tbuckley/cabot-search huggingface dataset:
Is Genetic Testing for Heart Disease Right for Me?
Authors: Tia Moscarello, Chloe Reuter, Euan A. Ashley
Journal: JAMA Cardiology (2019)

Is Genetic Testing for Heart Disease Right for Me?Heart disease is a leading cause of death worldwide and often runs in families.Certain heart conditions, such as those in the Figure, are caused by a single harmful DNA variation (or mutation) while others, such as heart attack and high blood pressure, are usually caused by the combined effect of many smaller-impact DNA variations.Tests for the latter are emerging but are not yet reliable enough for common use.Tests for the former can be ordered by cardiologists and genetic counselors.These tests can help patients and their families know who is at risk for disease.
Therapeutic Targeting of Aldolase A Interactions Inhibits Lung Cancer Metastasis and Prolongs Survival
Authors: Yu-Chan Chang, Jean Chiou, Yi-Fang Yang, Chia-Yi Su, Yuan-Feng Lin, Chia-Ning Yang, Pei-Jung Lu, Ming-Shyan Huang, Chih-Jen Yang, Michael Hsiao
Journal: Cancer Research (2019)

Cancer metabolic reprogramming promotes tumorigenesis and metastasis; however, the underlying molecular mechanisms are still being uncovered. In this study, we show that the glycolytic enzyme aldolase A (ALDOA) is a key enzyme involved in lung cancer metabolic reprogramming and metastasis. Overexpression of ALDOA increased migration and invasion of lung cancer cell lines in vitro and formation of metastatic lung cancer foci in vivo. ALDOA promoted metastasis independent of its enzymatic activity. Immunoprecipitation and proteomic analyses revealed γ-actin binds to ALDOA; blocking this interaction using specific peptides decreased metastasis both in vitro and in vivo. Screening of clinically available drugs based on the crystal structure of ALDOA identified raltegravir, an antiretroviral agent that targets HIV integrase, as a pharmacologic inhibitor of ALDOA-γ-actin binding that produced antimetastatic and survival benefits in a xenograft model with no significant toxicity. In summary, ALDOA promotes lung cancer metastasis by interacting with γ-actin. Targeting this interaction provides a new therapeutic strategy to treat lung cancer metastasis. SIGNIFICANCE: This study demonstrates the role of aldolase A and its interaction with γ-actin in the metastasis of non-small lung cancer and that blocking this interaction could be an effective cancer treatment.
Brachytherapy: An overview for clinicians
Authors: Cyrus Chargari, Eric Deutsch, Pierre Blanchard, Sebastien Gouy, Hélène Martelli, Florent Guérin, Isabelle Dumas, Alberto Bossi, Philippe Morice, Akila N. Viswanathan, Christine Haie‐Meder
Journal: CA A Cancer Journal for Clinicians (2019)

Abstract Brachytherapy is a specific form of radiotherapy consisting of the precise placement of radioactive sources directly into or next to the tumor. This technique is indicated for patients affected by various types of cancers. It is an optimal tool for delivering very high doses to the tumor focally while minimizing the probability of normal tissue complications. Physicians from a wide range of specialties may be involved in either the referral to or the placement of brachytherapy. Many patients require brachytherapy as either primary treatment or as part of their oncologic care. On the basis of high‐level evidence from randomized controlled trials, brachytherapy is mainly indicated: 1) as standard in combination with chemoradiation in patients with locally advanced cervical cancer; 2) in surgically treated patients with uterine endometrial cancer for decreasing the risk of vaginal vault recurrence; 3) in patients with high‐risk prostate cancer to perform dose escalation and improve progression‐free survival; and 4) in patients with breast cancer as adjuvant, accelerated partial breast irradiation or to boost the tumor bed. In this review, the authors discuss the clinical relevance of brachytherapy with a focus on indications, levels of evidence, and results in the overall context of radiation use for patients with cancer.
Weight change among breast cancer patients receiving chemotherapy: A retrospective analysis
Authors: B. P. Nair, O. Khalil, V. R. Phooshkooru, L. F. Hutchins
Journal: Journal of Clinical Oncology (2007)

19535 Background: Weight gain occurs in patients with early stage breast cancer receiving chemotherapy. The etiology is unknown. Most pre-menopausal patients receiving chemotherapy enter menopause during the course of treatment. We explored the relation between weight gain and development of menopause in breast cancer patients. We hypothesized that, among breast cancer patients receiving chemotherapy, those in the pre/perimenopausal group will gain more weight compared to postmenopausal group in the first 2 years. Methods: The electronic database at University of Arkansas was queried for breast cancer patients treated with chemotherapy between May 1992 and Nov 2003. Age, chemotherapy and weight at multiple time points (diagnosis, 6, 12, 24 and 60 months) were obtained. The mean weight changes across these time points were then calculated for the entire population and also after categorizing by age. Age was used as a surrogate for menstrual status. Women aged &gt;=50 yrs were considered postmenopausal, those &lt;50 yrs were considered pre or perimenopausal. Results: 617 patients were included in the analysis. There were 371 patients in the &gt;=50 age group and 246 patients in the &lt;50 age group. The average baseline weight for the entire population was 75.21 kg: 74.44 for women &lt;50 yrs and 75.71 for women &gt;= 50 yrs. Patients &lt;50 yrs of age gained weight in the first 2 yrs: 1.11 kg weight in the 1st year and 0.65 kg in the second yr. This was followed by loss of 1.19 kg over next 3 yrs which paralleled the loss of weight in the &gt;=50 group. The mean weight of the &gt;=50 age decreased by 0.27 kg in the first 2 years and then by 1.16 kg over the next 3 yrs following chemotherapy. Conclusions: Pre/perimenopausal breast cancer patients in our study gained weight, while postmenopausal patients had slight weight loss during the first 2 years. These findings imply that onset of menopause itself may be playing a significant role in weight gain among pre/perimenopausal breast cancer patients receiving chemotherapy. [Table: see text] No significant financial relationships to disclose.
Clinical relevance of specialist pathologic testicular tumor review.
Authors: David N. Church, Andrew Protheroe, Ian SD Roberts, Gemma Louise Crane, Gareth D Turner, Clare Verrill
Journal: Journal of Clinical Oncology (2012)

4599 Background: Therapeutic options in stage IA/B testicular cancer include surveillance, retroperitoneal lymph node dissection, and adjuvant chemotherapy/radiotherapy; clinician and patient choice is guided by recurrence risk. Specialist pathologic review is important in informing this decision as it may alter diagnosis and staging. Methods: Analysis of a prospective supraregional database of 627 testicular tumors diagnosed in Oxford or referred for central review between 2004 and 2012. Tumor histology, stage (AJCC 7 th ed.), and other factors predictive of relapse were compared between referring and final pathology reports. Results: Of 402 cases referred from 11 hospitals during the study period, 370 primary testicular tumors with an informative initial pathology report were analysed. There was a discrepancy between referring and final reports in 116 cases (31.4%), with significant variation between referring units in the frequency of discordance (20.0-89.9%, p&lt;0.0001, x 2 ). Changes to histological diagnosis in 34 cases (9.2%) were minor alterations in type and proportion of non-seminomatous germ cell tumor (NSGCT) elements of no clinical significance, with exception of one classical seminoma reclassified as spermatocytic seminoma. For seminomas (n=201) the commonest discrepancies were in identification of rete testis invasion (RTI) (15.9%); lymphovascular invasion (LVI) (9.5%); and spermatic cord invasion (SCI) (5.0%). RTI was more frequently under-reported (14.4%), and LVI over-reported (8.0%) on initial assessment. Disparity of tumor size in 2 cases (1.0%) was of no clinical significance. For NSGCT (n=150) the commonest discrepancies were in RTI (9.3%), LVI (7.3%) and SCI (6.7%), with LVI typically over-reported (4.0%) and RTI and SCI under-reported (6.7%, 5.3% respectively) on primary analysis. Central review resulted in change of primary tumor stage in 45 cases (12.1%). 12 (6.0%) and 16 (8.0%) seminomas, and 12 (8.0%) and 5 (3.3%) NSGCTs were upstaged and downstaged respectively. Conclusions: Central pathology review results in frequent alteration of factors predictive of relapse in stage IA/B testicular cancer. Particular attention should be directed to review of RTI, LVI and SCI to ensure accurate prognostication.
MICA immune complex formed with alpha 3 domain-specific antibody activates human NK cells in a Fc-dependent manner
Authors: Changchun Du, Jack Bevers, Ryan Cook, T. Noelle Lombana, Kamalakannan Rajasekaran, Marissa Matsumoto, Christoph Spiess, Jeong M. Kim, Zhengmao Ye
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> One of the mechanisms by which tumors evade immune surveillance is through shedding of the major histocompatibility complex (MHC) class I chain-related protein A and B (MICA/B) from their cell surface. MICA/B are ligands for the activating receptor NKG2D on NK and CD8 T cells. This shedding reduces cell surface levels of MICA/B and impairs NKG2D recognition. Shed MICA/B can also mask NKG2D receptor and is thought to induce NKG2D internalization, further compromising immune surveillance by NK cells. <h3>Methods</h3> We isolated human primary NK cells from normal donors and tested the suppressive activity of soluble recombinant MICA in vitro. Utilizing a panel of novel anti-MICA antibodies, we further examined the stimulatory activities of anti-MICA antibodies that reversed the suppressive effects of soluble MICA. <h3>Results</h3> We show that suppressive effects of soluble MICA (sMICA) on NK cell cytolytic activity was not due to the down-regulation of cell surface NKG2D. In the presence of an α3 domain-specific MICA antibody, which did not obstruct NKG2D binding, sMICA-mediated NK cell suppression was completely reversed. Reversal of NK cell inhibition by sMICA was mediated by immune complex formation that agonized NKG2D signaling. Furthermore, this restorative activity was dependent on antibody Fc effector function as the introduction of Fc mutations to abrogate Fc receptor binding failed to reverse sMICA-mediated NK cell suppression. Furthermore, MICA immune complexes preformed with an α3 domain-specific antibody (containing a wild-type Fc) induced IFN-γ and TNF-α secretion by NK cells in the absence of cancer cells, whereas MICA immune complexes preformed with the Fc effectorless antibody failed to induce IFN-γ and TNF-α secretion. Finally, we demonstrated that MICA immune complexes formed with the α3 domain-specific antibody activates NKG2D on NK cells leading to the release of IFN-γ. <h3>Conclusions</h3> Our results demonstrate that an α3 domain-specific MICA antibody can circumvent sMICA-mediated suppression of NK cell cytolytic activity. Moreover, our data suggest that MICA immune complexes formed with α3-specific antibodies can activate NKG2D receptor and restore NK cell function in a Fc-dependent manner. The clinical utility of α3 domain-specific MICA/B antibodies may hold great promise as a new strategy for cancer immunotherapy.
Impact of setup error on integral dose in head and neck cancer treated with intensity modulated radiation therapy
Authors: R. V. Prabhakar, K. P. Haresh, M. A. Laviraj, G. K. Rath, P. K. Julka
Journal: Journal of Clinical Oncology (2009)

e17056 Background: Intensity modulated radiation therapy (IMRT) has been widely used in the treatment of head and neck cancer and has the potential of escalating the dose with less morbidity. Integral dose is a concern in radiotherapy especially with IMRT as it may lead to an increase in second malignancies. Setup error is another important issue in radiotherapy which affects the final treatment outcome. In this study, the effect of setup error on non-target integral dose (NTID) for head and neck cancer treated with IMRT has been studied. Methods: Twelve patients of carcinoma of nasopharynx treated by IMRT with simultaneous integrated boost technique were included. The dose to the gross tumor volume (PTV70), CTV1 (PTV59.4) and CTV2 (PTV54) were planned for 70 Gy, 59.4 Gy and 54 Gy respectively in 33 fractions. All the patients were planned with nine equally spaced beams. The IMRT plan was generated in Eclipse treatment planning system using sliding window technique. Keeping it as the base plan, the patient setup error was simulated in the treatment planning system for 3 mm, 5 mm and 10 mm by shifting the isocenter in all three dimensions viz. anterior, posterior, superior, inferior, right lateral and left lateral. NTID was calculated from the following relation NTID = (non-target tissue volume X mean non-target tissue dose)/1000. Paired sample t-test was performed to compare NTID for different shifts with no shift (statistical significance: p &lt; 0.05). Results: The mean NTID for no shift was 120.75 ± 22.85 (median: 116.59). The mean NTID with isocenter shift along the anterior direction were 119.87 ± 22.80, 119.24 ± 22.80, 117.97 ± 22.52 for 3 mm, 5 mm and 10 mm respectively. Similarly, the NTID for the posterior shifts were 121.59 ± 22.96, 122.08 ± 23.07 and 123.26 ± 23.34 for 3 mm, 5 mm and 10 mm respectively. The anterior and posterior setup error showed statistically significant difference (p &lt; 0.0001) for NTID compared to no shift whereas lateral, superior and inferior setup errors were found to be statistically insignificant. Conclusions: Setup error is an important issue in radiotherapy. Our study shows that setup error along the posterior direction significantly increases NTID. Hence, the setup error along the posterior direction may increase the risk of second malignances in IMRT. No significant financial relationships to disclose.
Mapping and Making Sense of Noncoding Mutations in the Genome
Authors: Jiekun Yang, Mazhar Adli
Journal: Cancer Research (2019)

Whole-genome sequencing efforts of tumors and normal tissues have identified numerous genetic mutations, both somatic and germline, that do not overlap with coding genomic sequences. Attributing a functional role to these noncoding mutations and characterizing them using experimental methods has been more challenging compared with coding mutations. In this review, we provide a brief introduction to the world of noncoding mutations. We discuss recent progress in identifying noncoding mutations and the analytic and experimental approaches utilized to interpret their functional roles. We also highlight the potential mechanisms by which a noncoding mutation may exert its effect and discuss future challenges and opportunities.
68Ga-DOTATATE PET/CT in Focal Fatty Sparing of the Liver
Authors: Nir Hod, Daniel Levin, Reut Anconina, Benjamin H. Taragin, Julia Dudnik, Sophie Lantsberg
Journal: Clinical Nuclear Medicine (2019)

Ga-DOTATATE imaging is commonly used for the detection of metastatic disease in neuroendocrine tumors. We present a case of a 69-year-old woman postsurgery for lung carcinoid tumor in which sequential follow-up Ga-DOTATATE PET/CT studies identified focal hepatic uptake that was presumed to represent a liver metastasis. However, correlative imaging with MRI revealed a focal fatty sparing of the liver composed of benign hepatic parenchyma at that area accompanied with diffuse liver steatosis in the background of the "pseudolesion." This report demonstrates a potential "false-positive" hepatic finding that can strikingly mimic a metastasis in neuroendocrine tumor imaging.
Integrated laboratory networks for a successful biomarker implementation strategy in personalized medicine.
Authors: Maria fe Paz, Jose Luis Ferreiro, Peter Keeling
Journal: Journal of Clinical Oncology (2012)

e21158 Background: Much work has been done to ensure that biomarkers research and the development of targeted therapies in Oncology can be translated into a better stratification of patients. However, when it comes to the implementation of those biomarkers into the clinical setting, laboratories are not commonly consider an essential stakeholder. Unfortunately, the laboratories are often the forgotten third arm of a successful foundation in personalized medicine (PM), for molecular diagnostics in oncology. In order to truly enhance the power of companion diagnostics, and to better meet healthcare demands and finally, patient needs, superior integrated laboratory services are crucial. This presentation will provide a brief introduction from Labceutics highlighting the need for highest quality laboratory networks across Europe. In addition it would feature results of a Delphi survey of leading EU laboratories on the gaps and shortfalls they face in implementing companion diagnostics Methods: Delphi survey study conducted over a representative sample of the +120 partners in the Labceutics European Laboratory network. Statistical analysis was performed with SPSS software. Results: this research reveals that that fewer than 10% of these laboratories had been contacted directly by pharmaceutical companies to discuss the future implementation issues they may face in introducing companion diagnostics in their Lab. Additionally, the study confirmed that 25% of the laboratories surveyed, preferred to begin their testing service of a novel diagnostics with an IVD kit purchased from a diagnostic company. On the other hand, 77% either preferred to develop their own in house method or consider the business case, since so many of the new diagnostics have very low volumes in the initial 3 to 5 years. Conclusions: this exhaustive will provide the audience with insights into the main issues about best practices for laboratories to ensure appropriate implementation of testing services. It will reveal as well, the importance and sequence of "early prelaunch" engagement with a laboratory network to accelerate post launch diffusion of testing.
A multiplex methylation-specific PCR assay for detection of early-stage ovarian cancer using cell-free serum DNA.
Authors: Beihua Kong, Qing Zhang, Guohong Hu, Qifeng Yang, Ruifen Dong, Xing Xie, Ding Ma, Keng Shen
Journal: Journal of Clinical Oncology (2013)

5535 Background: Epithelial ovarian cancer (EOC) remains the most lethal disease among gynecological malignancies. Prompt diagnosis is challenging because of the non-specific symptoms exhibited during the early stage of the disease. So there is an urgent need for better detection methods. Here we performed this work to build up a platform of multiplex methylation-specific PCR (MSP) assay to improve the early detection of ovarian cancer, via identifying the methylation status of cell-free serum DNA. Methods: After screening, we chose seven genes (APC, RASSF1A, CDH1, RUNX3, TFPI2, SFRP5 and OPCML) with a high frequency of methylation as candidate genes to construct the multiplex-MSP assay. When methylation of at least one of the seven genes was observed, the multiplex-MSP assay was considered positive. We performed the retrospective and screening study to verify its specificity and sensitivity in the detection of EOC. Results: The methylation status of cell-free serum DNA was examined in the preoperative serum of 202 patients, including 87 EOC cases (stage I, n=41, stage II-IV, n=46), 53 benign ovarian tumors and 62 healthy controls. As expected, multiplex MSP assay achieved a sensitivity of 85.3% and a specificity of 90.5% in stage I EOC, strikingly higher than that of single CA125, producing a sensitivity of 56.1% at 64.15% specificity [p=0.0036](Table). Conclusions: Multiplex MSP assay analyzing the methylation status of cell-free serum DNA is a suitable and reliable approach to improve the early detection of ovarian cancer, potentially benefiting a broad range of applications in clinical oncology. [Table: see text]
Relationship of the emergence of KRAS mutations and resistance to panitumumab in second-line treatment of colorectal cancer (CRC).
Authors: Krastan B. Blagoev, Mauricio Emmanuel Burotto Pichun, Julia Wilkerson, Montserrat Blanco-Codesido, Edward Espinal Dominguez, Pilar Garcia-Alfonso, Antonio Tito Fojo
Journal: Journal of Clinical Oncology (2013)

e14592 Background: Multiple analyses have concluded anti-EGFR antibodies are detrimental to a majority of patients (pts) whose CRCs harbor mutant KRAS. While panitumumab may benefit some pts with tumors harboring WT KRAS, in the majority the added benefit is small and transient. Recent studies have claimed emergence of KRAS mutations mediates acquired resistance to EGFR inhibitors. Methods: We analyzed published and unpublished data to assess this possibility, calculating growth and regression rate constants and estimating doubling times of CRC. Results: Amongst 24 pts with CRC whose tumors were initially KRAS WT, circulating mutant KRAS transcripts were detected in 9 treated in second line with panitumumab plus chemotherapy [Diaz et al, Nature 2012]. The growth rate of tumor in the 9 pts with circulating MT KRAS was 0.0019 days -1 . This value is statistically indistinguishable [p = .2439] from the growth rate of 0.0021 days -1 calculated for tumors in 15 pts with no detectable circulating MT KRAS transcripts. Both values were also statistically indistinguishable [p = .3055 for MT KRAS; p = .7688 for WT KRAS] from the growth rate [0.002 days -1 ] of tumors in a cohort treated in second line with the same chemotherapy without an EGFR inhibitor. Similar results were observed when growth rates were calculated using CEA values [WT, 0.00087 days -1 ; MT, 0.0024 days -1 ; p = .1265] and similar regression rate constants were also calculated [WT, 0.0114 days -1 ; MT, 0.0117 days -1 ; p = .858]. Furthermore, in pts with detectable serum MT KRAS transcripts the growth rate remained constant even as MT KRAS transcripts appeared to increase. The growth rates allowed us to estimate tumor doubling times of 110 to 124 days in these pts receiving second line therapies, consistent with clinical data for disease progression in second line; and similar to the estimated doubling time of 116 days in the cohort that did not receive panitumumab. Conclusions: Resistance to panitumumab in tumors harboring WT KRAS cannot be explained by overgrowth of cells with MT KRAS. Other mechanisms must be sought to explain the limited efficacy of panitumumab. The data suggest such mechanism(s) are inherent and likely present in the majority of cells.