A Phase II Study of Oxaliplatin, Pemetrexed, and Bevacizumab in Previously Treated Advanced Non-small Cell Lung Cancer

IntroductionSingle agent chemotherapy is standard for second and third line treatment of non-small cell lung cancer (NSCLC). Combination therapy to date has not proven to be superior to single agents in this setting, often adding toxicity without any additional efficacy. We investigated the activity and tolerability of the combination of oxaliplatin, pemetrexed, and bevacizumab in patients with previously treated advanced NSCLC.MethodsThis multicenter phase II trial evaluated the safety and efficacy of the combination of pemetrexed (500 mg/m2), oxaliplatin (120 mg/m2), and bevacizumab (15 mg/kg), given every 21 days, in patients with previously treated advanced NSCLC. Eligibility criteria included performance status 0 to 1, nonsquamous histology, and at least one prior chemotherapy regimen. Patients with treated brain metastases were allowed. The primary end point was response rate, with secondary endpoints of progression-free survival and overall survival.ResultsThirty-six patients were enrolled on this study. Treatment was well tolerated; the most common grade 3 toxicity was hypertension, which was easily managed with oral medications. The nine (25%) patients with treated brain metastases had no episodes of cerebral hemorrhage. Of the 34 patients evaluable for tumor response, none had complete response, nine (27%) had partial response, 15 (44%) had stable disease, and 10 (29%) had progressive disease. Median progression-free survival was 5.8 months (95% confidence interval 4.1–7.8 months) and median overall survival was 12.5 months (95% confidence interval 7.3–17 months).ConclusionsTreatment with oxaliplatin and pemetrexed in combination with the targeted antiangiogenic agent bevacizumab yielded promising efficacy with manageable toxicity in the previously treated advanced NSCLC population

Neuronal pentraxins mediate synaptic refinement in the developing visual system

Peer reviewedPublisher PD

Rapidly fatal advanced EGFR -mutated lung cancers and the need for rapid tumor genotyping in clinical practice

Use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is associated with dramatic, durable, and tolerable responses and side effect profiles, respectively, when applied for palliation of advanced EGFR-mutated non-small-cell lung cancers (NSCLCs). Expert guidelines recommend that EGFR mutation testing results should be available within 10 working days of receipt of tumor specimen by the testing laboratory; in circumstances where the tumor specimen needs to be sent to an external laboratory for testing, the sample should be sent within 3 working days of receiving the request for testing. We report here 2 cases, out of 109 EGFR-mutated (exon 19 deletion or L858R) NSCLCs seen at our institution, experiencing rapid clinical deterioration and death within the window of time prescribed by consensus testing guidelines. We hypothesize that a faster turn-around time may have changed the clinical outcome. Improving rapid turnaround times for tumor genotyping may afford more optimal palliation vis-à-vis early initiation of oral targeted therapy in patients with advanced EGFR-mutated NSCLC

Dynamic scaling for 2D superconductors, Josephson junction arrays and superfluids

The value of the dynamic critical exponent $z$ is studied for two-dimensional superconducting, superfluid, and Josephson Junction array systems in zero magnetic field via the Fisher-Fisher-Huse dynamic scaling. We find $z\simeq5.6\pm0.3$, a relatively large value indicative of non-diffusive dynamics. Universality of the scaling function is tested and confirmed for the thinnest samples. We discuss the validity of the dynamic scaling analysis as well as the previous studies of the Kosterlitz-Thouless-Berezinskii transition in these systems, the results of which seem to be consistent with simple diffusion ($z=2$). Further studies are discussed and encouraged.Comment: 19 pages in two-column RevTex, 8 embedded EPS figure

Brain metastases in patients with EGFR -mutated or ALK -rearranged non-small-cell lung cancers

Introduction—Brain metastases (BM) are common in non-small-cell lung cancer (NSCLC). However, the baseline incidence and evolution of BM over time in oncogene-driven NSCLCs are seldom reported. In this study, we evaluated the frequency of BM in patients with epidermal growth factor receptor (EGFR)-mutated or anaplastic lymphoma kinase (ALK)-rearranged NSCLC. Methods—The presence of BM, clinicopathologic data, and tumor genotype were retrospectively compiled and analyzed from a cohort of 381 patients. Results—We identified 86 EGFR-mutated (90.7% with metastatic disease; 85.9% received an EGFR inhibitor) and 23 ALK-rearranged (91.3% with metastatic disease; 85.7% received an ALK inhibitor) NSCLCs. BM were present in 24.4% of EGFR-mutated and 23.8% of ALK-rearranged NSCLCs at the time of diagnosis of advanced disease. This study did not demonstrate a difference in the cumulative incidence of BM over time between the two cohorts (EGFR/ALK cohort competing risk regression [CRR] coefficient of 0.78 [95% CI 0.44–1.39], p=0.41). In still living patients with advanced EGFR-mutated NSCLC, 34.2% had BM at 1 year, 38.4% at 2 years, 46.7% at 3 years, 48.7% at 4 years, and 52.9% at 5 years. In still living patients with advanced ALKrearranged NSCLC, 23.8% had BM at 1 year, 45.5% at 2 years, and 58.4% at 3 years. Conclusions—BM are frequent in advanced EGFR-mutated or ALK-rearranged NSCLCs, with an estimated >45% of patients with CNS involvement by three years of survival with the use of targeted therapies. These data point toward the CNS as an important unmet clinical need in the evolving schema for personalized care in NSCLC

Experience with targeted next generation sequencing for the care of lung cancer: Insights into promises and limitations of genomic oncology in day-to-day practice

Introduction Tumor genotyping using single gene assays (SGAs) is standard practice in advanced non-small-cell lung cancer (NSCLC). We evaluated how the introduction of next generation sequencing (NGS) into day-to-day clinical practice altered therapeutic decision-making. Methods Clinicopathologic data, tumor genotype, and clinical decisions were retrospectively compiled over 6 months following introduction of NGS assay use at our institution in 82 patient-tumor samples (7 by primary NGS, 22 by sequential SGAs followed by NGS, and 53 by SGAs). Results SGAs identified abnormalities in 34 samples, and all patients with advanced EGFR-mutated or ALK-rearranged tumors received approved tyrosine kinase inhibitors (TKIs) or were consented for clinical trials. NGS was more commonly requested for EGFR, ALK, and KRAS-negative tumors (p<0.0001). NGS was successful in 24/29 (82.7%) tumors. Of 17 adenocarcinomas (ACs), 11 (7 from patients with ≤15 pack-years of smoking) had abnormalities in a known driver oncogene. This led to a change in decision-making in 8 patients, trial consideration in 6, and off-label TKI use in 2. Of 7 squamous cell (SC) carcinomas, 1 had a driver aberration (FGFR1); 6 had other genomic events (all with TP53 mutations). In no cases were clinical decisions altered (p=0.0538 when compared to ACs). Conclusions Targeted NGS can identify a significant number of therapeutically-relevant driver events in lung ACs; particularly in never or light smokers. For SC lung cancers, NGS is less likely to alter current practice. Further research into the cost effectiveness and optimal use of NGS and improved provider training in genomic oncology are warranted

Success and failure rates of tumor genotyping techniques in routine pathological samples with non-small-cell lung cancer

Introduction—Identification of some somatic molecular alterations in non-small-cell lung cancer (NSCLC) has become evidence-based practice. The success and failure rate of using commercially-available tumor genotyping techniques in routine day-to-day NSCLC pathology samples is not well described. We sought to evaluate the success and failure rate of EGFR mutation, KRAS mutation, and ALK FISH in a cohort of lung cancers subjected to routine clinical tumor genotype. Methods—Clinicopathologic data, tumor genotype success and failure rates were retrospectively compiled and analyzed from 381 patient-tumor samples. Results—From these 381 patients with lung cancer, the mean age was 65 years, 61.2% were women, 75.9% were white, 27.8% were never smokers, 73.8% had advanced NSCLC and 86.1% had adenocarcinoma histology. The tumor tissue was obtained from surgical specimens in 48.8%, core needle biopsies in 17.9%, and as cell blocks from aspirates or fluid in 33.3% of cases. Anatomic sites for tissue collection included lung (49.3%), lymph nodes (22.3%), pleura (11.8%), bone (6.0%), brain (6.0%), among others. The overall success rate for EGFR mutation analysis was 94.2%, for KRAS mutation 91.6% and for ALK FISH 91.6%. The highest failure rates were observed when the tissue was obtained from image-guided percutaneous transthoracic core-needle biopsies (31.8%, 27.3%, and 35.3% for EGFR, KRAS, and ALK tests, respectively) and bone specimens (23.1%, 15.4%, and 23.1%, respectively). In specimens obtained from bone, the failure rates were significantly higher for biopsies than resection specimens (40% vs 0%, p=0.024 for EGFR) and for decalcified compared to non-decalcified samples (60% vs 5.5%, p=0.021 for EGFR). Conclusions—Tumor genotype techniques are feasible in most samples, outside small imageguided percutaneous transthoracic core-needle biopsies and bone samples from core biopsies with decalcification, and therefore expansion of routine tumor genotype into the care of patients with NSCLC may not require special tissue acquisition or manipulation

Targeted Destruction of Photosensitive Retinal Ganglion Cells with a Saporin Conjugate Alters the Effects of Light on Mouse Circadian Rhythms

Non-image related responses to light, such as the synchronization of circadian rhythms to the day/night cycle, are mediated by classical rod/cone photoreceptors and by a small subset of retinal ganglion cells that are intrinsically photosensitive, expressing the photopigment, melanopsin. This raises the possibility that the melanopsin cells may be serving as a conduit for photic information detected by the rods and/or cones. To test this idea, we developed a specific immunotoxin consisting of an anti-melanopsin antibody conjugated to the ribosome-inactivating protein, saporin. Intravitreal injection of this immunotoxin results in targeted destruction of melanopsin cells. We find that the specific loss of these cells in the adult mouse retina alters the effects of light on circadian rhythms. In particular, the photosensitivity of the circadian system is significantly attenuated. A subset of animals becomes non-responsive to the light/dark cycle, a characteristic previously observed in mice lacking rods, cones, and functional melanopsin cells. Mice lacking melanopsin cells are also unable to show light induced negative masking, a phenomenon known to be mediated by such cells, but both visual cliff and light/dark preference responses are normal. These data suggest that cells containing melanopsin do indeed function as a conduit for rod and/or cone information for certain non-image forming visual responses. Furthermore, we have developed a technique to specifically ablate melanopsin cells in the fully developed adult retina. This approach can be applied to any species subject to the existence of appropriate anti-melanopsin antibodies