Immunosuppression and the Risk of Post-Transplant Malignancy Among Cadaveric First Kidney Transplant Recipients

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73619/1/j.1600-6135.2003.00274.x.pd

Correlations of EGFR mutations and increases in EGFR and HER2 copy number to gefitinib response in a retrospective analysis of lung cancer patients

<p>Abstract</p> <p>Background</p> <p>Gefitinib, a small molecule tyrosine kinase inhibitor of the Epidermal Growth Factor Receptor (<it>EGFR</it>), has shown limited efficacy in the treatment of lung cancer. Recognized clinical predictors of response to this drug, specifically female, non-smoker, Asian descent, and adenocarcinoma, together suggest a genetic basis for drug response. Recent studies have addressed the relationship between response and either sequence mutations or increased copy number of specific receptor tyrosine kinases. We set out to examine the relationship between response and the molecular status of two such kinases, <it>EGFR </it>and <it>HER2</it>, in 39 patients treated with gefitinib at the BC Cancer Agency.</p> <p>Methods</p> <p>Archival patient material was reviewed by a pathologist and malignant cells were selectively isolated by laser microdissection or manual recovery of cells from microscope slides. Genomic DNA was extracted from 37 such patient samples and exons 18–24, coding for the tyrosine kinase domain of <it>EGFR</it>, were amplified by PCR and sequenced. <it>EGFR </it>and <it>HER2 </it>copy number status were also assessed using FISH in 26 samples. Correlations between molecular features and drug response were assessed using the two-sided Fisher's exact test.</p> <p>Results</p> <p>Mutations previously correlated with response were detected in five tumours, four with exon 19 deletions and one with an exon 21 missense L858R point mutation. Increased gene copy number was observed in thirteen tumours, seven with <it>EGFR </it>amplification, three with <it>HER2 </it>amplification, and three with amplification of both genes. In our study cohort, a correlation was not observed between response and <it>EGFR </it>mutations (exon 19 deletion p = 0.0889, we observed a single exon 21 mutation in a non-responder) or increases in <it>EGFR </it>or <it>HER2 </it>copy number (p = 0.552 and 0.437, respectively).</p> <p>Conclusion</p> <p>Neither mutation of <it>EGFR </it>nor increased copy number of <it>EGFR </it>or <it>HER2 </it>was diagnostic of response to gefitinib in this cohort. However, validation of these features in a larger sample set is appropriate. Identification of additional predictive biomarkers beyond <it>EGFR </it>status may be necessary to accurately predict treatment outcome.</p

Rapidly Changing Treatment Algorithms for Metastatic Nonsquamous Non-Small-Cell Lung Cancer

Background: The treatment paradigm for metastatic nonsquamous non-small-cell lung cancer (NSCLC) continues to change. Algorithms published only 6 months ago are outdated today and are dramatically different from those published a few years ago. New driver mutations continue to be identified, and the development of therapies to inhibit oncogenic addiction is ongoing. Patient survival is improving as treatments become more personalized and effective. Methods: This review looks at the outcomes of recent trials and discusses treatment options for patients with metastatic NSCLC of nonsquamous histology. Algorithms continue to change quickly, and an attempt is made to keep the paradigm current and applicable into the near future. Results: Treatment algorithms for nsclc tumours with EGFR mutations, ALK rearrangements, and ROS1 rearrangements, and for wild-type tumours are presented. A future algorithm based on new immunotherapy data is proposed. The treatment algorithm for EGFR mutation is changing with the proven efficacy of osimertinib for the acquired T790M mutation. All patients taking first- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors must be tested. Conclusions: The treatment algorithm for ALK rearrangement has changed with the proven superiority of alectinib compared with crizotinib in the first-line setting. The approval of crizotinib for ROS1 rearrangements now means that patients also must be tested for that mutation. The biomarker for checkpoint inhibitors continues to be PD-L1 by immunohistochemistry stain, but whether testing will be necessary for patient selection if chemotherapy combinations are implemented will be determined soon

Advanced Typical and Atypical Carcinoid Tumours of the Lung: Management Recommendations

Background: Neuroendocrine tumours (NETS) are classified by site of origin, with lung being the second most common primary site after the gastrointestinal tract. Lung nets are rare and heterogeneous, with varied pathologic and clinical features. Typical and atypical carcinoid tumours are low-grade lung nets which, compared with the more common high-grade nets, are associated with a more favourable prognosis. Still, optimal treatment strategies are lacking. Methods: This review concentrates on classification and treatment strategies for metastatic low-grade lung nets, considering both typical and atypical carcinoids. The terminology can be confusing, and an attempt is made to simplify it. Promising results from recent trials that included lung nets are presented and discussed. Finally, guidelines from Europe and North America are discussed, and differences are noted. Results: Even within the group of patients with low-grade nets, the presentation, the locations of metastasis, and the speed of progression can be very different. The initial work-up and an understanding of the tumour’s biology are key in making management decisions. Various treatment options—including somatostatin analogs, peptide receptor radioligand therapy, and biologic systemic therapy, specifically with the mtor (mechanistic target of rapamycin) inhibitor everolimus—are now available and are presented in a treatment algorithm. Summary: Although lung nets are rare and evidence supporting optimal treatment strategies is lacking, the recent publication of trials that have included patients with lung nets advances evidence-based therapy for these tumours. Many variables have to be considered in managing these tumours that have received little attention. Education for treating physicians is needed