THE EPIDEMIOLOGY OF TETRACYCLINE AND CEFTIOFUR RESISTANCE IN COMMENSAL ESCHERICHIA COLI MATTHEW THOMAS MCGOWAN B.S., Kansas State University, 2011 submitted in partial fulfillment of the requirements for the degree MASTER OF SCIENCE Department of Biomedical Science College of Veterinary Medicine KANSAS STATE UNIVERSITY Manhattan, Kansas Dr. H. Morgan Scott
Saturday 18th October – Day 4 Saturday 18th October – Day 4 Australian Lung Cancer Conference
Day in Review
Australian Lung Cancer Conference OPTIMAL LUNG CANCER CARE right care – right time - right place Session S5: Looking forward
Chairs: Emily Stone and Bill Musk
What is new in EBUS for the management
of lung cancer?
Blood tests for lung cancer
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Speaker: Paul De Souza
Speaker: Kazuhiro Yasufuku
Summary: Paul de Souza, Professor of Medical Oncology at the University of
Summary: Kazuhiro Yasufuku, Associate Professor of Surgery, University of Toronto
16-18 October 2014, Brisbane
Western Sydney, spoke about the reasons for looking at blood-based biomarkers and Thoracic Surgeon at the Division of Thoracic Surgery at the Toronto General in general, and the utility of circulating tumour cel s (CT) and CT-DNA in particular. Hospital gave an update of EBUS (endobronchial ultrasonography) in the management He outlined methods of cell harvesting and potential uses of these biomarkers of lung cancer. He also detailed his research into lymph node characteristics which including stratification of disease, detection of micrometastatic disease and resistant may in future aid the bronchoscopist to determine which lymph nodes, and which In today's review:
to this Day in Review for Saturday, 18th October
of the Australian Lung Cancer Conference (ALCC).
disease, and the ability to determine the mechanisms driving disease or resistance.
areas of lymph nodes contain cancer cel s.
Lung cancer immunotherapy The Australian Lung Cancer Conference is endorsed by the International Association for the Study of Comment: The talk by Paul De Souza on blood-based biomarkers covered the
Comment: Kazuhiro Yasufuku talked about the basics of EBUS procedures,
Lung Cancer (IASLC ). The 2014 program is an exciting combination of science, technology, research importance of proteomics and peptidomics, mRNA and circulating tumour cel s including established techniques (EBUS, transbronchial biopsy and radial probe and supportive care. The meeting is hosting 7 international experts from the specialties representing the for diagnosing and monitoring lung cancer. He believes they are very important EBUS biopsy). He then talked about various types of imaging modalities that multidisciplinary team. They are Bil y W Loo Jr (Radiation Oncologist), David Carbone (Medical Oncologist), for monitoring response and disease progression, and possibly, but maybe are being developed using the newer scopes, and certain concepts of EBUS Primer on immunotherapies John Field (Pulmonologist), Kazuhiro Yasufuku (Thoracic Surgeon), Keith M Kerr (Consultant Pathologist), not specific, for diagnosis. They are certainly accessible and getting cheaper, identifiable lymph node morphology, which may help predict the likelihood of node Natalie Doyle (Nurse Consultant) and Noelle O'Rourke (Clinical Consultant).
but their performance characteristics need further evaluation.
malignancy – there are many nodes visible on EBUS that cannot be biopsied. The other major development is a smal er EBUS scope, reportedly due later this year. Lung cancer vaccines We hope you enjoy this Day in Review.
Breath tests for lung cancer
This smal er scope may permit access to some of the less readily accessible nodes. Session S1: Immunotherapeutics
Speaker: Annette Dent
Radiotherapy and Surgical management of CT screening detected nodules
Summary: Respiratory Scientist at the Department of Thoracic Medicine, Prince
Speaker: Kazuhiro Yasufuku
Chairs: Craig Lewis and Jeff Bowden
Charles Hospital and University of Queensland, Annette Dent presented an overview Lung cancer immunotherapy update
of the use of breath tests for lung cancer. Many methods are now available for Summary: Kazuhiro Yasufuku went on to describe use of video-assisted
detecting the different compounds exhaled in breath, although dogs, able to detect thoracoscopic surgery (VATS) localising techniques for peripheral lung nodules. ALTG flagship results – NITRO Speaker: David Carbone
compounds at concentrations of only a few parts per tril ion, may still be the gold He discussed various techniques including intraoperative imaging, percutaneous Summary: Professor David Carbone, Director James Thoracic Center, Ohio State University noted that
standard method. In a 2006 study dogs distinguished lung cancer patients from injection of liquid under CT guidance, wire coil localisation and preoperative healthy individuals with a sensitivity and specificity of 99%.
Antibody drug conjugates we are now starting to see real progress in this area. He reviewed the process of antigen presentation, and the mechanisms by which tumours evade immune surveil ance. He discussed the latest literature in relation to agents targeting PD-1, PDL-1 and CTLA-4 with reference to efficacy and toxicity, and the use Comment: Annette Dent talked on exhaled breath analysis, which was "invented"
Comment: For his talk on surgical approaches to nodules detected on CT
by Hippocrates and popularised by Sherlock Holmes. It is very good for renal and screening, Kazuhiro Yasufuku presented a case of a small peripheral nodule in New immunotherapies of biomarkers to predict response.
liver failure and diabetes, but a role for diagnosing lung diseases is now emerging, a patient who was part of the PanCan dataset. A small ground-glass opacity in targeting macrophages Comment: The presentation by Prof Carbone focussed on the role of immunotherapy in lung cancer
especial y lung cancer. It depends on volatile organic compounds (VOCs). the lower lobe increased in solidity and size over a couple of years. CT-guided and on the importance of immune checkpoint inhibitors. There was discussion about CTLA-4 inhibition, The standard way of analysing exhaled breath has been gas chromatography, biopsy was not diagnostic. He then went on to describe the many and varied but portable, easy to use, electronic VOC detectors with the potential to be procedural options that are underway to approach such lesions. He described but also significant presentations on the important four new PD1 and PDL-1 inhibitors. He provided detailed discussion on the results of early-phase trials of the four compounds that have entered the diagnostical y useful have been developed.
VATS as the procedure of choice for surgical biopsy of peripheral nodules, clinical research arena. All of the studies have clearly demonstrated benefits for these agents in patients addressing complexities such as the inability to palpate ground glass nodules or nodules >5mm from the visceral pleura. Various options of preoperative Blood tests for lung cancer heavily pretreated with chemotherapy. One important message that has emerged is that smokers appear more likely to respond than nonsmokers, perhaps due to various mutations in cancers of marking of nodules were described, all of which have limitations, but are al being pursued – these include wires, fiducial y and marker dyes. He then wowed Breath tests for lung cancer smokers. There were also suggestions that responses are: i) seen in both squamous cell carcinomas and adenocarcinomas; ii) often rapid in onset; ii ) frequently prolonged in duration; and iv) sometimes the audience with a presentation on the Guided Therapeutics programme in Lung Cancer
Toronto, which includes an $8 mil ion surgical room which looked like the Starship apparent after the immune checkpoint inhibitor has been ceased. The other important aspect of the Enterprise and was equipped for many and varied surgical techniques, including What is new in EBUS for the PD1 and PDL-1 inhibitors is that they are generally very well tolerated, with side effect profiles that are several types of CT-guided approaches and real-time imaging. He addressed the management of lung cancer? completely different to standard chemotherapy agents. There remain a number of challenges associated To subscribe visit www.researchreview.com.au benefits of navigational bronchoscopy and possible endobronchial approaches with these agents that need to be addressed, particularly related to the use of the PDL-1 biomarker. for coil placement. He made the point that navigational bronchoscopy real y does Responses have been seen in both PDL-1-positive and PDL-1-negative patients. The limitations of the provide excel ent anatomical training for fel ows, and then referred to the future Surgical management of CT PDL-1 biomarker include the fact that expression is dynamic and heterogeneous within tumours, and potential benefit of focal ablation.
screening detected nodules the level of expression that is important is still unclear. Trials to date have focussed on heavily pretreated patients, but are rapidly progressing to the early-phase setting, including as neoadjuvant therapy and in combinations with chemotherapy and other immune checkpoint inhibitors.
Expert commentary by:
Emily Stone, Respiratory Physician at St Vincent's Hospital, Sydney.
Professor Bill Musk, Respiratory Physician at Sir Charles Gairdner Hospital,
Western Australia. To subscribe visit www.researchreview.com.au Day in Reviews are prepared with an independent commentary from relevant specialists.To become a reviewer please email [email protected]
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2014 RESEARCH REVIEW Saturday 18th October – Day 4 Saturday 18th October – Day 4 Australian Lung Cancer Conference
Australian Lung Cancer Conference
Day in Review
Day in Review
Primer on immunotherapies
Session S2: New Targets
Speaker: Rina Hui
Summary: Dr Rina Hui, Senior Medical Oncologist at
Chairs: Rina Hui and Richard Sul ivan
Westmead Hospital and founding Coordinator of the Western Sydney Lung Cancer Service gave an update ALTG flagship results – NITRO
on what she cal ed the basics of immunotherapy. Speaker: Andrew Davidson
She discussed various modalities which have potential to upregulate the immune system in order to combat Summary: Dr Andrew Davidson, a Medical Oncologist at Royal Perth Hospital presented interim results for
cancers; cytokine therapy; anti-tumour antibodies such the ALTG (Australian Lung Cancer Trials Group) NITRO trial. This large (n=380), multi-centre, open-label, as trastuzumab; preventive and therapeutic vaccination; phase II , randomised clinical trial which compared chemotherapy with chemotherapy plus nitroglycerin patch immune checkpoint inhibitors such as anti-CTLA-4, in patients with advanced NSCLC has shown negative results in the interim analysis.
anti PD-1 and anti PDL-1 antibodies.
Comment (RH): The presentation on the NITRO study (which turned out to be a negative study) highlighted the
Comment: This session looked at immunotherapy
co-operation of different Australian cancer centres working together to recruit a huge number of participants The first approved irreversible
for cancer, particularly lung cancer. This is a rapidly for the study. This will help us in the future for other similar, more exciting studies. It also highlights how evolving area of research in advanced disease, and to look at other targets, in this case, how to deal with the tumour microenvironment, improving hypoxia. Even though the proof of principle was not confirmed, it is still important that we keep thinking of new ErbB family blocker in stage IIIB/IV
is also rapidly progressing to trials in early-stage disease. This presentation by Dr Hui focussed on target areas for research.
the mechanisms of immunotherapy as we currently Comment (DG): The NITRO study was very impressive in that there was such extensive co-operation
NSCLC patients with common
across Australia enabling it to be undertaken and answer its question. It was great that Andrew Davidson was very strategic in his presentation, talking about where and how this sort of co-operation should be Lung cancer vaccines
used in the future.
Speaker: Paul Mitchel
New immunotherapies and antibody drug conjugates
Raising the bar for patient outcomes in EGFR mutation-positive Summary: Associate Professor Paul Mitchel , Senior
Medical Oncologist at Austin Health and Director of Speaker: Ken O'Byrne
advanced NSCLC vs pemetrexed/cisplatin1,3 the North Eastern Metropolitan Integrated Cancer Summary: Ken O'Byrne, Professor of Medical Oncology at Princess Alexandra Hospital Brisbane presented
Service updated delegates on the most recent data an overview of potential new immunotherapeutic targets and their mechanisms of action. He highlighted the for therapeutic vaccines in lung cancer. He specifical y importance of macrophage targets such as anti CD-47 antibodies to induce macrophage phagocytosis of ∙ GIOTRIF exceeds 12 months mPFS vs pemetrexed/cisplatin:3
focused on three targets, the cancer-testis antigens, tumour cel s and mentioned other potential new targets such as CD-96, important in natural kil er cel activation. − 13.6 months vs 6.9 months, respectively (p<0.0001; common mutations*)3
which are expressed in the placenta and frequently He closed by giving an update on antibody drug conjugates in lung cancer.
in malignancy, but only in the testis in healthy adults; − 11.1 months vs 6.9 months, respectively (p=0.0004; the glycopeptide mucin-1 (MUC1) which is present in Comment (RH): The session on new targets highlighted the importance of translating basic science to
all mutations, ITT primary endpoint)3 many malignant tissues, and the TGF-beta blocker look for new targets to further improve lung cancer treatment outcomes. We are currently in a very exciting era, with a lot of new cancer treatments becoming available, particularly targeted therapies like EGFR, TKIs and ALK fusion inhibitors. However, resistance is still a major chal enge, with disease progression common Comment: Paul Mitchel presented on vaccines
∙ GIOTRIF significantly improved global health and quality of life
after a certain period of time.
vs pemetrexed/cisplatin (p=0.015; all mutations, ITT)4 in lung cancer. While the studies thus far have been largely disappointing, there is considerable Comment (DG): It is very exciting that we have an expert such as Ken O'Byrne working in the basic science
promise for combinations of vaccine therapy and of cancer immunology in Australia. He presented some very interesting basic science approaches that may other immunomodulatory therapies, particularly well move to the clinic soon.
mPFS – median progression-free survival, ITT – intention-to-treat * Common EGFR mutations (90% of ITT) – exon 19 deletions, Beyond TKI failure: progress in targeting ALK and EGFR in NSCLC
exon 21 L858R point mutation Radiotherapy and immunotherapy
Speaker: Ben Solomon
Speaker: Catherine Bettington
Summary: Associate Professor Ben Solomon, Medical Oncologist at Peter MacCal um Cancer Centre in
Melbourne, discussed the multiple and complex mechanisms by which tumours can develop resistance to first PBS Information: This product is not listed on the PBS.
Summary: Catherine Bettingon, Radiation Oncologist
at the Royal Brisbane and Women's Hospital introduced generation TKIs. Crizotinib resistance can derive from target alterations such as mutations or amplifications the idea that radiotherapy plus immunotherapy may of the ALK gene which prevent binding. Bypass mechanisms and pharmacological failure of crizotinib in the Before prescribing, please review the full Product Information, offer a systemic anti-tumour effect. She discussed the brain may also occur. Ben also described the 2nd generation ALK inhibitors which have activity against ALK abscopal effect of radiotherapy, thought to be immune- secondary mutations, in addition to being more potent inhibitors of ALK than crizotinib. Similarly resistance to available at www.boehringer-ingelheim.com.au/PI mediated, and noted that radiotherapy has been shown EGFR TKIs arises from a mutation in EGFR kinase (T790M) in 50-60% of cases.
MINIMUM PRODUCT INFORMATION GIOTRIF® (afatinib) 20 mg, 30 mg, 40 mg, 50 mg film-coated tablets. INDICATION: GIOTRIF is indicated as monotherapy for the
treatment of patients with advanced or metastatic non-squamous non-small cell carcinoma of the lung, either as first line therapy or after failure of cytotoxic chemotherapy. Tumours to play a role in all stages of the immune response to a must have Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or L858R substitution mutations. CONTRAINDICATIONS: Hypersensitivity to afatinib or to any of the
tumour, from expression of tumour antigen to priming Comment (RH): The presentation ‘Beyond TKI failure' highlighted that quite a number of new-generation
excipients. PRECAUTIONS: Diarrhoea; skin related adverse events; monitoring recommended in female patients, patients with lower body weight and underlying renal impairment;
of T-cel s and cytotoxic activity by T-cel s.
targeted therapies are becoming available opening up further potential improvements in outcomes. This session Interstitial Lung Disease; severe hepatic impairment; keratitis; left ventricular dysfunction; pancreatitis; contains lactose; pregnancy; lactation; phototoxicity. INTERACTIONS:
also covered other new targets, including new immunotherapies, adding to a number of presentations made Strong P-gp inhibitors may increase exposure to afatinib. Strong P-gp inducers may decrease exposure to afatinib. Others, see full PI. ADVERSE REACTIONS: Very common:
Expert commentary by:
during the entire conference on treatments to ‘release the brakes' of the immune system for fighting cancer, paronychia, decreased appetite, epistaxis, diarrhoea, stomatitis, rash, dermatitis acneiform, pruritis, dry skin. Common: cystitis, dehydration, hypokalemia, dysgeusia, conjunctivitis, particularly on immune checkpoint inhibitors targeting T-cel s. In this particular presentation, we heard about dry eye, rhinorrhoea, dyspepsia, cheilitis, ALT increased, AST increased, palmar-plantar erythrodysesthesia syndrome, muscle spasms, renal impairment/renal failure, pyrexia, weight Associate Professor Craig Lewis, Medical
other targets of the immune system, including macrophages and natural kil er cel s. It is great to be able decreased. Others, see full PI. DOSAGE AND ADMINISTRATION: 40 mg orally once daily. Food should not be consumed 3 hours before or 1 hour after a dose of GIOTRIF. Continue
Oncologist, Prince of Wales Hospital, Sydney.
treatment until disease progression or until no longer tolerated. November 2013. REFERENCES: 1. GIOTRIF Product Information November 2013. 2. Solca F et al. J Pharmacol Exp
Jeff Bowden, Thoracic Physician and Head of
to co-opt all the players in the immune system and try and look into combination therapies in the future.
Ther 2012; 343(2): 342–50. 3. Sequist LV et al. J Clin Oncol 2013; 31: 3327–34. 4. Yang JC et al. J Clin Oncol 2013; 31: 3342–50.
Respiratory, Al ergy and Sleep Services, Southern Comment (DG): Ben Solomon is the world expert on ALK therapies, and he gave a great talk about the
approach in patients who receive targeted therapy but then relapse. He also spoke a little bit about the GIOTRIF® is a Registered Trademark of Boehringer Ingelheim Pty Ltd. Adelaide Health Network.
ABN 52 000 452 308. 78 Waterloo Road, North Ryde, NSW 2113. approach with regulatory authorities, which is an important aspect for providing access to these therapies AUS/GIO-141000. March 2014. AM5048/RRb.
for our patients.
Contact RESEARCH REVIEW
Expert commentary by:
The landscape has evolved Rina Hui, Medical Oncologist Westmead Hospital, Sydney.
Phone 1300 132 322
Dishan Gunawardana, Medical Oncologist Royal Melbourne and Western Health, Victoria.
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MArch 2015 The 2014 Drug TrenD reporT Commercially Insured Year in Review Medicare Year in Review A Look at Overall Drug Trend for 2014 A Look at Medicare Overall Drug Trend for 2014Medicare: Traditional Therapy Classes and Insights Therapy class revIew Top 10 Medicare Traditional Drugs Comparison of Medicare and Commercial Trend: Traditional Therapy Classes