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Supplementary Data Table 2 from Nonsynonymous Coding Single-Nucleotide Polymorphisms Spanning the Genome in Relation to Glioblastoma Survival and Age at Diagnosis

Supplementary Data Table 3 from Nonsynonymous Coding Single-Nucleotide Polymorphisms Spanning the Genome in Relation to Glioblastoma Survival and Age at Diagnosis

Purpose: Our aim was to discover possible inherited factors associated with glioblastoma age at diagnosis and survival. Although new genotyping technologies allow greatly expanded exploration of such factors, they pose many challenges.Experimental Design: In this pilot study, we (a) genotyped 112 newly diagnosed glioblastoma patients ascertained through a population-based study (group 1) with the ParAllele assay panel of ∼10,000 nonsynonymous coding single-nucleotide polymorphisms (SNP), (b) used several statistical and bioinformatic techniques to identify 17 SNPs potentially related to either glioblastoma age at diagnosis or survival, and (c) genotyped 16 of these SNPs using conventional PCR methods in an independent group of 195 glioblastoma patients (group 2).Results: In group 2, only one of the 16 SNPs, rs8057643 (located on 16p13.2), was significantly associated with glioblastoma age at diagnosis (nominal P = 0.0017; Bonferroni corrected P = 0.054). Median ages at diagnosis for those with 0, 1, or 2 T alleles were 66, 57, and 59 years in group 1 and 64, 57, and 55 years in group 2 (combined P = 0.001). Furthermore, Cox regression analyses of time to death with number of T alleles adjusted for gender and patient group yielded a hazard ratio of 0.82 (95% confidence interval, 0.68-0.98; P = 0.03).Conclusions: Although limited by a relatively small sample size, this pilot study, using well-characterized, unambiguous disease characteristics, illustrates the necessity of independent replication owing to the likelihood of false positives. Several other challenges are discussed, including attempts to incorporate information on the potential functional importance of SNPs in genome-disease association studies.

We and others have reported previously that adults with glioma are 1.5- to 4-fold less likely than controls to report a variety of allergic conditions. The consistent nature of this relationship calls for a biological explanation so that preventative or therapeutic modalities can be explored. We enrolled 403 newly diagnosed adult glioma cases in the San Francisco Bay Area over a 3-year period using a population-based cancer registry and 402 age/gender/ethnicity frequency-matched controls identified via random digit dialing. We assessed total, food-specific, and respiratory-specific IgE in available case (n = 228) and control (n = 289) serum samples. IgE levels were associated with gender, age, smoking status, and ethnicity among cases and/or controls. Among the cases, IgE levels were not associated with aspects of glioma therapy including radiation, chemotherapy, or tumor resection. Total IgE levels were lower in cases than controls: age/gender/ethnicity/education/smoking-adjusted odds ratio (OR) for elevated versus normal total IgE was 0.37 [95% confidence interval (CI), 0.22–0.64]. For the food panel, OR was 0.12 (95% CI, 0.04–0.41). For the respiratory panel, OR was 0.76 (95% CI, 0.52–1.1). Among respiratory allergies, late age of onset (>12 years) but not IgE levels defined a group with strong associations with risk (OR, 0.50; 95% CI, 0.33–0.75). These results corroborate and strengthen our findings of an inverse association between allergic reactions and glioma by showing a relationship with a biomarker for allergy and cancer for the first time. Furthermore, the results indicate a complex relationship between allergic disease and glioma risk that varies by allergen and allergic pathology.

Supplementary Table 1-5 from Reduced Immunoglobulin E and Allergy among Adults with Glioma Compared with Controls

Supplementary Figure S1 from Inhibition of Phosphatidylinositol 3-Kinase Destabilizes Mycn Protein and Blocks Malignant Progression in Neuroblastoma

Lumpectomy and breast radiotherapy (RT) achieve good longterm control of disease in patients diagnosed with ductal carcinoma in situ (DCIS). In the combined analysis of NSABP B-17/B-24 DCIS trials, these treatments were shown to reduce invasive ipsilateral breast tumor recurrences by 52% compared to lumpectomy alone. RT has been consistently used as an adjuvant to surgery and therefore, little is known of its activity on intact/untreated DCIS. Elucidating the effectiveness of radiation therapy may help optimize the treatment of DCIS and avoid over-treatment.Trial Design The objective of the ongoing phase 2 pilot trial is to evaluate the ablative and treatment effects of neoadjuvant RT (neoRT) on DCIS. Patients diagnosed with DCIS on core needle biopsy are randomized to upfront lumpectomy (Arm 1) followed by partial breast irradiation (PBI) or neoRT PBI followed by delayed surgical excision (Arm 2). Arm 1 serves as a reference group for pathological-radiological correlations as well as to ascertain the rate of upstaging to invasive cancer. The neoRT regimen consists of 6 Gy daily x 5 (consecutive or non-consecutive days) to the intact tumor with a 0.5 cm margin. Surgical excision is delayed 12-16 weeks, allowing for the ablative effects of neoRT to occur. Specific Aims •To determine if neoRT can completely ablate 30% of DCIS cases•To determine if DCIS subtypes exhibit differential sensitivity to neoRT•To evaluate microscopic treatment effects; wound complication rates; post-RT breast imaging changes; and invasive carcinoma rate.Eligibility Women 18 years of age or older diagnosed with DCIS by core needle biopsy and intending to receive breast conserving surgery are eligible. Tumors must be ≤4 cm, discovered as mammographic microcalcifications and/or MRI non-mass enhancement measuring with evidence of residual imaging abnormality after diagnostic needle biopsy. Statistics A total of 50 patients will be recruited. Upstaging to invasive cancer is anticipated to be approximately 10%. With 25 subjects in each arm, we will have 80% power to detect a 30% or higher improvement in the DCIS complete response rate following neoadjuvant PBI. Accrual 10 (open 2019) Contact wapnir@stanford.edu. Wapnir IL, Dignam JJ, Fisher B, et al. Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst. 2011;103(6):478-488. doi:10.1093/jnci/djr027.McCormick B, Winter K, Hudis C, et al. RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol. 2015;33(7):709-715. doi:10.1200/JCO.2014.57.9029. Citation Format: Irene Wapnir, Carol Marquez, Kimberly Stone, Kimberly Allison, Wendy DeMartini, Catherine Salem, Jacqueline Tsai, Robert West, Alex McMillan, Melinda Telli, Kathleen Horst. A randomized study comparing surgical excision versus NeOadjuvant Radiotherapy followed by delayed surgical excision of Ductal carcinoma In Situ (NORDIS) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-09-01.

A randomized phase II study comparing surgical excision versus NeOadjuvant Radiotherapy followed by delayed surgical excision of Ductal carcinoma In Situ (NORDIS) Breast radiotherapy (RT) for DCIS has been studied only in the adjuvant setting, following lumpectomy surgery. Adjuvant RT reduced invasive recurrences by 52% in the combined analysis of the two largest DCIS trials NSABP B-17/B-24, and reduced recurrences even for low or intermediate grade DCIS in the RTOG 9804 trial (recurrence 0.9% with RT versus 6.7% without RT). The mechanism of action is hypothesized to be elimination of occult disease and/or inhibition of neoplastic transformation in normal breast tissue. Trial Design To understand the ablative effects of RT on pure DCIS, we are conducting a prospective randomized trial comparing histopathological findings of surgical excision (Arm 1) to neoadjuvant partial breast irradiation (neoRT) followed by delayed surgical excision (Arm 2) for patients with core needle biopsy proven DCIS. Arm 1 will provide a reference group for upstaging to invasive cancer, molecular markers and pathological-radiological correlations. Arm 2 participants will receive 6 Gy daily x 5 to the intact tumor with a 0.5 cm margin of normal tissue. Surgical excision will be delayed 12-16 weeks to allow for the radioablative effects to occur and radiation-induced inflammation to subside. Specific Aims To determine if neoRT can completely ablate at least 30% of pure DCISTo determine if DCIS subtypes exhibit differential sensitivity to neoRTTo determine the radiation-induced treatment effects; wound complication rates; radiological Eligibility Women 18 years of age or older with DCIS diagnosed on vacuum assisted core needle biopsy who intend to receive breast conserving surgery are eligible, excluding those with a prior history of ipsilateral breast cancer. The imaging abnormality must be mammographic microcalcifications and/or MRI non-mass enhancement measuring Statistics A total of 50 patients will be recruited. Upstaging to invasive cancer is anticipated to be approximately 10% in the reference group. With 25 subjects in each arm, we will have 80% power to detect a 30% or higher improvement in the DCIS complete response rate following neoRT. Accrual Opened to accrual June 1, 2019 Contact wapnir@stanford.edu Wapnir IL, Dignam JJ, Fisher B, et al. Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst. 2011;103(6):478-488. doi:10.1093/jnci/djr027. McCormick B, Winter K, Hudis C, et al. RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol. 2015;33(7):709-715. doi:10.1200/JCO.2014.57.9029. Citation Format: Irene Wapnir, Wendy DeMartini, Kimberly Allison, Kimberly Stone, Frederick Dirbas, Carol Marquez, Debra Ikeda, Sunita Pal, Jacqueline Tsai, Rachel Yang, Robert West, Alex McMillan, Melinda Telli, Kathleen Horst. A randomized phase II study comparing surgical excision versus NeOadjuvant Radiotherapy followed by delayed surgical excision of Ductal carcinoma In Situ (NORDIS) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-09-04.

We demonstrate the use of Hong-Ou-Mandel interference to resolve < 10µm scale depth-features of a semi-transparent sample and incorporate confocal imaging for 3D microscopy using photons from a wavelength-entangled pair photon source.

A limitation of free-space optical communications is the ease with which the information can be intercepted. This limitation can be overcome by hiding the information within background optical noise. We demonstrate the transfer of images over free-space using a photon-pair source emitting two correlated beams. One of these beams contains image information, to which noise is added, and the other correlated beam is used as a heralding trigger so that the intended recipient can differentiate this image signal from the background noise. The system uses spontaneous parametric down-conversion to create photon-pairs with a wide spectral bandwidth and a gated intensified camera to extract the image from the background noise. The high-dimensionality of the image space means that the information content can be many bits per detected photon, whereas the heralding photon can be restricted to a single spatial-mode within a secure fiber which itself could be protected against interception by traditional low-dimensionality quantum key protocols.

Background: Talazoparib, a PARP1 inhibitor, is active in germline BRCA1/2 mutant advanced HER2-negative breast cancer, but its activity beyond BRCA1/2 less well understood. The Talazoparib Beyond BRCA clinical trial treated 20 patients with germline (g) or somatic (s) mutations in HR pathways genes other than BRCA1/2, which included PALB2, CHEK2, ATM, BRIP1, RAD50, ATR, PTEN, and FANCA. Talazoparib treatment was associated with a 31% overall response rate in patients with breast cancer, including tumor regression from baseline as best response in 6 out of 6 patients treated gPALB2 mutations. We now present the results of additional genomic studies to further characterize treatment responses and resistance mechanisms. Methods: Primary and metastatic tumor biopsies were assessed using the commercially-available next-generation sequencing HRD assay (Myriad). Panel gene sequencing of tumors was performed for 108 genes associated with genomic instability. Loss-of-heterozygosity (LOH) was assessed in tumors. Tumor/normal exome sequencing identified pre-treatment somatic variants. Circulating-tumor DNA at baseline and disease progression was assessed by targeted panel sequencing and plasma whole exome sequencing. Results: Of the 18 HRD assays performed, 3 failed and were thus excluded. Seven patients had HRD analysis performed on both primary and metastatic tumors. For these patients the HRD score was significantly higher in the metastasis versus the primary (means 46.2 versus 36.5, p = 0.018 by paired t-test). By panel sequencing of tumors (n=18) the most common alterations detected included mutations in PIK3CA (n=8), PALB2 (n=6), ATM (n=5), KRAS (n=4), PTEN (n=5) and TP53 (n=4). In all cases except one, the HR-associated mutation used as entry criteria were detected. LOH analysis showed that of tumors with gPALB2 mutations, 3 of the 6 had LOH for PALB2, and an additional two tumors had 2 independent PALB2 mutations suggesting bi-allelic inactivation. The one remaining tumor had an uncertain LOH result due to test failure. Thus, it is likely that most, if not all, of the tumors in our cohort with gPALB2 mutations had complete inactivation of PALB2 gene function. Other detected mutations that were associated with LOH included all sTP53 mutations (n=4), all gCHEK2 mutations (n=3), gFANCA (n=1), all sRB1 mutations (n=3) and NF1 (n=1). Of the three gATM mutations one had LOH, while the others had two independent mutations, suggestive of bi-allelic inactivation. sATM mutations were associated with LOH in a breast cancer and with 2 independent (possibly bi-allelic) mutations in a non-breast cancer. Additional results from ctDNA targeted sequencing and plasma whole exome sequencing of baseline and progression samples will be presented. Conclusions: In this proof-of-concept phase II study, talazoparib demonstrated activity in HER2-negative advanced breast cancer patients with a HR pathway mutation beyond BRCA1/2, especially in patients with gPALB2 mutations and high HRD scores. These additional genomic analyses provide evidence that HRD scores may be significantly higher in metastatic samples compared to primary tumors. Also, we detected either LOH or bi-allelic inactivation for most HR-associated mutations used to determine eligibility. These findings may inform selection of patients for PARP inhibitor monotherapy beyond BRCA1/2. Citation Format: Joshua J Gruber, Anosheh Afghahi, Alyssa Hatton, Wyatt Gross, Jessica Foran, Alex McMillan, James M Ford, Melinda L Telli. Genomic analysis from the talazoparib beyond BRCA clinical trial: Homologous recombination (HR) deficiency scores, loss-of-heterozygosity and mutations in non-BRCA1/2 mutant tumors with other HR mutations [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-12.

Traditional remote sensing applications are often based on pulsed laser illumination with a narrow linewidth and characteristic repetition rate, which are not conducive to covert operation. Whatever methods are employed for covert sensing, a key requirement is for the probe light to be indistinguishable from background illumination. We present a method to perform single-pixel imaging that suppresses the effect of background light and hence improves the signal-to-noise ratio by using correlated photon-pairs produced via spontaneous parametric down conversion. One of the photons in the pair is used to illuminate the object whilst the other acts as a temporal reference, allowing the signal photons to be distinguished from background noise. This heralding method shows how the noise regime is key to producing higher contrast images.

Quantum light generated in non-degenerate squeezers has many applications such as sub-shot-noise transmission measurements to maximise the information extracted by one photon or quantum illumination to increase the probability in target detection. However, any application thus far fails to consider the thermal characteristics of one half of the bipartite down-converted photon state often used in these experiments. We show here that a maximally mixed state, normally viewed as nuisance, can indeed be used to extract information about the position of an object while at the same time providing efficient camouflaging against other thermal or background light.

We use a spatial light modulator and a genetic algorithm to manipulate the spatial profile of the pump beam of a down-conversion source in order to improve its Klyshko efficiency.

Squeezed light enables measurements with sensitivity beyond the quantum noise limit (QNL) for optical techniques such as spectroscopy, gravitational wave detection, magnetometry and imaging. Precision of a measurement -- as quantified by the variance of repeated estimates -- has also been enhanced beyond the QNL using squeezed light. However, sub-QNL sensitivity is not sufficient to achieve sub-QNL precision. Furthermore, demonstrations of sub-QNL precision in estimating transmission have been limited to picowatts of probe power. Here we demonstrate simultaneous enhancement of precision and sensitivity to beyond the QNL for estimating modulated transmission with a squeezed amplitude probe of 0.2 mW average (25 W peak) power, which is 8 orders of magnitude above the power limitations of previous sub-QNL precision measurements of transmission. Our approach enables measurements that compete with the optical powers of current classical techniques, but have both improved precision and sensitivity beyond the classical limit., Comment: 5 page main text, 9 page appendix, 2 figures

We demonstrate 3D time-of-flight imaging from a scattering target illuminated with a heralded single photon source. Our image reconstruction algorithm achieves millimeter depth resolution with only 0.3 average detected photons per image pixel.

Patient-derived orthotopic xenograft (PDOX) models have been verified as a useful method for studying human cancers in mice. Previous studies on the extent of metastases in these models have been limited by the necessity of welfare euthanasia (primary tumors reaching threshold size), at which point metastases may only be micrometers in diameter, few in number, and solely identified by step-sectioning of formalin-fixed paraffin-embedded tissue. These small micro-metastases are less suitable for many downstream molecular analyses than macro-metastases. Resection of the primary tumor by survival surgery has been proven to allow further time for metastases to grow. Although PDOX models of triple-negative breast cancer (TNBC) shed circulating tumor cells (CTCs) into the bloodstream and metastasize, similar to human TNBC, little data has been collected in these TNBC PDOX models regarding the association between CTC characteristics and distant metastasis following excision of the primary tumor xenograft. This study assembles a timeline of PDOX tumor shedding and metastatic tumor progression before and after tumor excision surgery. We report the ability to use tumorectomies to increase the lifespan of TNBC PDOX models with the potential to obtain larger metastases. CTC clusters and CTCs expressing a mesenchymal marker (vimentin) were associated with metastatic burden in lung and liver. The data collected through these experiments will guide the further use of PDOX models in studying metastatic TNBC.

Optical quantum sensing strategies that utilise features of quantum states of light have implications for precision measurement in areas as wide ranging as such as gravitational wave sensing [1] and biological imaging [2]. Optical absorption estimation is the task of estimating the transmission parameter η which is defined by the ratio of input, I in , to output, I out , intensity of light from a sample of interest (I out = ηΙ ίη ). The optimal quantum strategy provides a quantum advantage (per incident photon) of 1/(1-η) over the best classical strategy [3]. This technique has been demonstrated experimentally in single parameter estimation and imaging scenarios [4,5].

By exploiting the quantised nature of light, we demonstrate a sub-shot-noise scanning optical transmittance microscope. Our microscope demonstrates, with micron scale resolution, a factor of improvement in precision of 1.76(9) in transmittance estimation gained per probe photon relative to the theoretical model, a shot-noise-limited source of light, in an equivalent single-pass classical version of the same experiment using the same number of photons detected with a 90% efficient detector. This would allow us to observe photosensitive samples with nearly twice the precision, without sacrificing image resolution or increasing optical power to improve signal-to-noise ratio. Our setup uses correlated twin-beams produced by parametric down-conversion, and a hybrid detection scheme comprising photon-counting-based feed-forward and a highly efficient CCD camera.

TPS1109 Background: PALB2 (Partner and Localizer of BRCA2) plays a critical role in the maintenance of genomic integrity through its role in the Fanconi anemia and homologous recombination DNA repair pathways. Our recently reported phase II clinical trial (Gruber, et al. JCO 2019) showed that talazoparib monotherapy was associated with single agent activity in germline PALB2 (gPALB2) mutation-associated advanced breast cancers. Of 5 patients with a germline PALB2 mutation, all 5 had reduction in target lesions > 20% with 3 of 5 achieving a RECIST 1.1 response. All patients had visceral metastases and were heavily pretreated; one response occurred in a patient with 8 prior lines of therapy for metastatic breast cancer. Clinical activity of the PARP inhibitor olaparib was also demonstrated in breast cancer patients with gPALB2 mutations in the Olaparib Expanded trial (TBCRC 048). Thus, we believe there is significant value in generating additional PARP inhibitor monotherapy data in subjects with advanced PALB2 mutation-associated breast cancer. We propose this phase II trial to better estimate the rate of RECIST 1.1 objective response in this patient population. Methods: This is a single-arm, two-stage, non-randomized study to assess the objective response rate (ORR) of talazoparib monotherapy in patients with PALB2 mutation-associated advanced breast cancer. Eligible subjects will be adults with inoperable locally advanced or metastatic breast cancer with a germline or somatic PALB2 mutation with 0-3 prior therapies for advanced disease. Eligible patients must have a deleterious or suspected deleterious mutation in PALB2 on a CLIA approved commercial germline or next generation sequencing tumor assay. Study treatment is talazoparib 1 mg PO daily. In stage 1, ORR will be assessed after 15 patients; if at least 2 responses are observed then an additional 15 patients will be enrolled; if less than 2 responses are observed the study will be terminated. The primary objective is to evaluate whether talazoparib monotherapy can induce a 30% ORR in subjects with advanced breast cancer associated with a PALB2 mutation. Response will be assessed by RECIST 1.1. Secondary objectives include safety, PFS, clinical benefit rate, and patient-reported quality-of-life. Exploratory endpoints will assess for the presence of PALB2 loss-of-heterozygosity, biallelic mutations, correlation of ctDNA profile with treatment response and the correlation of germline versus somatic mutations with response rate. This trial is currently activated and enrolling at Stanford Cancer Center and it is expected that 4 additional sites will be added. Conclusion: This trial will evaluate gPALB2 as a biomarker for PARP inhibitor monotherapy in advanced or metastatic HER2- breast cancer. Clinical trial information: pending .

Background: TNBC patients with homologous recombination (HR) deficient tumors have significantly higher pathologic complete response (pCR, ypT0/is ypN0) rates when treated with platinum-based chemotherapy regimens than TNBC patients whose tumors are HR non-deficient. We performed a pooled analysis of 5 phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to better estimate the pCR rates amongst HR deficient and HR non-deficient tumors. Methods: Patients with TNBC and known HR deficiency status from the following clinical trials were available for analysis: PrECOG 0105 (N=72), NCT00148694/NCT00580333 (N=50), NCT01372579 (N=26), TBCRC 008 (N=18). Neoadjuvant chemotherapy regimens included 1) carboplatin, gemcitabine, iniparib, 2) cisplatin with or without bevacizumab 3) carboplatin, eribulin, 4) carboplatin, nab-paclitaxel, with or without vorinostat. HR deficiency status was defined as a high HRD score (42 or higher) and/or presence of a BRCA1/2 tumor mutation (tBRCA). Logistic regression models were used to adjust for study effects. The addition of data from the TNBC platinum-treated arm of GeparSixto (n=101) to this pooled analysis will be available at the time of presentation bringing the total sample size to 267. Results: pCR was achieved in 51 patients (31%) and 104 patients (63%) were HR deficient (31 with high HRD score and tBRCA mutation, 67 with high HRD score only, and 6 with tBRCA mutation only). Patients with HR deficient tumors were more likely to achieve a pCR than those with HR non-deficient tumors: 44% vs. 8% (p Likelihood of pCR adjusting for studyModel #Predictor VariablePopulation (n)Adjusted Odds RatioLower 95% CIUpper 95% CIP Value1HR DeficiancyAll (166)12.54.237.3 Conclusion: HR deficiency status is a robust predictor of pCR across different neoadjuvant platinum-based regimens. This pooled analysis suggests that HRD can be used to identify TNBC patients with a high probability of obtaining pCR with a platinum-based neoadjuvant chemotherapy regimen. Citation Format: Telli ML, McMillan A, Ford JM, Richardson AL, Silver DP, Isakoff SJ, Kaklamani VG, Gradishar W, Stearns V, Connolly RM, Loibl S, Elkin EP, Timms K, Hartman A-R, von Minckwitz G. Homologous recombination deficiency (HRD) as a predictive biomarker of response to neoadjuvant platinum-based therapy in patients with triple negative breast cancer (TNBC): A pooled analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-12.

We demonstrate a scanning microscopy system for high resolution, sub-shot-noise absorption imaging. A genuine quantum advantage of factor 1.66 in information gained per probe photon, relative to an ideal classical measurement, is demonstrated.

We demonstrate sub-Poissonian intensity correlations of twin beams at short wavelengths: 442nm and 665nm. The beams are generated via four-wave mixing in photonic crystal fiber, measured with a CCD camera.

Engineering apparatus that harness quantum theory promises to offer practical advantages over current technology. A fundamentally more powerful prospect is that such quantum technologies could out-perform any future iteration of their classical counterparts, no matter how well the attributes of those classical strategies can be improved. Here, for optical direct absorption measurement, we experimentally demonstrate such an instance of an absolute advantage per photon probe that is exposed to the absorbative sample. We use correlated intensity measurements of spontaneous parametric downconversion using a commercially available air-cooled CCD, a new estimator for data analysis and a high heralding efficiency photon-pair source. We show this enables improvement in the precision of measurement, per photon probe, beyond what is achievable with an ideal coherent state (a perfect laser) detected with 100% efficient and noiseless detection. We see this absolute improvement for up to 50% absorption, with a maximum observed factor of improvement of 1.46. This equates to around 32% reduction in the total number of photons traversing an optical sample, compared to any future direct optical absorption measurement using classical light.

Harnessing the unique properties of quantum mechanics offers the possibility of delivering alternative technologies that can fundamentally outperform their classical counterparts. These technologies deliver advantages only when components operate with performance beyond specific thresholds. For optical quantum metrology, the biggest challenge that impacts on performance thresholds is optical loss. Here, we demonstrate how including an optical delay and an optical switch in a feed-forward configuration with a stable and efficient correlated photon-pair source reduces the detector efficiency required to enable quantum-enhanced sensing down to the detection level of single photons and without postselection. When the switch is active, we observe a factor of improvement in precision of 1.27 for transmission measurement on a per-input-photon basis compared to the performance of a laser emitting an ideal coherent state and measured with the same detection efficiency as our setup. When the switch is inoperative, we observe no quantum advantage.

We introduce and experimentally demonstrate a method for realising a quantum channel using the measurement-based model. Using a photonic setup and modifying the bases of single-qubit measurements on a four-qubit entangled cluster state, representative channels are realised for the case of a single qubit in the form of amplitude and phase damping channels. The experimental results match the theoretical model well, demonstrating the successful performance of the channels. We also show how other types of quantum channels can be realised using our approach. This work highlights the potential of the measurement-based model for realising quantum channels which may serve as building blocks for simulations of realistic open quantum systems., 8 pages, 4 figures

In the light of the progress in quantum technologies, the task of verifying the correct functioning of processes and obtaining accurate tomographic information about quantum states becomes increasingly important. Compressed sensing, a machinery derived from the theory of signal processing, has emerged as a feasible tool to perform robust and significantly more resource-economical quantum state tomography for intermediate-sized quantum systems. In this work, we provide a comprehensive analysis of compressed sensing tomography in the regime in which tomographically complete data is available with reliable statistics from experimental observations of a multi-mode photonic architecture. Due to the fact that the data is known with high statistical significance, we are in a position to systematically explore the quality of reconstruction depending on the number of employed measurement settings, randomly selected from the complete set of data, and on different model assumptions. We present and test a complete prescription to perform efficient compressed sensing and are able to reliably use notions of model selection and cross-validation to account for experimental imperfections and finite counting statistics. Thus, we establish compressed sensing as an effective tool for quantum state tomography, specifically suited for photonic systems., Comment: 12 pages, 5 figures

211 Background: Patient reported outcomes (PROs) allow for systematic and more continuous capture of the patient experience. PROs have been associated with improved symptom management and quality of life in patients with advanced cancer; however how to do this in a real world setting is not thoroughly described. We sought to provide a description of the implementation and feasibility of a digital PRO application in patients with advanced cancer at one academic center. Methods: This is an ongoing randomized trial, comparing digital PRO intervention vs standard of care, in advanced cancer patients from three oncology groups (thoracic, gastrointestinal, genitourinary). Prior to trial initiation, a lead in period to test workflows was conducted, as well as key stakeholder interviews to optimize engagement with the platform. Clinical team members (e.g. nurses, advanced practice providers) were critical to the workflows developed, thus operational leadership buy-in was required. We were unable to integrate our PRO platform with our digital EHR. Regular sponsor meetings addressed technical concerns and patient/provider feedback. Processes were tailored for each disease group to handle varying degrees of symptoms (mild, moderate and severe). Patient and clinician satisfaction and qualitative feedback was collected. We defined feasibility as > 70% questionnaire completion on the platform. Results: There are 64 patients on the intervention arm and 64 on the control arm. Of eligible patients, 93% (128/138) enrolled in the study. During the study period, 447 digital symptom questionnaires were sent by the platform, of which 333 were completed (74%). The majority of clinicians (82%, n = 18) and patients (85%, n = 64) felt neutral or positive when asked if the tool was easy to use. Approximately half of clinicians (45%, n = 10) and patients (46%, n = 36) would probably or definitely recommend the platform. Conclusions: Web-based PRO reporting for patients with advanced cancer is feasible. Clinicians and patients found the platform both acceptable and easy to use. Future directions include integration with our EHR, expansion across disease groups and other centers, and creation of workflows that are integrated into routine clinical practice.

3006 Background: Talazoparib, a PARP inhibitor, is active in germline BRCA1/2 mutant advanced HER2-negative breast cancer, but its activity beyond BRCA1/2 is unknown. We conducted a single institution phase II trial to evaluate talazoparib in patients (pts) with advanced HER2-negative breast cancer or other solid tumors with a germline (g) or somatic (s) alteration in HR pathway genes not including BRCA1/2. Methods: Eligible pts had measurable disease, lacked a germline or somatic mutation in BRCA1/2, received at least one prior therapy for advanced HER2-negative breast cancer or other solid tumor and had a HR pathway gene mutation: PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD50, RAD51C, RAD51D, MRE11, ATR, PTEN, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL. Pts with no progression on or within 8 weeks of their last platinum dose were eligible. Pts were treated with talazoparib 1 mg po daily until disease progression. Response was assessed every 8 +/- 1 weeks. If 2 or more responses were observed in 10 pts in stage I, the study would proceed to stage II and enroll 10 additional pts. The null hypothesis of a ≤ 5% objective response rate would be rejected if at least 3 of 20 respond. Results: Twenty pts were enrolled; 13 breast cancer (12 HR+/HER2-, 1 TNBC) and 7 non-breast cancer (pancreas, colon, uterine, testicular, parotid salivary). Median age was 54 years. Of 12 response evaluable pts with breast cancer, 3 had a RECIST response (ORR = 25%, 2 g PALB2, 1 g CHEK2/g FANCA/sPTEN) and 3 additional pts (g PALB2, s ATR, s PTEN) had SD ≥ 6 months (CBR = 50%). No responses were seen in non-breast tumors; 2 (g CHEK2 testicular, g ATM colon) had SD ≥ 6 months. Talazoparib was well tolerated; 5 patients required dose reduction for hematologic toxicity. Results of tumor HR deficiency status assessment from metastatic biopsies and serial ctDNA profiling will be presented. Conclusions: In this proof-of-concept phase II study, single agent talazoparib demonstrated activity in HER2-negative advanced breast cancer pts with a HR pathway mutation beyond BRCA1/2. Further evaluation of talazoparib in this population is warranted. Clinical trial information: NCT02401347.

Joint or simultaneous measurements of non-commuting quantum observables are possible at the cost of increased unsharpness or measurement uncertainty. Many different criteria exist for defining what an "optimal" joint measurement is, with corresponding different tradeoff relations for the measurements. Understanding the limitations of such measurements is of fundamental interest and relevant for quantum technology. Here, we experimentally test a tradeoff relation for the sharpness of qubit measurements, a relation which refers directly to the form of the measurement operators, rather than to errors in estimates. We perform the first optical implementation of the simplest possible optimal joint measurement, requiring less quantum resources than have previously often been employed. Using a heralded single-photon source, we demonstrate quantum-limited performance of the scheme on single quanta., 7 pages, 6 figures

Multipartite entangled states are a fundamental resource for a wide range of quantum information processing tasks. In particular, in quantum networks, it is essential for the parties involved to be able to verify if entanglement is present before they carry out a given distributed task. Here we design and experimentally demonstrate a protocol that allows any party in a network to check if a source is distributing a genuinely multipartite entangled state, even in the presence of untrusted parties. The protocol remains secure against dishonest behaviour of the source and other parties, including the use of system imperfections to their advantage. We demonstrate the verification protocol in a three- and four-party setting using polarization-entangled photons, highlighting its potential for realistic photonic quantum communication and networking applications., Multipartite entangled states are a fundamental resource for quantum information processing tasks; it is thus important to verify their presence. Here the authors present and demonstrate a protocol that allows any party in a network to verify if an untrusted source is distributing multipartite entangled states.

Stimulatory antiplatelet derived growth factor receptor α (PDGFRA) antibodies have been associated with extensive chronic graft-versus-host disease (cGVHD). We performed a phase 1 dose escalation trial of imatinib in corticosteroid-dependent/refractory cGVHD to assess the safety of imatinib and test the hypothesis that abrogation of PDGFRA signaling can ameliorate the manifestations of cGVHD. Fifteen patients were enrolled. Mean follow-up time was 56.6 weeks (range, 18-82.4 weeks). Imatinib 400 mg daily was associated with more frequent moderate to life-threatening adverse events than 200 mg daily. The main adverse events were nausea, edema, confusion, diarrhea, liver function test elevation, fatigue, and myalgia. The overall response rate was 40% (6 of 15). The treatment failure rate was 40% (6 of 15). Twenty percent (3 of 15) of subjects had stable disease. Of 4 subjects with phospho-PDGFRA and phospho-PDGFRB immunohistochemistry studies before and after treatment, inhibition of phosphorylation was observed in 3 but correlated with response in one. Anti-PDGFRA antibodies were observed in 7 of 11 evaluable subjects but correlated with clinical activity in 4. We conclude that cGVHD responds to imatinib through multiple pathways that may include PDGFRA signal transduction. This study is registered at www.clinicaltrials.gov as #NCT00760981.

Single autologous hematopoietic cell transplant (AHCT) with high-dose melphalan prolongs survival in patients with multiple myeloma but is not curative. We conducted a study of intensive single AHCT using tandem chemomobilization with CY and etoposide followed by high-dose conditioning with melphalan 200 mg/m2 plus carmustine 15 mg/kg. One hundred and eighteen patients in first consolidation (CON1) and 58 patients in relapse (REL) were transplanted using this intensified approach. Disease response improved from 32% very good PR (VGPR) + CR pre-mobilization to 76% VGPR + CR post transplant in CON1. With a median follow-up of 4.7 years, the median EFS was 2.8 years, and the median OS was 5.1 years in CON1. OS from time of transplant was significantly shorter for REL (3.4 years) compared with CON1 (5.1 years; P = 0.02). However, OS from time of diagnosis was similar in REL (6.1 years) and CON1 (6.0 years; P = 0.80). The 100-day non-relapse mortality in the CON1 and REL groups was 0% and 7%, respectively. In summary, intensified single AHCT with tandem chemo-mobilization and augmented high-dose therapy is feasible in multiple myeloma and leads to high-quality response rates.

The International Prognostic Scoring System (IPSS) was created for evaluating clinical outcomes of patients with myelodysplastic syndromes (MDS). We evaluated the depth of cytopenias to determine whether this parameter could further refine the prognostic ability of the IPSS. Correlation was determined between the depth of cytopenias in 816 patients from the International MDS Risk Analysis Workshop database and patients' clinical features. Univariate analyses of hemoglobin (Hb), absolute neutrophil count, and platelet depth levels were assessed relative to the IPSS risk groups, refined French-American-British categories, cytogenetic groups, bone marrow blast percentage (%), age groups, overall survival (OS), and time to evolution of acute myeloid leukemia (AML). Multivariate analysis of different cytopenic levels was performed to determine whether depth of cytopenias was prognostically additive to the IPSS. All cytopenic categories had statistically significant rank correlations with IPSS, bone marrow blast %, and refined French-American-British categories. In multivariate analysis, Hb levels had additive prognostic value to the IPSS for evaluation of OS, but not time to AML, with greatest prognostic value in Intermediate-1 and Intermediate-2 categories. In contrast, platelet or absolute neutrophil count levels alone or in combination lacked additive prognostic value to the IPSS regarding OS or time to AML evolution. The depth of Hb level per se at the time of diagnosis has additive predictive value to the IPSS for OS in the intermediate-risk groups. This information should prove useful for aiding therapeutic decision-making, prognostic classification, and designing clinical trials for patients with MDS.

The peripheral T cell lymphomas (PTCL) carry a worse prognosis compared to B cell non-Hodgkin lymphoma. There is no uniform standard therapy for PTCL, and autologous hematopoietic cell transplant (AHCT) is often offered as consolidation in first remission or at relapse because of the poor outcomes with conventional therapy. We conducted a retrospective review of patients who underwent AHCT for PTCL from 1989 to 2006. Fifty-three cases were identified consisting of systemic anaplastic large cell (n = 18), PTCL unspecified (n = 17), angioimmunoblastic (n = 9), nasal type extranodal NK/T (n = 7), hepatosplenic (n = 2), and adult T cell leukemia/lymphoma (n = 1). Fifteen patients were transplanted in first complete or partial response (CR1/PR1), 32 in second or beyond CR or PR (CR2/PR2+), and 11 with primary refractory disease (REF). With a median follow-up was 5 years (range: 1.0-11.5), the 5-year progression-free survival (PFS) and overall survival (OS) were 25% and 48%, respectively. Disease status at AHCT had a significant impact on PFS and OS. The 5-year PFS for patients in CR1/PR1, CR2/PR2+, and REF was 51%, 12%, and 0%, respectively, and the corresponding figures for OS were 76%, 40%, and 30%, respectively. The pretransplant factors that impacted survival were disease status and the number of prior regimens. Histology, age, sex, stage, B symptoms, bone marrow involvement, and duration of first response did not significantly affect PFS or OS. Based on these results, AHCT as consolidation therapy in first complete or partial response may offer a durable survival benefit. However, AHCT with conventional salvage chemotherapy has minimal durable benefit in patients with relapsed or refractory PTCL, and thus novel strategies and/or allogeneic HCT should be more aggressively explored in lieu of AHCT for relapsed/ refractory PTCL.

Several studies have demonstrated substantial variability among individual radiation oncologists in defining target volumes using computed tomography (CT). The objective of this study was to determine the impact of combined positron emission tomography and computed tomography (PET/CT) on inter-observer variability of target volume delineation in rectal cancer. We also compared the relative concordance of two PET imaging tracers, 18F-fluorodeoxyglucose (FDG) and 18F-fluorodeoxythymidine (FLT), against conventional computed tomography (CT). Six consecutive patients with locally advanced rectal cancer were enrolled onto an institutional protocol involving preoperative chemoradiotherapy and correlative studies including FDG- and FLT-PET scans acquired in the treatment position. Using these image data sets, four radiation oncologists independently delineated primary and nodal gross tumor volumes (GTVp and GTVn) for a hypothetical boost treatment. Contours were first defined based on CT alone with observers blinded to the PET images, then based on combined PET/CT. An inter-observer similarity index (SI), ranging from a value of 0 for complete disagreement to 1 for complete agreement of contoured voxels, was calculated for each set of volumes. For primary gross tumor volume (GTVp), the difference in estimated SI between CT and FDG was modest (CT SI = 0.77 vs. FDG SI = 0.81), but statistically significant (p = 0.013). The SI difference between CT and FLT for GTVp was also slight (FLT SI = 0.80) and marginally non-significant (p < 0.082). For nodal gross tumor volume, (GTVn), SI was significantly lower for CT based volumes with an estimated SI of 0.22 compared to an estimated SI of 0.70 for FDG-PET/CT (p < 0.0001) and an estimated SI of 0.70 for FLT-PET/CT (p < 0.0001). Boost target volumes in rectal cancer based on combined PET/CT results in lower inter-observer variability compared with CT alone, particularly for nodal disease. The use of FDG and FLT did not appear to be different from this perspective.

BACKGROUND. Primary lymphoma of the breast has been reported to have a high local and central nervous system recurrence (CNS) rate, suggesting the need for consolidation radiotherapy and CNS prophylaxis. A retrospective study was done to evaluate the institutional experience in this patient population. METHODS. In all, 37 patients with lymphoma involving the breast at initial diagnosis and managed at Stanford University from 1981–2005 were included. Diagnostic tissue biopsies were obtained either from the breast mass or an involved lymph node. Treatment and response data, patterns of recurrence, and outcomes were reviewed. RESULTS. Diffuse large B cell lymphoma (DLBCL) was the most common histologic subtype seen in 18 of 37 (49%) patients. Follicular and marginal zone subtypes were seen in 38%. Most patients presented with an incidental breast mass in stage IE or IIE. Four (11%) patients presented with bilateral breast involvement, with only 1 patient presenting with CNS disease. DLBCL patients received doxorubicin-based chemotherapy, with 70% receiving involved field radiotherapy and a single patient receiving intrathecal therapy. No recurrences occurred in the involved breast and a single parenchymal CNS recurrence was recorded. Among the DLBCL patients, the 5-year progression-free survival (PFS) was 61%, with a median follow-up of 3.8 years (range, 5 months to 19 years) and the 5-year overall survival (OS) was estimated at 82%. Patients with indolent lymphoma had an estimated 5-year PFS of 76% and an OS of 92%. CONCLUSIONS. DLBCL of the breast was successfully treated with doxorubicin-based chemotherapy alone or with involved field radiotherapy in an estimated 61% of patients at 5 years. A single CNS recurrence was observed in our series of patients, most of whom presented with limited disease. Cancer 2007. © 2007 American Cancer Society.

70 Objectives Clinical measures of Parkinson’s disease progression suggest a slow process with significant variability both between patients and also within the individual over the course of disease. A number of “objective” imaging and non-imaging measures have been proposed as putative progression biomarkers although there is limited validation data available. The Parkinson9s (PD) progression marker initiative (PPMI) is an international, multicenter, longitudinal study assessing biochemical, clinical, and imaging biomarkers of disease progression. Scintigraphic biomarkers are being evaluated as indicators of progression include dopamine transporter (DAT) imaging with 123-I ioflupane SPECT. This study evaluates subregion-dependent striatal changes in dopamine transporter (DAT) binding using 123-I Ioflupane SPECT in PD participants in the PPMI study. Methods Baseline (n= 241), 1 year, and 2 year 123-I Ioflupane SPECT scans were acquired from 22 centers. Data were reconstructed, attenuation corrected, and analyzed by the core lab using a volume of interest template for extraction of counts and calculation of specific binding ratios (SBRs) and percent SBRs changes over time in six striatal subregions. Results Ongoing serial evaluation shows SBR reduction at 1 yr in 80% of 241 PD subjects. Specific binding ratios demonstrate 11.6% and 7.4% reductions over one year in the ipsilateral and contralateral striatum, respectively. Differences in the rates of DAT signal change are evident in subregions of the striatum. The fastest rates of change annualized over two years were noted, in order, for ipsilateral striatum; posterior putamen (-9.2% +/-11.4), anterior putamen(-8.7% +/- 8.8), and caudate( -6.9% +/-8.9). In contrast, contralaterally, posterior putamen (-6.4% +/-15.4), demonstrated the slowest rate of change with the anterior putamen (-8.0% +/-10.3), and the caudate ( -7.5%+/-9.4). Conclusions These data have implications for the potential use of dopamine transporter imaging as a serial marker of change in longitudinal Parkinson9s studies. Specifically, areas with greatest signal change and lowest variability might be more sensitive for detecting slowing rates of change with a disease modifying therapy. In summary, this study shows consistently increasing signal loss over one and two years with regional differences demonstrated for DAT imaging and confirmation of previously noted between subject variability.

The outcome of sequential azacitidine with lenalidomide has not been reported in previously treated patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). This study describes a phase 2 study evaluating the safety and efficacy of this combination in elderly patients with AML and MDS with prior hypomethylating agent (HMA) and/or immunomodulatory agent exposure. Patients were treated on a 42-day cycle with azacitidine at 75 mg/m2 SQ/IV daily on days 1–7, followed by lenalidomide 50 mg orally daily on days 8–28. The median number of treatment cycles on study was two (range = 1–11). Of 32 evaluable patients, the overall response rate was 25%. Neutropenic fever was the most common serious adverse event, but overall the combination was well-tolerated. The median overall survival (OS) for responders vs non-responders was 9.8 vs 4.0 months, respectively (HR = 0.36, p = 0.016). In conclusion, this combination demonstrated modest clinical activity in this poor risk popula...

We consider the effect of self-phase modulation and cross-phase modulation on the joint spectral amplitude of photon pairs generated by spontaneous four-wave mixing. In particular, the purity of a heralded photon from a pair is considered, in the context of schemes that aim to maximise the purity and minimise correlation in the joint spectral amplitude using birefringent phase-matching and short pump pulses. We find that non-linear phase modulation effects will be detrimental, and will limit the quantum interference visibility that can be achieved at a given generation rate. An approximate expression for the joint spectral amplitude with phase modulation is found by considering the group velocity walk-off between each photon and the pump, but neglecting the group-velocity dispersion at each wavelength. The group-velocity dispersion can also be included with a numerical calculation, and it is shown that it only has a small effect on the purity for the realistic parameters considered., Comment: 11 pages, 10 figures

Amplification of MYCN occurs commonly in neuroblastoma. We report that phosphatidylinositol 3-kinase (PI3K) inhibition in murine neuroblastoma (driven by a tyrosine hydroxylase-MYCN transgene) led to decreased tumor mass and decreased levels of Mycn protein without affecting levels of MYCN mRNA. Consistent with these observations, PI3K inhibition in MYCN-amplified human neuroblastoma cell lines resulted in decreased levels of Mycn protein without affecting levels of MYCN mRNA and caused decreased proliferation and increased apoptosis. To clarify the importance of Mycn as a target of broad-spectrum PI3K inhibitors, we transduced wild-type N-myc and N-myc mutants lacking glycogen synthase kinase 3β phosphorylation sites into human neuroblastoma cells with no endogenous expression of myc. In contrast to wild-type N-myc, the phosphorylation-defective mutant proteins were stabilized and were resistant to the antiproliferative effects of PI3K inhibition. Our results show the importance of Mycn as a therapeutic target in established tumors in vivo, offer a mechanistic rationale to test PI3K inhibitors in MYCN-amplified neuroblastoma, and represent a therapeutic approach applicable to a broad range of cancers in which transcription factors are stabilized through a PI3K-dependent mechanism. (Cancer Res 2006; 66(16): 8139-46)

Approximately 30% of patients with thyroid nodules have indeterminate or suspicious fine-needle aspiration (FNA) biopsy results. Because their risk of cancer is approximately 20%, these patients undergo thyroidectomy. We hypothesized that genes that regulate cell-cycle progression would be differentially expressed in malignant versus benign thyroid nodules and could serve as diagnostic markers and markers of disease aggressiveness. We used a cDNA array with 96 cell-cycle regulatory genes to identify differentially expressed genes in pooled benign versus malignant thyroid neoplasms. Genes up- or down-regulated by more than 2-fold in malignant thyroid neoplasms were further evaluated by real-time quantitative polymerase chain reaction (PCR) in 95 patients with hyperplastic nodules (n = 19), follicular adenoma (n = 19), follicular thyroid cancer (n = 19), the follicular variant of papillary thyroid cancer (n = 19), and papillary thyroid cancer (n = 19). cDNA array analysis showed that cyclin B1, MCM5, MCM7, RAD9, ubiquitin C, CDK6, SKP2, and APAF1 were up-regulated in malignant thyroid neoplasms. Real-time quantitative PCR showed that MCM5, MCM7, and RAD9 mRNA expression were significantly higher in malignant than in benign thyroid neoplasms (≤0.0012). The combined use of MCM5, MCM7, and RAD9 mRNA expression had a sensitivity of 98.2% and a specificity of 65.7%. The level of MCM7 mRNA expression was higher in T4 than in T1, T2, and T3 differentiated thyroid cancers (P < 0.0127). MCM5, MCM7, and RAD9 are overexpressed in malignant thyroid neoplasms of follicular cell origin. These genes may be useful markers of malignant thyroid neoplasms as an adjunct to FNA biopsy. MCM7 mRNA expression is higher in locally invasive differentiated thyroid cancer.

Adrenocortical carcinoma (ACC), a rare and aggressive malignancy, accounts for up to 14% of adrenal incidentalomas. The only chance of cure for ACC is diagnosis at an early stage; therefore, a main indication for adrenalectomy in patients with adrenal incidentaloma has been the potential risk of ACC. Recent studies suggest that this has led to earlier stage of ACC at diagnosis, more curative operations, and better survival.We analyzed data on ACC from The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. Four equal time quartiles (1973-1979, 1980-1986, 1987-1993, and 1994-2000) were compared for changes in demographics, pathology, treatment, and cause-specific mortality.The average age was 51.2 years (range: 1-97), and 45.9% of patients were men. The average tumor size was 12 cm (range: 2-36 cm), and only 4.2% wereor = 6 cm. Most (88%) patients had surgical resection of their tumor, and external beam radiotherapy was used in only 12% of patients. Between the time quartiles compared (as well as annually), there was no significant difference at presentation in age at diagnosis, sex, race/ethnicity, tumor size, tumor grade, the frequency of distant metastasis, and overall TNM stage. Low tumor grade, lower stage of ACC, later time quartile, and surgical resection were associated with a lower cause-specific mortality by univariate analysis (Por = 0.002) and by multivariate analysis (Por = 0.031).Although adrenal incidentalomas have become a common indication for adrenalectomy, this has not resulted in patients with ACC being diagnosed earlier or treated at a lower stage of disease at the national level. The most important predictors of survival in these patients are tumor grade, tumor stage, and surgical resection.

We compare survival estimates for population-based glioma cases by using two diagnostic coding schemes, (1) the International Classification of Diseases, Oncology, second edition (ICD-O-2) as reported by the Surveillance, Epidemiology, and End Results (SEER) program and (2) central neuropathology review diagnosis based on the World Health Organization II classification. In addition, among review categories, we estimate survival in relation to several patient demographic and treatment factors. Eligible cases included adults residing in the San Francisco Bay SEER Area with newly diagnosed, histologically confirmed glioma during the years 1991-1994 and 1997-1999. The study group included participating subjects for whom subsequent central neuropathology review confirmed glioma. We determined treatments, vital status, and other factors by using registry, interview, medical record, and active follow-up data. Survival differences between anaplastic astrocytoma (AA) and astrocytoma were apparent from review diagnoses (median months of survival for AA, 13.0 [95% CI, 9.9-19.5], and astrocytoma, 101.3 [95% CI lower limit, 42.1; upper limit not yet reached]), but not with ICD-O-2 diagnoses reported by SEER (median months of survival for AA, 16.6 [95% CI, 12.0-20.7], and astrocytoma, not otherwise specified, 17.2 [95% CI, 10.6-71.6]). This finding emphasizes the need for improvements in coding for nonglioblastoma astrocytomas to provide better population survival estimates. When review diagnosis was used, younger age and resection (vs. biopsy) were statistically significant for all histology groups analyzed by multivariable Cox proportional hazard models. Additional statistically significant variables were as follows: among 517 glioblastoma patients, radiation treatment and being married; among 105 AA patients, inclusion of chemotherapy in the initial treatment; and among 106 patients with nonanaplastic oligodendroglial tumors, college education. Further consideration of impact of marital status, education, and other social factors in glioma survival may be warranted.

ERCC2 and ERCC1 are important in DNA nucleotide excision repair and lie on chromosome 19q13.3 near a putative glioma suppressor region. We genotyped constitutive variants ERCC1 C8092A and ERCC2 K751Q and R156R in approximately 450 adults with glioma and 500 controls from two independent population-based series, uniformly reviewed patients’ tumors to determine histopathologic category, and determined a variety of tumor markers among astrocytic tumors. Odds ratios (ORs) for glioblastoma for those carrying two ERCC1 A alleles versus none or one were 1.67 in series 1 and 1.64 in series 2, which yielded a combined OR of 1.67 (95% CI, 0.93–3.02; P = 0.09), adjusted for age, gender, ethnicity, and series. Odds ratios for the ERCC2 variants were not consistently elevated or reduced for the two series in all cases versus controls. However, among whites, for those with ERCC2 K751Q genotype QQ versus QK/KK, the OR for nonglioblastoma histologies versus controls was 1.82 (95% CI, 0.97–3.44; P = 0.06). Also, among whites, glioma patients were significantly more likely than controls to be homozygous for variants in both ERCC1 C8092A and ERCC2 K751Q (OR, 3.2; 95% CI, 1.1–9.3). Given the numbers of comparisons made, these findings could be due to chance. However, the results might warrant clarification in additional series in conjunction with the nearby putative glioma suppressor genes (GLTSCR1 and GLTSCR2)