotherapy. Survivors with the homozygous minor allele (GG) genotype of rs2504063 (ESR1: estrogen receptor type 1) had a lower BMDTB values (–1.16 vs. –0.82; P = 0.01) than those with the AG/AA genotype; however, BMDLS was not different. Carriers of two minor alleles (GG) of rs599083 (LRP5: low-density lipoprotein receptor) revealed lower BMDTB (–1.20 vs. –0.78; P = 0.02) and lower BMDLS (–0.95 vs. –0.46; P = 0.01) values than those with the TT/TG genotype.
CCSs who are carriers of candidate SNPs in the ESR1 or LRP5 genes seem to have an impaired bone mass at an early adult age. Information on genetic variation, in addition to patient- and treatment-related factors, may be helpful in identifying survivors who are at risk for low bone density after childhood cancer treatment.
Pegylated-asparaginase (PEG-ASP) is a critical treatment for pediatric acute lymphoblastic leukemia (ALL) and has traditionally been delivered via intramuscular (IM) injection. In an attempt to reduce pain and anxiety, PEG-ASP has increasingly been delivered via intravenous (IV) administration. The study objective was to perform a meta-analysis and systematic review to compare and generate pooled hypersensitivity rates for IM and IV PEG-ASP.
A systematic literature search was conducted for all epidemiological studies that investigated IV and IM hypersensitivity rates for pediatric ALL. Included studies were critically appraised using the GRACE checklist. Pooled estimates and odds ratios with 95% confidence intervals (CIs) for IM and IV hypersensitivity rates were derived based on either a random or fixed effects model.
Four studies satisfied the inclusion criteria and were of adequate quality. The random effects pooled hypersensitivity rates were 23.5% (95% CI 14.7–33.7) and 8.7% (95% CI 5.4–12.8) for IV and IM, respectively. The fixed effects pooled odds ratio after adjusting for publication bias was 2.49 (95% CI 1.62–3.83), indicating a significantly higher risk of hypersensitivity for IV over IM PEG-ASP. This risk is far more pronounced for high-risk (HR) patients compared with standard-risk (SR) patients (IV vs. IM: HR 35.2% and SR
2.9%).
Although administering PEG-ASP through IV is preferable for patients, it poses a significantly higher risk of hypersensitivity when compared with IM administration, especially for HR patients. We recommend pediatric oncologists consider treating patients with HR pediatric ALL with IM PEG-ASP to reduce the risk of hypersensitivity.
Interindividual variability in thiopurine-related toxicity could not be completely explained by thiopurine S-methyltransferase (TPMT) polymorphisms, as a number of patients who are homozygous wild type or normal for TPMT still develop toxicity that necessitates 6-mercaptopurine (MP) dose reduction or protocol interruption. Recently, few studies reported on an inherited nucleoside diphosphate-linked moiety X motif 15 (NUDT15) c.415C>T low-function variant that is associated with decreased thiopurine metabolism and leukopenia in childhood acute lymphoblastic leukemia (ALL) and other diseases.
The aim of this study is to measure the frequency of TPMT and NUDT15 polymorphisms and assess whether they are predictors of MP intolerance in children treated for ALL. One hundred thirty-seven patients with ALL of whom 121 were Lebanese were evaluated. MP dose intensity was calculated as the ratio of the tolerated MP dose to planned dose during continuation phase to maintain an absolute neutrophil count (ANC) dose above 300 per μl.
One patient was NUDT15 heterozygous TC and tolerated only 33.33% of the planned MP dose, which was statistically significantly different from the median-tolerated MP dose intensity of the rest of the cohort (76.00%). Three patients had the TPMT*3A haplotype and tolerated 40.00–66.66% of the planned MP dose, which was also statistically significantly different from the rest of the cohort.
This is the first report on the association of TPMT and NUDT15 polymorphisms with MP dose intolerance in Arab patients with ALL. Genotyping for additional polymorphisms may be warranted for potential gene/allele-dose effect.
Adolescent brothers were diagnosed with testicular germ cell tumors within the same month. Both were found to have multiple renal cysts on pretreatment imaging done for staging. The proband, his brother, and their mother, were all found to have a novel splice variant in intron 8 of the PKD1 gene by clinical exome sequencing. This is the second family reported with both familial testicular germ cell tumor (FTGCT) and autosomal dominant polycystic kidney disease (ADPKD), and the first described association of FTGCT with a splice variant in PKD1. We suggest that this novel variant in PKD1 may convey increased risk for FTGCT in addition to causing ADPKD.
The aim of the study was to compare the two irradiation modes with (FF) and without flattening filter (FFF) for three different treatment techniques for simultaneous integrated boost radiation therapy of patie...
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The use of imaging in colorectal cancer (CRC) has significantly evolved over the last twenty years, establishing important roles in surveillance, diagnosis, staging, treatment selection and follow up. The range of modalities has broadened with the development of novel tracer and contrast agents, and the fusion of technologies such as positron emission tomography (PET) and computed tomography (CT). Traditionally, the most widely used modality for assessing treatment response in metastasised colon and rectal tumours is CT, combined with use of the RECIST guidelines. However, a growing body of evidence suggests that tumour size does not always adequately correlate with clinical outcomes. Magnetic resonance imaging (MRI) is a more versatile technique and dynamic contrast-enhanced (DCE)-MRI and diffusion-weighted (DW)-MRI may be used to evaluate biological and functional effects of treatment. Integrated fluorodeoxyglucose (FDG)-PET/CT combines metabolic and anatomical imaging to improve sensitivity and specificity of tumour detection, and a number of studies have demonstrated improved diagnostic accuracy of this modality in a variety of tumour types, including CRC. These developments have enabled the progression of treatment strategies in rectal cancer and improved the detection of hepatic metastatic disease, yet are not without their limitations. These include technical, economical and logistical challenges, along with a lack of robust evidence for standardisation and formal guidance. In order to successfully apply these novel imaging techniques and utilise their benefit to provide truly personalised cancer care, advances need to be clinically realised in a routine and robust manner.
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Adherence to cancer prevention recommendations has been associated with lower incidence of breast cancer in previous studies, but evidence in African American women is limited. This project evaluated the association between adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations and breast cancer incidence among African American women. The Black Women's Health Study (analytic cohort=49,103) is an ongoing prospective cohort study of African American women, ages 21-69 years at baseline (1995). Adherence scores for seven WCRF/AICR recommendations (adherent=1, partial adherence=0.5, non-adherence=0) were calculated using questionnaire data and summed for overall (Maximum=7) and diet only (Maximum=5) scores. Associations between baseline and time-varying adherence scores and breast cancer incidence (N=1,827 incident cases through 2011) were evaluated using proportional hazards regression. In this cohort, 8.5% adhered >4 recommendations. Adherence at baseline was not associated with breast cancer incidence. Higher overall time-varying adherence (per 0.5 point increase) was associated with lower breast cancer incidence (HR: 0.90, 95% CI: 0.84-0.96). Adherence to physical activity, sugar beverage, and red and processed meat recommendations were also associated with reduced risk. Adherence to the WCRF/AICR recommendations was low and may be associated with lower breast cancer incidence in African American women. This article is protected by copyright. All rights reserved.
Background: Mechanisms of acquired resistance to trastuzumab-based treatment in gastric cancer are largely unknown.
Patients and Methods: In this study, we analysed 22 pairs of tumor samples taken at baseline and post-progression in patients receiving chemotherapy and trastuzumab for advanced HER2-positive (immunohistochemistry [IHC] 3+ or 2+ with in-situ hybridization [ISH] amplification) gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over-expression were defined as post-trastuzumab IHC score <3+ and absence of ISH amplification, and IHC "downscoring" from 2+/3+ to 0/1+, respectively.
Results: HER2 IHC was always performed, while ISH was missing in 3 post-progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over-expression was observed in 32% and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinico-pathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80% vs. 14%; p=0.008) and HER2 over-expression (63% vs. 14%; p=0.025).
Conclusion: As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab-based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti-HER2 second-line strategies in initially HER2-positive disease. This article is protected by copyright. All rights reserved.
The Piwi-piRNA pathway is important for germ cell maintenance, genome integrity, DNA methylation and retrotransposon control and thus may be involved in cancer development. In the present study, we comprehensively analyzed prognostic roles of 3,116 common SNPs in PIWI-piRNA pathway genes in melanoma disease-specific survival. A published genome-wide association study (GWAS) by The University of Texas M.D. Anderson Cancer Center was used to identify associated SNPs, which were later validated by another GWAS from the Harvard Nurses' Health Study and Health Professionals Follow-up Study. After multiple testing correction, we found that there were 27 common SNPs in two genes (PIWIL4 and DCP1A) with false discovery rate < 0.2 in the discovery dataset. Three tagSNPs (i.e., rs7933369 and rs508485 in PIWIL4; rs11551405 in DCP1A) were replicated. The rs11551405 A allele, located at the 3' UTR microRNA binding site of DCP1A, was associated with an increased risk of melanoma disease-specific death in both discovery dataset [adjusted Hazards ratio (HR) = 1.66, 95% confidence interval (CI) = 1.21-2.27, P =1.50 × 10−3] and validation dataset (HR = 1.55, 95% CI = 1.03-2.34, P = 0.038), compared with the C allele, and their meta-analysis showed an HR of 1.62 (95% CI,1.26-2.08, P =1.55 × 10−4). Using RNA-seq data from the 1000 Genomes Project, we found that DCP1A mRNA expression levels increased significantly with the A allele number of rs11551405. Additional large, prospective studies are needed to validate these findings. This article is protected by copyright. All rights reserved.
Future Oncology Ahead of Print.
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Next Generation Sequencing (NGS) has become a valuable tool for molecular landscape characterization of cancer genomes, leading to a better understanding of tumor onset and progression, and opening new avenues in translational oncology. Formalin-fixed paraffin-embedded (FFPE) tissue is the method of choice for storage of clinical samples, however low quality of FFPE genomic DNA (gDNA) can limit its use for downstream applications.
To investigate the FFPE specimen suitability for NGS analysis and to establish the performance of two solution-based exome capture technologies, we compared the whole-exome sequencing (WES) data of gDNA extracted from 5 fresh frozen (FF) and 5 matched FFPE lung adenocarcinoma tissues using: SeqCap EZ Human Exome v.3.0 (Roche NimbleGen) and SureSelect XT Human All Exon v.5 (Agilent Technologies).
Sequencing metrics on Illumina HiSeq were optimal for both exome systems and comparable among FFPE and FF samples, with a slight increase of PCR duplicates in FFPE, mainly in Roche NimbleGen libraries. Comparison of single nucleotide variants (SNVs) between FFPE-FF pairs reached overlapping values >90 % in both systems. Both WES showed high concordance with target re-sequencing data by Ion PGM™ in 22 lung-cancer genes, regardless the source of samples. Exon coverage of 623 cancer-related genes revealed high coverage efficiency of both kits, proposing WES as a valid alternative to target re-sequencing.
High-quality and reliable data can be successfully obtained from WES of FFPE samples starting from a relatively low amount of input gDNA, suggesting the inclusion of NGS-based tests into clinical contest. In conclusion, our analysis suggests that the WES approach could be extended to a translational research context as well as to the clinic (e.g. to study rare malignancies), where the simultaneous analysis of the whole coding region of the genome may help in the detection of cancer-linked variants.
Human epidermal growth factor receptor-2 (HER2) is a transmembrane tyrosine kinase receptor that is overexpressed in 25 to 30 % of human breast cancers and is preferentially localized in lipid rafts. Stomatin is a membrane protein that is absent from the erythrocyte plasma membrane in patients with congenital stomatocytosis and is the major component of the lipid raft.
In a total of 68 clinical cases of HER2-positive breast cancer, the absence of stomatin expression was associated with a decreased 5-year survival (65 % vs. 93 %, p = 0.005) by survival analysis. For stage I-III HER2-positive breast cancer, the absence of stomatin expression was associated with a decreased 5-year disease-free survival (57 % vs. 81 %, p = 0.016) and was an independent prognostic factor by multivariate analysis. Negative stomatin expression predicts distant metastases in a hazard ratio of 4.0 (95 % confidence interval from 1.3 to 12.5).
These results may suggest that stomatin is a new prognostic indicator for HER2-positive breast cancer.
Ganglioneuroma is a rare benign tumor originating from the sympathetic nerves, and its origination from the trigeminal nerves is even rarer. Only 4 cases of ganglioneuroma originating from the trigeminal nerve have previously been reported, and these studies only reported conventional MRI manifestations. To our knowledge, the advanced MRI features of trigeminal ganglioneuroma have not been reported thus far.
This study reports a case of trigeminal ganglioneuroma in the left cerebellopontine angle. Advanced MRI showed the following tumor characteristics: significantly increased perfusion on perfusion imaging; isointense on diffusion-weighted imaging, whorled appearance within the tumor and no significant signs of damage to the white matter fiber tracts in the fractional anisotropy color map, and compare to the adjacent brain tissue, Choline didn't show markedly elevation, and N-acetylaspartate peak showed slightly reduction on magnetic resonance spectroscopy. The tumor was completely resected, and the diagnosis of ganglioneuroma was confirmed by postoperative pathological examination.
This case demonstrates the conventional as well as advanced MRI manifestations of this rare extra-axial tumor, which have never been previously reported. In addition, we reviewed the literature to demonstrate the advanced MRI features of trigeminal ganglioneuroma, in order to aid preoperative diagnosis and differentiation.
The Cancer Rehabilitation Evaluation System (CARES) is a quality of life (QOL) and needs assessment instrument of US origin that was developed in the 90's. Since November 2012 the copyright and user fee were abolished and the instrument became publicly available the present study aims to reinvestigate the psychometric properties of the CARES for the Flemish population in Belgium.
The CARES was translated into Flemish following a translation-back translation process. A sample of 192 cancer patients completed the CARES, concurrent measures, and questions on socio-demographic and medical data. Participants were asked to complete the CARES a second time 1 week later, followed by some questions on their experiences with the instrument. Internal consistency, test-retest reliability, content validity, construct validity, concurrent validity and feasibility of the CARES were subsequently assessed.
The Flemish CARES version demonstrated excellent reliability with high internal consistency (range .87–.96) and test-retest ratings (range .70–.91) for all summary scales. Factor analysis replicated the original factor solution of five higher order factors with factor loadings of .325–.851. Correlations with other instruments ranging from |.43|–|.75| confirmed concurrent validity. Feasibility was indicated by the low number of missing items (mean 2.3; SD 5.0) and positive feedback of participants on the instrument.
The Flemish CARES has strong psychometric properties and can as such be a valid tool to assess cancer patients' QOL and needs in research, for example in international comparisons. The positive feedback of participants on the CARES support the usefulness of this tool for systematic assessment of cancer patients' well-being and care needs in clinical practice.
ClinicalTrials.gov: NCT02282696 (July 16, 2014).
Pathologic complete response (pCR) after neoadjuvant chemotherapy for breast cancer is associated with improved prognosis in aggressive tumor subtypes, including ERBB2- positive tumors. Recent adoption of pCR as a surrogate endpoint for clinical trials in early stage breast cancer in the neoadjuvant setting highlights the need for biomarkers that, alone or in combination, help predict the likelihood of response to treatment.
Biopsy specimens from 29 patients with invasive ductal carcinoma treated with trastuzumab-based therapy prior to definitive resection and pathologic staging were evaluated by dual color bright field in situ hybridization (dual ISH) using probes for MET, TOP2A, PTEN, and PIK3CA genes, each paired with centromeric probes to their respective chromosomes (chromosomes 7, 17, 10, and 3). Ki-67 expression was assessed by immunohistochemistry (IHC). Various parameters describing copy number alterations were evaluated for each gene and centromere probe to identify the optimal parameters for clinical relevance. Combinations of ISH parameters and IHC expression for Ki-67 were also evaluated.
Of the four genes and their respective chromosomes evaluated by ISH, two gene copy number parameters provided statistically significant associations with pCR: MET gain or loss relative to chromosome 7 (AUC = 0.791, sensitivity = 92 % and specificity = 67 % at optimal cutoff, p = 0.0032) and gain of PTEN (AUC = 0.674, sensitivity = 38 % and specificity = 100 % at optimal cutoff, p = 0.039). Ki-67 expression was also found to associate significantly with pCR (AUC = 0.726, sensitivity = 100 % and specificity = 42 % at optimal cutoff, p = 0.0098). Combining gain or loss of MET relative to chromosome 7 with Ki-67 expression further improved the association with pCR (AUC = 0.847, sensitivity = 92 % and specificity = 83 % at optimal cutoffs, p = 0.0006).
An immunogenotypic signature of low complexity comprising MET relative copy number and Ki-67 expression generated by dual ISH and IHC may help predict pCR in ERBB2-positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab. These findings require validation in additional patient cohorts.
To date, no guideline is proposed for elderly nasopharyngeal carcinoma (NPC) due to lack of prospective clinical trials. The present study comparing the survivals and toxicities in elderly NPC patients received either induction chemotherapy followed by radiotherapy(IC + RT) or concurrent chemoradiotherapy (CCRT) was therefore undertaken to provide a more accurate basis for future clinical practice.
The eligible elderly NPC patients were retrospectively enrolled. Propensity score matching generated a matched cohort (1:2) composed from CCRT and IC + RT groups. The survivals and treatment-induced toxicities were compared between two groups. Multivariable analysis was carried to identify significant prognostic factors.
The 5-year overall survival, cancer-specific survival, locoregional failure-free survival, distant failure-free survival for all patients were 58.3 %, 62.7 %, 88.7 %, 83.0 %, respectively. No significant survival differences were found between CCRT and IC + RT groups in the propensity-matched cohort. In comparison with the patients who received IC + RT, patients who underwent CCRT were associated with more severe acute toxicities including leucopenia (30 % vs. 6.8 %, P = 0.005), anemia (20 % vs. 4.1 %, P = 0.027), mucositis (63.3 % vs. 34.2 %, P = 0.007), weight loss (23.4 % vs. 4.1 %, P = 0.009). Basicranial bone involvement was an independent prognostic factor that predicted all-cause death (HR = 0.553, 95 % CI 0.329–0.929; P = 0.025) and cancer specific death (HR = 0.558, 95 % CI 0.321–0.969; P = 0.038) in elderly patients.
In the context of no guideline for elderly NPC, the present study suggested IC + RT should be a preferable modality compared with CCRT, with similar treatment outcomes but less acute toxicities.
Melanoma accounts for the majority of skin cancer deaths. It has over thirty different subtypes. Different races have been observed to differ in multiple aspects of melanoma.
SEER (Surveillance, Epidemiology, and End Results) data on six major subtypes, namely melanoma in situ (MIS), superficial spreading melanoma (SSM), nodular melanoma (NM), lentigo maligna melanoma (LMM), acral lentiginous melanoma malignant (ALM), and malignant melanoma NOS (NOS), were analyzed. The racial groups studied included NHW (non-Hispanic white), HW (Hispanic white), Black, and Asian/PI (Pacific Islanders). Univariate and multivariate analysis was conducted to quantify racial differences in patients' characteristics, incidence, treatment, and survival.
Significant racial differences are observed in patients' characteristics. For all subtypes except for ALM, NHWs have the highest incidence rates, followed by HWs, while Blacks have the lowest. For ALM, HWs have the highest rate, followed by NHWs. In stratified analysis, interaction between gender and race is observed. For the first five subtypes and localized and regional NOS, the dominating majority of patients had surgery, while for distant NOS, the distribution of treatment is more scattered. Significant racial differences are observed for distant ALM and NOS. For MIS, SSM, NM, LMM, and ALM, there is no significant racial difference in survival. For NOS, significant racial differences in survival are observed for the localized and regional stages, with NHWs having the best and Blacks having the worst five-year survival rates.
Racial differences exist for the six major melanoma subtypes in the U.S. More data collection and analysis are needed to fully describe and interpret the differences across racial groups and across subtypes.
The whole-body positron emission tomography (PET)/magnetic resonance (MR) scan is a cutting edge technology providing comprehensive structural information from MR imaging and functional features from PET in a single session. Recent research findings and clinical experience have shown that 18F-fluorodeoxyglucose (FDG) whole-body PET/MR imaging has a diagnostic performance comparable with or superior to that of PET/CT in the field of oncology, including for breast cancer. In particular, FDG PET/MR mammography in the prone position with the breast hanging in a pendant manner can provide more comprehensive information about the metabolism, anatomy, and functional features of a breast lesion than a whole-body PET/MR scan. This article reports on current state-of-the-art PET/MR mammography in patients with breast cancer and the prospects for potential application in the future.
Integrin-linked kinase (ILK) is a multifunctional adaptor protein which is involved with protein signalling within cells to modulate malignant (cancer) cell movement, cell cycle, metastasis and epithelial–mese...
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In addition to treating acute promyelocytic leukemia, arsenic trioxide (ATO) suppresses other solid tumors, including chondrosarcoma. However, the effects of ATO on metastasis in chondrosarcoma cells, and the ...
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In addition to treating acute promyelocytic leukemia, arsenic trioxide (ATO) suppresses other solid tumors, including chondrosarcoma. However, the effects of ATO on metastasis in chondrosarcoma cells, and the underlying molecular mechanisms remain unclear.
The effects of ATO on the migratory and invasive capacities of chondrosarcoma cells were investigated by Wound healing, Transwell and EMT assays. The expression of miR-125b in human chondrosarcoma tissues and cell lines was detected by real-time PCR analysis. Bisulfite sequencing analysis (BSP) was used to detect the effects of ATO on the expression of miR-125b. The gain-of-function and loss-of-function experiments were performed on chondrosarcoma cell lines to investigate the effects of miR-125b on chondrosarcoma invasion, and to determine whether signal transducer and activator of transcription 3(Stat3) mediates these effects. Dual-luciferase reporter assay was used to identify whether Stat3 is a direct target of miR-125b.
MiR-125b was significantly downregulated in human metastatic chondrosarcoma tissues and cell lines but not in non-metastatic chondrosarcoma tissues. ATO up-regulates the expression of miR-125b by the demethylation of DNA. ATO induces MET and attenuates the invasive capacities of chondrosarcoma cells through miR-125b. Stat3 was verified as a direct target of miR-125b, which is involved in ATO regulating EMT-associated traits.
These findings, for the first time, provides evidence that the miR-125b-mediated inhibition of Stat3 is involved in the ATO-induced attenuation of metastasis in chondrosarcoma cells.
Integrin-linked kinase (ILK) is a multifunctional adaptor protein which is involved with protein signalling within cells to modulate malignant (cancer) cell movement, cell cycle, metastasis and epithelial–mesenchymal transition (EMT). Our previous experiment demonstrated that ILK siRNA inhibited the growth and induced apoptosis of bladder cancer cells as well as increased the expression of Ribonuclease inhibitor (RI), an important cytoplasmic protein with many functions. We also reported that RI overexpression inhibited ILK and phosphorylation of AKT and GSK3β. ILK and RI gene both locate on chromosome 11p15 and the two genes are always at the adjacent position of same chromosome during evolution, which suggest that ILK and RI could have some relationship. However, underlying interacting mechanisms remain unclear between them. Here, we postulate that RI might regulate ILK signaling pathway via interacting with ILK.
Co-immunoprecipitation, GST pull-down and co-localization under laser confocal microscope assay were used to determine the interaction between ILK and RI exogenously and endogenously. Furthermore, we further verified that there is a direct binding between the two proteins by fluorescence resonance energy transfer (FRET) in cells. Next, The effects of interplay between ILK and RI on the key target protein expressions of PI3K/AKT/mTOR signaling pathway were determined by western blot, immunohistochemistry and immunofluorescence assay in vivo and in vitro. Finally, the interaction was assessed using nude mice xenograft model.
We first found that ILK could combine with RI both in vivo and in vitro by GST pull-down, co-immunoprecipitation (Co-IP) and FRET. The protein levels of ILK and RI revealed a significant inverse correlation in vivo and in vitro. Subsequently, The results showed that up-regulating ILK could increase cell proliferation, change cell morphology and regulate cell cycle. We also demonstrated that the overexpression of ILK remarkably promoted EMT and expressions of target molecules of ILK signaling pathways in vitro and in vivo. Finally, we found that ILK overexpression significantly enhanced growth, metastasis and angiogenesis of xenograft tumor; Whereas, RI has a contrary role compared to ILK in vivo and in vitro.
Our findings, for the first time, directly proved that the interplay between ILK and RI regulated EMT via ILK/PI3K/AKT signaling pathways for bladder cancer, which highlights the possibilities that ILK/RI could be valuable markers together for the therapy and diagnosis of human carcinoma of urinary bladder.
A metronomic schedule of chemotherapy (resulting in a greater frequency of drug delivery) has shown efficacy in head and neck cancer. Our aim was to investigate the overall survival in tongue cancer patients with metronomic neoadjuvant chemotherapy with bleomycin compared to those with surgery alone.
In this retrospective study, 117 patients with stages I–II tongue cancer, who had undergone surgery, were divided into the "surgery group" or "metronomic neoadjuvant chemotherapy with bleomycin (15 mg × 6) group." The rate of overall survival was the primary outcome measure; the secondary outcome measures included the rates of distant metastasis, regional recurrence, and local recurrence.
Of these patients, 54 underwent surgery alone and 63 received neoadjuvant chemotherapy. Neoadjuvant chemotherapy increased overall survival (76 vs. 90 %, P = 0.039). The neoadjuvant chemotherapy group had a significantly lower rates of distant metastasis (0 vs. 13 %, P = 0.003). There was no chemotherapy-related death.
Metronomic neoadjuvant chemotherapy decreased the rates of distant metastasis and increased the overall survival of tongue tumor patients.
Two large, recently published observational studies demonstate a clear down-trend in the use of radiotherapy (RT) over the last 15 years, both in the setting of follicular and diffuse large B-cell lymphoma. This change of practice might have a negative impact on clinical outcome. Even within the context of modern systemic therapy, omission of RT translates not only into a shorter progression-free survival (PFS), but also into a worse overall survival (OS). RT should therefore remain standard practice.
This short review is aiming to summarize current guidelines and the best evidence available in the management of non-Hodgkin's lymphoma. Potentially practice changing, ongoing trials will be highlighted.
Publication date: Available online 30 August 2016
Source:Journal of the Egyptian National Cancer Institute
Author(s): Ajeet Kumar Gandhi, Pavnesh Kumar, Menal Bhandari, Bharti Devnani, Goura Kishor Rath
India has a rapidly growing population inflicted with cancer diagnosis. From an estimated incidence of 1.45 million cases in 2016, the cancer incidence is expected to reach 1.75 million cases in 2020. With the limitation of facilities for cancer treatment, the only effective way to tackle the rising and humongous cancer burden is focusing on preventable cancer cases. Approximately, 70% of the Indian cancers (40% tobacco related, 20% infection related and 10% others) are caused by potentially modifiable and preventable risk factors. We review these factors with special emphasis on the Indian scenario. The results may help in designing preventive strategies for a wider application.
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A metronomic schedule of chemotherapy (resulting in a greater frequency of drug delivery) has shown efficacy in head and neck cancer. Our aim was to investigate the overall survival in tongue cancer patients with metronomic neoadjuvant chemotherapy with bleomycin compared to those with surgery alone.
In this retrospective study, 117 patients with stages I–II tongue cancer, who had undergone surgery, were divided into the "surgery group" or "metronomic neoadjuvant chemotherapy with bleomycin (15 mg × 6) group." The rate of overall survival was the primary outcome measure; the secondary outcome measures included the rates of distant metastasis, regional recurrence, and local recurrence.
Of these patients, 54 underwent surgery alone and 63 received neoadjuvant chemotherapy. Neoadjuvant chemotherapy increased overall survival (76 vs. 90 %, P = 0.039). The neoadjuvant chemotherapy group had a significantly lower rates of distant metastasis (0 vs. 13 %, P = 0.003). There was no chemotherapy-related death.
Metronomic neoadjuvant chemotherapy decreased the rates of distant metastasis and increased the overall survival of tongue tumor patients.
The aim of this study was to assess the clinical activity and toxicity of 131I-rituximab as consolidation therapy for patients with diffuse large B-cell lymphoma (DLBCL) who were treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone).
Patients who had been diagnosed with advanced stage (Ann Arbor III or IV) or bulky stage II DLBCL and achieved complete or partial response after six to eight cycles of R-CHOP were enrolled.
A total of 16 patients were enrolled and treated with a single dose of 131I-rituximab as consolidation therapy after the completion of six or eight cycles of R-CHOP between December 2005 and June 2011. This trial was terminated before the scheduled enrollment owing to low recruitment. Among the 16 patients who were treated with consolidative 131I-rituximab, 6 achieved complete response (CR) after three cycles of R-CHOP, and another 9 patients further achieved CR after the completion of six or eight cycles of R-CHOP. During the median follow-up period of 73 months, only four patients (25 %) experienced relapse. Two-year relapse-free survival was 88 %, and 5-year relapse-free survival was 81 %. Grade 3 or 4 treatment-related toxicity occurred in four patients and included neutropenia and thrombocytopenia.
131I-rituximab showed promising efficacy as consolidation treatment for patients with DLBCL. A future randomized phase III study to confirm our results is warranted.
High consumption of fruits and vegetables has been associated with reduced risk of debilitating diseases and improved cognition in aged populations. These beneficial effects have been attributed to the phytochemicals found in fruits and vegetables, which have previously been shown to be anti-inflammatory and modulate autophagy. Tart cherries contain a variety of potentially beneficial phytochemicals; however, little research has been done to investigate the effects of tart cherry on the aging brain. Therefore, the purpose of this study was to determine if tart cherry supplementation can improve cognitive and motor function of aged rats via modulation of inflammation and autophagy in the brain. Thirty 19-month-old male Fischer 344 rats were weight-matched and assigned to receive either a control diet or a diet supplemented with 2 % Montmorency tart cherry. After 6 weeks on the diet, rats were given a battery of behavioral tests to assess for strength, stamina, balance, and coordination, as well as learning and working memory. Although no significant effects were observed on tests of motor performance, tart cherry improved working memory of aged rats. Following behavioral testing, the hippocampus was collected for western/densitometric analysis of inflammatory (GFAP, NOX-2, and COX-2) and autophagy (phosphorylated mTOR, Beclin 1, and p62/SQSTM) markers. Tart cherry supplementation significantly reduced inflammatory markers and improved autophagy function. Daily consumption of tart cherry reduced age-associated inflammation and promoted protein/cellular homeostasis in the hippocampus, along with improvements in working memory. Therefore, addition of tart cherry to the diet may promote healthy aging and/or delay the onset of neurodegenerative diseases.
Although recent multimodality therapeutic protocols have led to improved survival in osteosarcoma (OS), the outcome still remains dismal. Ongoing international multicentric trials on OS aim to randomize patients for optimum management, based on histological response to NACT. The pathologic response to neoadjuvant chemotherapy (NACT) is the most important factor predicting prognosis. In this study of 23 cases of limb salvage surgery post neoadjuvant chemotherapy, mean age was 18.3 years, with male predominance. 65.5 % cases were conventional OS. Histologic assessment of chemotherapeutic effect done by Huvos grading revealed good response (Huvos lll and lV) in 15 (65.2 %) and poor response (Huvos l and ll) in eight (34.8 %). A scoring based on MRI with a scale of 1–6 was compared with histologic response. Five (62.5 %) of poor responders showed score of >3 and 73.3 % of good responders showed ≤3. Dose intensity of NACT was calculated and correlated with the histological response. 53.3 % of good responders showed ARDI > 0.9. Five (21.7 %) developed local recurrence and 10(43.4 %) had pulmonary metastasis. Adoption of more aggressive treatment modalities may ensure better histologic response and longer event free survival.
Ficolin-2 is a lectin complement pathway activator present in normal human plasma and usually associated with infectious diseases, but little is known about the role of ficolin-2 in human immunodeficiency virus (HIV) infection. Here, we describe our novel findings that serum ficolin-2 concentrations of 103 HIV-1 patients were much higher compared to those of 57 healthy donors. In vitro analysis showed that HIV-1 infection could enhance ficolin-2 expression. We further demonstrated that recombinant ficolin-2 protein could bind with HIV-1 envelope glycoprotein gp120, and subsequently induce complement dependent cytotoxicity. Moreover, ficolin-2 could block the entry of HIV-1 into target cells (TZM-b1 and MT-2 cells) and infection in a ficolin-2 dosedependent manner. To our knowledge, this is the first report about the protective role of ficolin-2 against HIV-1 infection and our study suggests that ficolin-2 is an important human innate immune molecule against HIV.
The objective of this study is to evaluate the effectiveness of preoperative endoscopic localization of colorectal cancer and tracing lymph nodes by carbon nanoparticle tattooing in laparoscopic colorectal cancer surgery.
From January 2013 to December 2014, 54 patients with colorectal cancer were recruited and divided into experimental (n = 27) and control (n = 27) groups. The patients in the experimental group were localized preoperatively by endoscopic carbon nanoparticle tattooing, whereas patients in the control group were not tattooed.
All injection sites in the experimental group were visible to surgeons. No abdominal pain, fever, diarrhea, and other symptoms of infection were found in the experimental group. The time for detecting the tumor (2.71 ± 2.13 min versus 6.91 ± 5.16 min, p < 0.001), operation time (151.22 ± 30.66 min versus 170.26 ± 33.13 min, p = 0.033), and blood loss during the operation (125.04 ± 29.48 mL versus 147.52 ± 34.35 mL, p = 0.013) were lower in the experimental group than in the control group. Average numbers of dissected lymph nodes in the experimental group exceeded those in the control group (14.41 ± 3.32 versus 8.96 ± 2.90, p < 0.001), and the rate of dissected lymph nodes ≥12 was higher in the experimental group than in the control group (70.37 versus 37.04 %, p < 0.001). Moreover, no difference in postoperative complications was found between the two groups.
Tattooing colorectal cancer with carbon nanoparticles in laparoscopic colorectal cancer surgery is safe and useful both in localization and lymph node tracing.
Emergency surgery for colon cancer, as a result of obstruction, has been vitiated by a high frequency of complications and poor survival. The concept of "bridge to surgery" includes either placement of self-expanding metallic stents (SEMS) or diverting stoma of an obstructing tumour and subsequent planned resection. The aim of this study was to compare acute resection with stoma or stent and later resection regarding surgical and oncological outcomes and total hospital stay.
This is a retrospective cohort study. All 2424 patients diagnosed with colorectal cancer during 1997–2013 were reviewed. All whom underwent acute surgery with curative intention for left-sided malignant obstruction were included in the study.
One hundred patients fulfilled the inclusion criteria. Among them, 57 patients were treated with acute resection and 43 with planned resection after either acute diverting colostomy (n = 23) or stent placement (n = 20). The number of harvested lymph nodes in the resected specimen was higher in the planned resection group compared with acute resection group (21 vs. 8.7; p = 0.001). Fewer patients were treated with adjuvant chemotherapy in the acute resection group than in the stoma group (14 % (8/57 patients) vs. 43 %, (10/23 patients; p = 0.024)). Patients operated with acute resection had a higher 30-day mortality rate and were more frequently left with a permanent stoma.
Decompression of emergency obstructive left colon cancer with stent or stoma and subsequent curative resection appears safer and results in a higher yield of lymph node harvest, and fewer patients are left with a permanent stoma.
A short statement on the most recent developments in the neuro-oncology field, including the new WHO Classification of Tumors of the Central Nervous System (2016) and current treatment strategies.
Survivin is an anti-apoptotic protein that is highly expressed in many cancers, including malignant gliomas. Preclinical studies established that the conjugated survivin peptide mimic SurVaxM (SVN53-67/M57-KLH) could stimulate an anti-tumor immune response against murine glioma in vivo, as well as human glioma cells ex vivo. The current clinical study was conducted to test safety, immunogenicity and clinical effects of the vaccine. Recurrent malignant glioma patients whose tumors were survivin-positive, and who had either HLA-A*02 or HLA-A*03 MHC class I allele-positivity, were given subcutaneous injections of SurVaxM (500 μg) in Montanide ISA 51 with sargramostim (100 μg) at 2-week intervals. SurVaxM was well tolerated with mostly grade one adverse events (AE) and no serious adverse events (SAE) attributable to the study drug. Six patients experienced local injection site reactions; three patients reported fatigue (grades 1 and 2), and 2 patients experienced myalgia (grade 1). Six of eight immunologically evaluable patients developed both cellular and humoral immune responses to vaccine. The vaccine also stimulated HLA-A*02, HLA-A*03 and HLA-A*24 restricted T cell responses. Three patients maintained a partial clinical response or stable disease for more than 6 months. Median progression-free survival was 17.6 weeks, and median overall survival was 86.6 weeks from study entry with seven of nine patients surviving more than 12 months.
Survivin is an anti-apoptotic protein that is highly expressed in many cancers, including malignant gliomas. Preclinical studies established that the conjugated survivin peptide mimic SurVaxM (SVN53-67/M57-KLH) could stimulate an anti-tumor immune response against murine glioma in vivo, as well as human glioma cells ex vivo. The current clinical study was conducted to test safety, immunogenicity and clinical effects of the vaccine. Recurrent malignant glioma patients whose tumors were survivin-positive, and who had either HLA-A*02 or HLA-A*03 MHC class I allele-positivity, were given subcutaneous injections of SurVaxM (500 μg) in Montanide ISA 51 with sargramostim (100 μg) at 2-week intervals. SurVaxM was well tolerated with mostly grade one adverse events (AE) and no serious adverse events (SAE) attributable to the study drug. Six patients experienced local injection site reactions; three patients reported fatigue (grades 1 and 2), and 2 patients experienced myalgia (grade 1). Six of eight immunologically evaluable patients developed both cellular and humoral immune responses to vaccine. The vaccine also stimulated HLA-A*02, HLA-A*03 and HLA-A*24 restricted T cell responses. Three patients maintained a partial clinical response or stable disease for more than 6 months. Median progression-free survival was 17.6 weeks, and median overall survival was 86.6 weeks from study entry with seven of nine patients surviving more than 12 months.
Two large, recently published observational studies demonstate a clear down-trend in the use of radiotherapy (RT) over the last 15 years, both in the setting of follicular and diffuse large B-cell lymphoma. Th...
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Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, is a first-line treatment for metastatic renal cell carcinoma (mRCC) in patients in 'low' and 'intermediate' Memorial Sloan Kettering Cancer Center and Heng risk groups. Disruptions of hematopoiesis, such as anemia, neutropenia, and thrombocytopenia, are typically observed during sunitinib treatment. When it comes to RBC parameters, an increase in mean cell volume (MCV) tends to occur, meeting the criteria for macrocytosis in some patients (MCV > 100 fL). We examined changes in RBC parameters of 27 mRCC patients treated with sunitinib (initial dose of 50 mg/day, 6-week treatment: 4 weeks on, 2 weeks off) and correlated them with progression-free survival time (PFS). Patients who had macrocytosis after 3 treatment cycles had significantly longer PFS than those whose MCV stayed less than 100 fL (not reached vs. 11.2 months, p < 0.001). We also found a correlation between MCV values after the first and third treatment cycles and the risk of progression: HR of 0.9 (0.81–0.99) and 0.76 (0.65–0.90) per 1 fL increase in MCV, respectively. The mechanism of MCV elevation during sunitinib treatment has not yet been fully explained. One of the probable causes is sunitinib's inhibitory influence on c-Kit kinase, as is the case with imatinib. For mRCC patients, this phenomenon could help predict PFS, but since our sample was small, further studies are essential.
We report the long-term follow-up in patients with locally advanced cervical cancer treated with neoadjuvant chemotherapy (NACT) + radical surgery (RS) + adjuvant chemotherapy (ACT) analyzing prognostic factors which may more influence, in a long time, the survival outcome using univariate and multivariate analysis. In this study, we included all patients with diagnosis of locally advanced cervical cancer (IB2-IIB) treated with NACT + RS + ACT from June 2000 and February 2007 as previously described by Angioli et al. (Gynecol Oncol 127(2):290–6, 2012). The primary end-point of the study was overall survival (OS) in patients with node metastases and in those without positive lymph nodes at the end of 10-year follow-up in order to confirm the prognostic role of nodes involvement for a long period. Moreover, we analyzed the impact of other prognostic factors, such as histotype, tumor size, grading and parametrial invasion. Secondary end-point was evaluated in the subgroup of patients with positive nodes the following prognostic factors: number of positive lymph nodes and site of positive lymph nodes. In the subgroup of patients with positive nodes, the OS was 63 %, and in that with negative nodes, the OS was 75 %. On multivariate analysis, the number of nodal metastases, parametrial involvement, grading and the lesion diameter were noted to be significant factors in determining OS. Neither the histotype nor the lymph nodal site is related to survival. Results suggest that CT alone may be an alternative postoperative therapy for patients with cervical cancer.
