Saturday, 18 August 2018

Basket study

Source: [4].

«Basket trials (or studies) test the effect of one drug on a single mutation in a variety of tumor types [baskets], at the same time. These studies also have the potential to greatly increase the number of patients who are eligible to receive certain drugs relative to other trials designs [1], «allowing researchers to analyze each cancer type individually, as well as assess the impact of the drug or drug combinations as a whole. Using this approach, it is possible to combine what would have been multiple phase 2 trials into a single study [4]». «In the evaluation of targeted therapies, basket trials have emerged as an approach to test the hypothesis that targeted therapies may be effective independent of tumor histology, as long as the molecular target is present [2].» «Most basket trials typically aim to answer multiple questions simultaneously [3].»

Bibliographic references:
[1] Clinical Trial Design and Methodology. ASCO. https://www.asco.org/research-progress/clinical-trials/clinical-trial-resources/clinical-trial-design-and-methodology. Accessed August 18, 2018.
[2] Redig AJ, Jänne PA. Basket trials and the evolution of clinical trial design in an era of genomic medicine. J Clin Oncol. 2015 Mar 20;33(9):975-7. Available at: https://doi.org/10.1200/JCO.2014.59.8433.
[3] Cunanan KM, Gonen M, Shen R, et al. Basket Trials in Oncology: A Trade-Off Between Complexity and Efficiency. J Clin Oncol. 2017 Jan 20;35(3):271-273. Available at: https://doi.org/10.1200/JCO.2016.69.9751.
[4] Illuminating ideas: Innovative clinical trial design. Roche.com. https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/innovative-clinical-trial-design.htm. Accessed August 18, 2018.

Heart radiation


Source: Kim M. Radiating The Heart Saves Patty Sweeney. ABC30 Fresno. https://abc30.com/health/radiating-the-heart-saves-patty-sweeney/3966266/. Published 2018. Accessed August 18, 2018.

Wednesday, 15 August 2018

Febrile neutropaenia

«Febrile neutropaenia is defined as an oral temperature of >38.3°C or two consecutive readings of >38.0°C for 2 h and an absolute neutrophil count of <0.5 × 109/L, or expected to fall below 0.5 × 109/L.»
Bibliographic reference: Klastersky J, de Naurois J, Rolston K, Rapoport B, Maschmeyer G, Aapro M, Herrstedt J, on behalf of the ESMO Guidelines Committee; Management of febrile neutropaenia: ESMO Clinical Practice GuidelinesAnnals of Oncology, Volume 27, Issue suppl_5, 1 September 2016, Pages v111–v118, https://doi.org/10.1093/annonc/mdw325.

Monday, 13 August 2018

Multi-arm multi-stage (MAMS) trial design

Advanced/metastatic NSCLC treatment algorithm

Advanced/metastatic NSCLC [non-small cell lung cancer] treatment algorithm:
ALK: anaplastic lymphoma kinase; EGFR: epidermal growth factor receptor; PD-L1: programmed cell death ligand 1; ROS1: proto-oncogene receptor tyrosine-protein kinase; TPS: tumor proportion score.
Source: Brahmer JR, Govindan R, Anders RA, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC). J Immunother Cancer. 2018 Jul 17;6(1):75. Available at: https://doi.org/10.1186/s40425-018-0382-2. Creative Commons license: https://creativecommons.org/publicdomain/zero/1.0/.


[French]


Sunday, 12 August 2018

Saturday, 28 July 2018

VMA (vanillylmandelic acid or DL-4-hydroxy-3-methoxymandelic acid)

It «is a chemical intermediate in the synthesis of artificial vanilla flavorings [1] and is an end-stage metabolite of the catecholamines, epinephrine, and norepinephrine. (...). VMA is found in the urine, along with other catecholamine metabolites, including homovanillic acid (HVA), metanephrine, and normetanephrine. In timed urine tests, the quantity excreted (usually per 24 hours) is assessed along with creatinine clearance, and the quantity of cortisols, catecholamines, and metanephrines excreted is also measured. Urinary VMA is elevated in patients with tumors that secrete catecholamines [2]. These urinalysis tests are used to diagnose an adrenal gland tumor called pheochromocytoma, (...). These tests may also be used to diagnose neuroblastomas [or other neuroendocrine tumors (e.g., ganglioblastoma, ganglioneuroma)], and to monitor treatment of these conditions [3].» Catecholamines «are released into the blood during times of physical or emotional stress, which are factors that may skew the results of the test [3].»
«The reference ranges of VMA in children are as follows [Burris, 2006, McPherson, 2011, and Wallach, 2011, cited by 4]:
  • Younger than 1 year: <27 mg/g creatinine;
  • Age 1-2 years: <18 mg/g creatinine;
  • Age 2-4 years: <13 mg/g creatinine;
  • Age 5-9 years: <8.5 mg/g creatinine;
  • Age 10-14 years: <7 mg/g creatinine.
The reference range in persons aged 15 years and older is 2-7 mg/24 hours [4].»
«In the evaluation of pheochromocytoma, vanillylmandelic acid is now considered the least-specific test for catecholamine metabolites, with a false-positive rate greater than 15%. Measurement of metanephrine, an intermediate metabolite between epinephrine and vanillylmandelic acid, is now considered the most sensitive and specific test for pheochromocytoma [4].»
Chemical formula: C9H10O5.
Bibliographic references:
[1] Fatiadi A, Schaffer R. An Improved Procedure for Synthesis of DL-4-Hydroxy-3-methoxymandelic Acid (DL-"Vanillyl"-mandelic Acid, VMA). Journal of Research of the National Bureau of Standards - A. Physics and Chemistry. 1974;78A(3):411–412. Available at: https://doi.org/10.6028/jres.078A.024.
[2] Magera MJ, Thompson AL, Matern D, Rinaldo P. Liquid chromatography-tandem mass spectrometry method for the determination of vanillylmandelic acid in urine. Clin Chem. 2003 May;49(5):825-6. Available at: https://doi.org/10.1373/49.5.825.
[3] Vanillylmandelic acid. En.wikipedia.org. https://en.wikipedia.org/wiki/Vanillylmandelic_acid. Published 2018. Accessed July 28, 2018.
[4] Lee A, Van Durme DJ. Vanillylmandelic Acid (VMA): Reference Range, Interpretation, Collection and Panels. Emedicine.medscape.com. https://emedicine.medscape.com/article/2089620-overview#a1. Published 2014. Accessed July 28, 2018.

Gaseous myelography or pneumomyelography

«Myelography developed as an imaging technique to assess the status of the thecal sac, spinal cord, and nerve roots in diverse pathologic conditions. Before the development of myelography, the only definitive means of evaluating these structures was laminectomy and direct inspection [1].»
«Myelographic techniques have evolved over time. The requirement for dural puncture, although invasive, offered the opportunity to acquire cerebrospinal fluid (CSF) specimens for laboratory analysis as a part of the procedure. (...). After spinal puncture, a myelographic contrast agent was slowly injected into the subarachnoid space with fluoroscopic confirmation. (...). Myelography is an invasive procedure, requiring puncture of the subarachnoid space. The spinal puncture is generally done below the L1-2 disc space level. Subarachnoid puncture also can be performed in the cervical spine at the C1-2 level via a lateral approach, or at the craniocervical junction via a posterior midline approach. (...). Although myelography has become a relatively safe test, it is invasive. MR imaging of the spine with its improved soft tissue delineation and excellent ability to depict and characterize extradural, intradural, and intramedullary lesions has led to a significant decrease in the use of myelography [1].»
«Several contrast agents have been used for myelography»: air and other gases, Thorotrast® (a suspension containing particles of the radioactive compound thorium dioxide), Lipiodol (ethiodized oil), Abrodil (sodium iodomethane sulfonate), Conray (iothalamate meglumine), Pantopaque (iophendylate), Dimer-X (methylglucamine iocarmate), metrixamide, iohexol and other nonionics [1].
«In 1919, Dr. Walter Dandy [2] suggested that the intraspinal air that was used for pneumoencephalography could be also used for the diagnosis of intraspinal pathology. A few years later, Dandy [1922, cited by 1] reported his experience with pneumomyelography in the diagnosis of spinal cord tumors. Attractive features of gas, specifically air, as a contrast medium include low cost, lack of allergic reactions, and spontaneous reabsorption. Other gases, such as oxygen, were also used for pneumomyelography because of their greater diffusibility and more prompt resorption. Gas is a negative contrast agent, and the optical contrast provided by plain radiography or tomography was poor. Although not chemically toxic, a variety of unpleasant side effects, such as headache, nausea, and transient neurologic symptoms, were common with air myelography. (...). The other disadvantage of pneumomyelography was that fluoroscopic images could not be used; rather, radiographs were obtained using overpenetrated technique. Even with the best technique, these studies were extremely challenging to perform and interpret [1].» «Advancements in contrast media development have led to significant improvement in their safety profile [1].» «The development of water-soluble contrast media allowed the use of post-myelographic computed tomography, which was a major advance [1].»
«Although myelography has largely been supplanted by MRI [magnetic resonance imaging], it will continue to be a necessary tool and is most useful in evaluation of cerebrospinal fluid leaks and in patients unable to undergo MRI [1].»
Bibliographic references:
[1] Price DB, Ortiz AO. Myelography: From Lipid-Based to Gadolinium-Based Contrast Agents. Magn Reson Imaging Clin N Am. 2017 Nov;25(4):713-724. Available at: https://doi.org/10.1016/j.mric.2017.06.005.
[2] Dandy WE. Roentgenography of the brain after the injection of air into the spinal canal. Ann Surg1919 Oct;70(4):397–403. Available at: https://doi.org/10.1097/00000658-191910000-00004.

Friday, 27 July 2018

Complete remission

«The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. Also called complete response [1].» «Complete remission can also be described by some doctors as no evidence of disease (NED) [2]». «Remission may also refer to the disease-free period. Although remission is a word that can be used in relation to any cancer, it is most associated with leukemia and Hodgkin's disease and the other lymphomas [3].» «Remission is almost always the result of some form of cancer treatment, such as radiation or chemotherapy [not surgery], although there are documented cases in which cancer goes into remission on its own [4].»
Bibliographic references:
[1] NCI Dictionary of Cancer Terms. National Cancer Institute. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/complete-remission. Accessed July 27, 2018.
[2] What Is Cancer Remission?. Mesothelioma + Asbestos Awareness Center. https://www.maacenter.org/blog/what-is-cancer-remission/. Accessed July 27, 2018.
[3] Sarg M, Gross A. The Cancer Dictionary. 3rd ed. New York: Facts on Fire; 2007:268.
[4] Cancer Remission Definition - Southeast Radiation Oncology Group, P.A. - SERO - Treat Cancer. Southeast Radiation Oncology Group, P.A. - SERO - Treat Cancer. https://treatcancer.com/blog/cancer-remission-definition/. Accessed July 27, 2018.

Sunday, 22 July 2018

Molecular fingerprint

«Molecular fingerprints are a way of encoding the structure of a molecule. The most common type of fingerprint is a series of binary digits (bits) that represent the presence or absence of particular substructures in the molecule. Comparing fingerprints allows you to determine the similarity between two molecules, to find matches to a query substructure, etc. [1]». «Fingerprints are a very abstract representation of certain structural features of a molecule [2]». «The similarity-based virtual screening (a kind of ligand-based virtual screening) assumes that all compounds in a database that are similar to a query compound have similar biological activity. (...). To achieve high efficacy of similarity-based screening of databases containing millions of compounds, molecular structures are usually represented by molecular screens (structural keys) or by fixed-size or variable-size molecular fingerprints. Molecular screens and fingerprints can contain both 2D- and 3D-information [3]». «Molecular fingerprints encode properties of small molecules and assess their similarities computationally through bit string comparisons. Based on the similarity to a biologically active template, molecular fingerprint methods allow for identifying additional compounds with a higher chance of displaying similar biological activities against the same target – a process commonly referred to as virtual screening [4]». It is «a unique pattern indicating the presence of a particular molecule, based on specialized analytic techniques such as mass- or x-ray-spectroscopy, used to identify a pollutant, drug, contaminant, or other chemical in a test sample [5].»
Example [6]:
 Bibliographic references:
[1] 1. Molecular fingerprints and similarity searching — Open Babel v2.3.1 documentation. Openbabel.org. https://openbabel.org/docs/dev/Fingerprints/intro.html. Published 2011. Accessed July 22, 2018.
[2] 2. Daylight Theory: Fingerprints. Daylight.com. http://www.daylight.com/dayhtml/doc/theory/theory.finger.html. Published 2007. Accessed July 22, 2018.
[3] Chemical similarity. En.wikipedia.org. https://en.wikipedia.org/wiki/Chemical_similarity. Published 2018. Accessed July 22, 2018.
[4] Muegge I, Mukherjee P. An overview of molecular fingerprint similarity search in virtual screening. Expert Opin Drug Discov. 2016;11(2):137-48. Available at: https://doi.org/10.1517/17460441.2016.1117070.
[5] Chemical fingerprint dictionary definition | chemical fingerprint defined. Yourdictionary.com. http://www.yourdictionary.com/chemical-fingerprint. Published 2018. Accessed July 22, 2018.

[6] Luo W, Chan KC. Discovering patterns in drug-protein interactions based on their fingerprints. BMC Bioinformatics. 2012 Jun 11;13 Suppl 9:S4. Available at: https://doi.org/10.1186/1471-2105-13-S9-S4.

Sunday, 15 July 2018

Failed randomized clinical trials in Radiation Oncology: what can we learn?

Failed randomized clinical trials in Radiation Oncology: what can we learn?: Randomized clinical trials are essential to evidence-based medicine, yet a significant proportion fail to be completed. In Radiation Oncology, factors contributing to trial failure are not well understood. We sought to compare completed and incomplete clinical trials involving radiation therapy to identify predictors of trial failure.

Wednesday, 11 July 2018

Gorlin syndrome, nevoid basal cell carcinoma syndrome, or Gorlin-Goltz syndrome

It «is a condition that affects many areas of the body and increases the risk of developing various cancerous and noncancerous tumors. (...). Individuals with Gorlin syndrome typically begin to develop basal cell carcinomas during adolescence or early adulthood. (...). Some people with Gorlin syndrome never develop any basal cell carcinomas, while others may develop thousands of these cancers. (...). Most people with Gorlin syndrome also develop noncancerous (benign) tumors of the jaw, called keratocystic odontogenic tumors (...). Individuals with Gorlin syndrome have a higher risk than the general population of developing other tumors. A small proportion of affected individuals develop a brain tumor called medulloblastoma during childhood. A type of benign tumor called a fibroma can occur in the heart or in a woman's ovaries (...). Other features of Gorlin syndrome include small depressions (pits) in the skin of the palms of the hands and soles of the feet; an unusually large head size (macrocephaly) with a prominent forehead; and skeletal abnormalities involving the spine, ribs, or skull [1].» «Ectopic calcification, particularly in the falx, is present in more than 90% of affected individuals by age 20 years [2].»
Mutations in the PTCH1 (protein patched homolog 1) gene cause Gorlin syndrome [1,3]. This protein «is the receptor for sonic hedgehog, a secreted molecule implicated in the formation of embryonic structures and in tumorigenesis. This gene functions as a tumor suppressor. The PTCH1 gene product is a transmembrane protein that suppresses the release of another protein called smoothened, and when sonic hedgehog binds PTCH1, smoothened is released and signals cell proliferation [3].» «The characteristic features of Gorlin syndrome can also be associated with a chromosomal change called a 9q22.3 microdeletion, in which a small piece of chromosome 9 is deleted in each cell. This deletion includes the segment of chromosome 9 that contains the PTCH1 gene [1].
«Gorlin syndrome is inherited in an autosomal dominant pattern [1].»
«Life expectancy (...) is not significantly different from average [2].»
These patients have a relative contraindication for radiotherapy [4].
Bibliographic reference:
[1] Gorlin syndrome. Genetics Home Reference. https://ghr.nlm.nih.gov/condition/gorlin-syndrome#genes. Published 2018. Accessed July 11, 2018.
[2] Evans DG, Farndon PA. Gorlin syndrome - Conditions - GTR - NCBI. Ncbi.nlm.nih.gov. https://www.ncbi.nlm.nih.gov/gtr/conditions/C0004779/. Accessed July 11, 2018.
[3] PTCH1. En.wikipedia.org. https://en.wikipedia.org/wiki/PTCH1. Published 2017. Accessed July 11, 2018.
[4] Singer L, Yom SS. Chapter 1 - Skin Cancer. In: Hansen EK, Roach III M. Handbook Of Evidence-Based Radiation Oncology. 3rd ed. Cham, Switzerland: Springer; 2018:10. Available at: https://doi.org/10.1007/978-3-319-62642-0.

Wednesday, 20 June 2018

Comparison of local recurrence among early breast cancer patients treated with electron intraoperative radiotherapy vs hypofractionated photon radiotherapy: an observational study

Comparison of local recurrence among early breast cancer patients treated with electron intraoperative radiotherapy vs hypofractionated photon radiotherapy: an observational study: PURPOSE: To evaluate local recurrence (LR) in women with early breast cancer (BC) who underwent intraoperative radiation therapy with electrons particles (IORT-E) or adjuvant hypofractionated external radiotherapy (HYPOFX). MATERIALS AND METHODS:We retrospectively analyzed 470 patients with early BC treated at our center from September 2009 to December 2012. 235 women were treated with breast-conserving surgery and immediate IORT-E (21 Gy/1 fraction) while 235 patients underwent wide excision followed by hypofractionated whole breast irradiation. Radiotherapy modality was chosen according an individualized decision based on tumour features, stage, technical feasibility, age, acceptance to be enrolled in the IORT-E group.RESULTS: After a median follow-up of 6 years, we observed 8 (3.4%) and 1 (0.42%) LR in the IORT-E and in the HYPOFX group (p=0.02), respectively. The two groups differed in the prevalence of clinical characteristics (p4 and 1 women in the IORT-E and HYPOFX group died for breast cancer, respectively (p=0.167). OS and DFS hazard ratio [HR] were 2.14 (95% IC, 1.10 to 4.15) and 2.09 (95% IC, 1.17 to 3.73), respectively. CONCLUSIONS:Our comparison showed that IORT-E and HYPOFX are two effective radiotherapy modalities after conservative surgery in early BC. However, at 6 years a significant higher rate of LR occurred in patients submitted to IORT-E with respect to HYPOFX. This finding may be correlated to some subsets of patients who, depending on the biological...

Tuesday, 19 June 2018

Radiotherapy utilization and fractionation patterns during the first course of cancer treatment in the United States from 2004 to 2014

Radiotherapy utilization and fractionation patterns during the first course of cancer treatment in the United States from 2004 to 2014: The changing use of radiation as a first-line cancer therapy in the United States is poorly characterized. This study aims to report radiotherapy utilization and fractionation patterns during the first course of cancer treatment.

Sunday, 17 June 2018

PSAV (prostate specific antigen velocity)

Total PSA (prostate specific antigen) velocity, in ng/mL/year, is the change in total PSA values over time and it is «calculated as the running average of the rate of change during 3 consecutive visits by the equation 0.5{[(PSA2-PSA1)/(elapsed time in years)]+[(PSA3-PSA2)/(elapsed time in years)]}, where PSA1 is the first of the 3 measurements, PSA2 the second and PSA3 the third. Elapsed time refers to time between the 2 measurements [1]».
The rate of change in serum total PSA over time provides useful information and increases the specificity of PSA for cancer detection. Current recommendations for the use of PSAV include a collection of PSA levels over a period of no less than 18 months and the use of multiple values (minimum of 3) to perform the calculation. PSAV «has been best used in younger men who have elected to begin early detection programs before age 50». It «was designed to help avoid unnecessary, costly, and potentially morbid repeat biopsies in these men» [2]. «A rise in PSA of as little as 0.1 ng/ml per year is worrisome as to the long-term chance of being diagnosed with prostate cancer» [2,3]:

PSA VelocityProstate Cancer Risk by 10 Years
≤0.1 ng/ml/year3%
>0.1 ng/ml/year65%
Source: [2,3].

«Any rapid rise in PSA is worrisome both for the likelihood of developing cancer but of having more serious (high-grade prostate cancer.) A recent study [4] found that men whose PSA jumped more than 2 points in the year prior to being diagnosed had much higher death rate when treated with surgery (radical prostatectomy). Also, patients treated with radiation for prostate cancer whose PSA starts to rise do worse if the PSA doubles in less than 12 months» [2].
In patients with prostate cancer without metastases, those with a rapid PSAV and an otherwise long life expectancy should be encouraged to consider androgen deprivation therapy earlier [5].
A free online calculation can be found here: USRF - PSA Velocity [6].

Bibliographic references:
[1] Khan MA, Carter HB, Epstein JI, et al. Can prostate specific antigen derivatives and pathological parameters predict significant change in expectant management criteria for prostate cancer? J Urol. 2003 Dec;170(6 Pt 1):2274-8. Available at: https://doi.org/10.1097/01.ju.0000097124.21878.6b.
[2] PSA Velocity. Aboutcancercom. Available at: http://www.aboutcancer.com/psa_velocity.htm. Accessed June 17, 2018.
[3] Fang J, Metter EJ, Landis P, Carter HB. PSA velocity for assessing prostate cancer risk in men with PSA levels between 2.0 and 4.0 ng/ml. Urology. 2002 Jun;59(6):889-93; discussion 893-4. Available at: https://doi.org/10.1016/S0090-4295(02)01646-1.
[4] D'Amico AV, Chen MH, Roehl KA, Catalona WJ. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med. 2004 Jul 8;351(2):125-35. Available at: https://doi.org/10.1056/NEJMoa032975.
[5] Mohler J, Lee R, Antonarakis E, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) – Prostate Cancer – Version 2.2018 - March 8, 2018. Nccnorg. 2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed June 17, 2018.
[6] USRF - PSA Velocity. Usrforg. Available at: https://www.usrf.org/questionnaires/PSA_Velocity.html. Accessed June 17, 2018.

Tuesday, 5 June 2018

The scarcity of funding for radiotherapy trials

Characteristics of radiotherapy trials compared With other oncological clinical trials in the past 10 years.

The limited number of and the scarcity of funding for radiotherapy trials is concerning given the integral role of radiotherapy in the clinical management of patients with cancer worldwide. A multidisciplinary collaboration to promote and fund more radiotherapy research is warranted.

Liu X, Zhang Y, Tang LL, et al. JAMA Oncol. 2018 May 17. Available at: https://doi.org/10.1001/jamaoncol.2018.0887.