Treatment of ALK-rearranged non-small cell lung cancer: A review of the landscape and approach to emerging patterns of treatment resistance in the Australian context.

Since the identification of anaplastic lymphoma kinase (ALK) gene rearrangements in non-small cell lung cancer (NSCLC) in 2005, the treatment of ALK-rearranged NSCLC (ALK+ NSCLC) has evolved at a rapid pace. This molecularly distinct subset of NSCLC has uniquely important biology, clinicopathologic features and mechanisms of drug resistance which impact on the choice of treatment for a patient with this disease. There are multiple ALK tyrosine kinase inhibitors now available in clinical practice with efficacy data continuing to emerge and guide the optimal treatment algorithm. A detailed search of medical databases and clinical trial registries was conducted to capture all relevant articles on this topic enabling an updated detailed overview of the landscape of management of ALK-rearranged NSCLC.

Investigation of patterns of nodal metastases in BRAF mutant lung cancer.

Axillary lymph nodes (axLN) are a rare site of nodal metastases in patients with lung cancer. BRAF mutated lung cancer is a genetically distinct subtype that occurs in 2-5% of non-small cell lung carcinomas (NSCLC). A recent study identified a highly unusual pattern of metastatic spread to axLN in patients with BRAF mutated colorectal cancer (CRC). The purpose of the study is to assess the incidence of axLN metastases in BRAF mutated NSCLC. Baseline computed tomography (CT) imaging at diagnosis and all follow up CTs of patients with BRAF mutated NSCLC treated at our institution were retrospectively reviewed by two radiologists for evidence of axLN metastases. Positron emission tomography (PET)/CT was reviewed when available. A control group of patients with non-BRAF mutated NSCLC was assessed. Three criteria were used for the diagnosis of a metastatic node; pathologic confirmation, radiologic size greater ≥1.5cm in short axis diameter or fluorodeoxyglucose avidity on PET/CT and radiologic size ≥1.0cm in short axis diameter. Forty-six patients with BRAF mutated NSCLC and CT images on the institutional PACS were identified. 7 (15%) patients with BRAF mutated NSCLC had axLN metastases using the proposed diagnostic criteria. One patient had a pathologic proven axLN metastasis, 3 had axLNs measuring ≥1.5cm in short axis, and 3 had nodes which were FDG avid on PET/CT and measured ≥1.0cm in short axis. By comparison, 1 of 46 (2%) control patients with non-BRAF mutated NSCLC had axLN metastases. Previous series have reported the prevalence of axLN metastases in patients with NSCLC as 0.61-0.75%. We have found a higher incidence of axLN metastases in BRAF mutated NSCLC patients than described in non-BRAF mutated NSCLC patients. Examination of the axilla should be a routine part of physical examination in this genetically distinct subgroup of lung cancer patients.

Comparison of CT volumetric measurement with RECIST response in patients with lung cancer.

PURPOSE: To examine the correlations between uni-dimensional RECIST and volumetric measurements in patients with lung adenocarcinoma and to assess their association with overall survival (OS) and progression-free survival (PFS). MATERIALS AND METHODS: In this study of patients receiving chemotherapy for lung cancer in the setting of a clinical trial, response was prospectively evaluated using RECIST 1.0. Retrospectively, volumetric measurements were recorded and response was assessed by two different volumetric methods at each followup CT scan using a semi-automated segmentation algorithm. We subsequently evaluated the correlation between the uni-dimensional RECIST measurements and the volumetric measurements and performed landmark analyses for OS and PFS at the completion of the first and second follow-ups. Kaplan-Meier curves together with log-rank tests were used to evaluate the association between the different response criteria and patient outcome. RESULTS: Forty-two patients had CT scans at baseline, after the first follow up scan and second followup scan, and then every 8 weeks. The uni-dimensional RECIST measurements and volumetric measurements were strongly correlated, with a Spearman correlation coefficient (ρ) of 0.853 at baseline, ρ=0.861 at the first followup, ρ=0.843 at the 2nd followup, and ρ=0.887 overall between-subject. On first follow-up CT, partial responders and non responders as assessed by an "ellipsoid" volumetric criteria showed a significant difference in OS (p=0.008, 1-year OS of 70% for partial responders and 46% for non responders). There was no difference between the groups when assessed by RECIST criteria on first follow-up CT (p=0.841, 1-year OS rate of 64% for partial responders and 64% for non responders). CONCLUSION: Volumetric response on first follow-up CT may better predict OS than RECIST response. CLINICAL RELEVANCE STATEMENT: Assessment of tumor size and response is of utmost importance in clinical trials. Volumetric measurements may help to better predict OS than uni-dimensional RECIST criteria.

Non-contrast CT at comparable dose to an abdominal radiograph in patients with acute renal colic; impact of iterative reconstruction on image quality and diagnostic performance.

OBJECTIVES: The aim was to assess the performance of low-dose non-contrast CT of the urinary tract (LD-CT) acquired at radiation exposures close to that of abdominal radiography using adaptive statistical iterative reconstruction (ASiR). METHODS: Thirty-three patients with clinically suspected renal colic were prospectively included. Conventional dose (CD-CT) and LD-CT data sets were contemporaneously acquired. LD-CT images were reconstructed with 40 %, 70 % and 90 % ASiR. Image quality was subjectively and objectively measured. Images were also clinically interpreted. RESULTS: Mean ED was 0.48 ± 0.07 mSv for LD-CT compared with 4.43 ± 3.14 mSv for CD-CT. Increasing the percentage ASiR resulted in a step-wise reduction in mean objective noise (p < 0.001 for all comparisons). Seventy % ASiR LD-CT images had higher diagnostic acceptability and spatial resolution than 90 % ASiR LD-CT images (p < 0.001). Twenty-seven calculi (diameter = 5.5 ± 1.7 mm), including all ureteric stones, were correctly identified using 70 % ASiR LD-CT with two false positives and 16 false negatives (diameter = 2.3 ± 0.7 mm) equating to a sensitivity and specificity of 72 % and 94 %. Seventy % ASiR LD-CT had a sensitivity and specificity of 87 % and 100 % for detection of calculi >3 mm. CONCLUSION: Reconstruction of LD-CT images with 70 % ASiR resulted in superior image quality than FBP, 40 % ASIR and 90 % ASIR. LD-CT with ASIR demonstrates high sensitivity and specificity for detection of calculi >3 mm. TEACHING POINTS: • Low-dose CT studies for urinary calculus detection were performed with a mean dose of 0.48 ± 0.07 mSv • Low-dose CT with 70 % ASiR detected calculi >3 mm with a sensitivity and specificity of 87 % and 100 % • Reconstruction with 70 % ASiR was superior to filtered back projection, 40 % ASiR and 90 % ASiR images.

Self-healing of damage in fibre-reinforced polymer-matrix composites.

Self-healing resin systems have been discussed for over a decade and four different technologies had been proposed. However, little work on their application as composite matrices has been published although this was one of the stated aims of the earliest work in the field. This paper reports on the optimization of a solid-state self-healing resin system and its subsequent use as a matrix for high volume fraction glass fibre-reinforced composites. The resin system was optimized using Charpy impact testing and repeated healing, while the efficiency of healing in composites was determined by analysing the growth of delaminations following repeated impacts with or without a healing cycle. To act as a reference, a non-healing resin system was subjected to the same treatments and the results are compared with the healable system. The optimized resin system displays a healing efficiency of 65% after the first healing cycle, dropping to 35 and 30% after the second and third healing cycles, respectively. Correction for any healability due to further curing showed that approximately 50% healing efficiency could be achieved with the bisphenol A-based epoxy resin containing 7.5% of polybisphenol-A-co-epichlorohydrin. The composite, on the other hand, displays a healing efficiency of approximately 30%. It is therefore clear that the solid-state self-healing system is capable of healing transverse cracks and delaminations in a composite, but that more work is needed to optimize matrix healing within a composite and to develop a methodology for assessing recovery in performance.

SMAD3 represses androgen receptor-mediated transcription.

The androgen-signaling pathway is important in the growth and progression of prostate cancer. Androgen ablation therapy, which may result in programmed cell death, is often used to treat advanced prostate cancer. The growth-promoting effects of androgen are mediated mostly through the androgen receptor (AR). Transforming growth factor beta (TGF-beta) plays critical roles in controlling prostate cell proliferation, differentiation, and apoptosis. Normal transcripts and proteins of TGF-beta receptors are frequently lost in prostate cancer cells, especially in advanced stages of the disease. However, the mechanisms by which TGF-beta inhibits proliferation and induces apoptosis in prostate cancer cells is not clear. We investigated the molecular mechanism by which TGF-beta inhibits transcriptional activation mediated by AR. Using transient transfection systems, we demonstrated that Smad3 specifically represses transcriptional activation mediated by AR on two natural androgen-responsive promoters. This repression is transmitted through TGF-beta signaling and can be regulated by other Smad proteins. A protein-protein interaction between AR and Smad3 was identified in vitro and in vivo, and the transcription activation domain of AR and the MH2 of Smad3 were identified as being responsible for binding. Additional functional experiments showed that the repression of AR by Smad3 is mediated solely through the MH2 domain. These results provide fresh insight for understanding the mechanism by which TGF-beta regulates the androgen-signaling pathway in prostate cancer cells.

serpent, a GATA-like transcription factor gene, induces fat-cell development in Drosophila melanogaster.

The GATA-like transcription factor gene serpent is necessary for embryonic fat-cell differentiation in Drosophila (Sam, S., Leise, W. and Hoshizaki, D. K. (1996) Mech. Dev. 60, 197-205) and has been proposed to function in a cell-fate choice between fat cell and somatic gonadal precursors (Moore, L. A., Broihier, H. T., Van Doren, M. and Lehmann, R. (1998) Development 125, 837-44; Riechmann, V., Irion, U., Wilson, R., Grosskortenhaus, R. and Leptin, M. (1997) Development 124, 2915-22). Here, we report that deregulated expression of serpent in the mesoderm induces the formation of ectopic fat cells and prevents the migration and coalescence of the somatic gonadal precursors. The ectopic fat cells do not arise from hyperproliferation of the primary fat-cell clusters but they do associate with the endogenous fat cells to form a fat body that is expanded in both the dorsal/ventral and anterior/posterior axes. Misexpression of serpent also affects the differentiation of muscle cells. Few body-wall muscle precursors are specified and there is a loss of most body-wall muscle fibers. The precursors of the visceral mesoderm are also absent and concomitantly the visceral muscle is absent. We suggest that the ectopic fat cells might originate from cells that have the potential, but do not normally, differentiate into fat cells or from cells that have acquired a fat-cell fate. In light of our results, we discuss the role of serpent in fat-cell specification and in cell fate choices.

The naturally occurring mutants of DDB are impaired in stimulating nuclear import of the p125 subunit and E2F1-activated transcription.

The human UV-damaged-DNA binding protein DDB has been linked to the repair deficiency disease xeroderma pigmentosum group E (XP-E), because a subset of XP-E patients lack the damaged-DNA binding function of DDB. Moreover, the microinjection of purified DDB complements the repair deficiency in XP-E cells lacking DDB. Two naturally occurring XP-E mutations of DDB, 82TO and 2RO, have been characterized. They have single amino acid substitutions (K244E and R273H) within the WD motif of the p48 subunit of DDB, and the mutated proteins lack the damaged-DNA binding activity. In this report, we describe a new function of the p48 subunit of DDB, which reveals additional defects in the function of the XP-E mutants. We show that when the subunits of DDB were expressed individually, p48 localized in the nucleus and p125 localized in the cytoplasm. The coexpression of p125 with p48 resulted in an increased accumulation of p125 in the nucleus, indicating that p48 plays a critical role in the nuclear localization of p125. The mutant forms of p48, 2RO and 82TO, are deficient in stimulating the nuclear accumulation of the p125 subunit of DDB. In addition, the mutant 2RO fails to form a stable complex with the p125 subunit of DDB. Our previous studies indicated that DDB can associate with the transcription factor E2F1 and can function as a transcriptional partner of E2F1. Here we show that the two mutants, while they associate with E2F1 as efficiently as wild-type p48, are severely impaired in stimulating E2F1-activated transcription. This is consistent with our observation that both subunits of DDB are required to stimulate E2F1-activated transcription. The results provide insights into the functions of the subunits of DDB and suggest a possible link between the role of DDB in E2F1-activated transcription and the repair deficiency disease XP-E.

Effects of topical 10% ascorbate solution on established corneal ulcers after severe alkali burns.

When established corneal ulcers induced by alkali burning were treated with 10% ascorbate drops, no perforation occurred, in contrast to a 25% incidence in the control group. If perforations and descemetoceles were grouped together, these difference became insignificant (i.e., 14.2% ascorbate-treated vs. 25% control). Prolongation of descemetocele presence without perforation in the ascorbate-treated group indicated some therapeutic effect. We conclude that topical ascorbate does not substantially alter the outcome of established corneal ulcers.

The influence of parenteral ascorbate on the strength of corneal wounds.

Rabbits receiving subcutaneous ascorbate after corneal wounding showed significant elevation of aqueous humor ascorbate levels but no enhancement of wound breaking strength when compared to controls. In a second group of rabbits, perilimbal alkali burning reduced aqueous humor ascorbate levels one-half to one-third normal. In these perilimbally burned eyes with wounds in clear cornea, subcutaneous ascorbate significantly raised the aqueous humor ascorbate level and enhanced breaking wound strength compared to controls. We conclude that parenterally administered ascorbate has no salutory effect on the breaking strength of corneal wounds in the normal rabbit eye. In contrast, subcutaneous ascorbate has a very favorable effect on the breaking strengths of corneal wounds in those eye with depressed aqueous humor ascorbate.

The efficacy of ascorbate treatment after severe experimental alkali burns depends upon the route of administration.

Rabbit eyes were subjected to severe alkali burns (35 sec, 12 mm, 1N sodium hydroxide). In one experiment, rabbits in the treated group received a daily subcutaneous injection of neutralized ascorbic acid solution (0.5 gm/kg body weight), while control animals received no treatment. At the termination of the experiment (30 days), 11 of 16 eyes (68.8%) in the control group had ulcerated or formed descemetoceles, and in the experimental (treated) group, 15 of 20 eyes (75%) had ulcerated, formed descemetoceles, or perforated. In a second experiment, burned rabbits received topical 10% ascorbic acid while control eyes were given the vehicle only. At the termination of the experiment (34 days), 16 of 20 eyes (80%) in the control group had ulcerated or perforated, compared to five of 18 eyes (27.8%) in the ascorbate treated groups. The failure of systemic administration of ascorbic acid to prevent corneal ulceration could be explained on the basis of inadequate penetration of ascorbic acid into the anterior segment of severely burned rabbit eyes. On the other hand, immediate topical treatment of identically burned rabbit eyes achieved greatly elevated aqueous humor ascorbate levels and provided substantial protection from corneal ulceration and perforation.