tbuckley/cabot-search huggingface dataset:
P05.41 The influence of complex cytogenetic aberration patterns on recurrent meningiomas
Authors: S Hemmer, S Urbschat, J Oertel, R Ketter
Journal: Neuro-Oncology (2018)

Cytogenetically, meningiomas frequently harbour a normal karyotype or monosomy of chromosome 22. However, progression of meningiomas is associated with a non-random pattern of secondary losses of other autosomes. Deletions of the short arm of chromosome 1 are characteristic and specific alterations for the progression of these tumors. The aim of this study was to determine the influence of complex aberration patterns of the chromosomes 1, 10, 17 and 22 on the recurrence of meningiomas. The authors retrospectively reviewed all patients that underwent repeated surgery for recurrent meningiomas between 1999 and 2015. Patients were included in this study if tumor samples from two or more different meningiomas were available. A total of 7 patients underwent repeated surgery for recurrent meningiomas (4 males, 3 females, mean age: 45.4 years at the date of surgery) between 1999 and 2015. Collectively, 21 biopsies were analyzed with Fluorescence-in-situ-hybridization (FISH) for the chromosomes 10, 17, 22 and the chromosomal region 1p. 200 nuclei of every tumor were analyzed. Complex aberration patterns were defined as alterations of three or four chromosomes. 61.9 % of the tumors showed complex aberration patterns. Loss of chromosome 22 was detected in 80.9% (17/21 tumors), loss of the chromosomal region 1p was detected in 46.6% (10/21 tumors), loss of chromosome 10 was detected in 28.6% (6/21) and loss of chromosome 17 was detected in 95.2% (20/21 tumors) of all specimens. Recurrence of meningiomas seems to be associated with complex aberrations of the four chromosomes that were analyzed in this study. According to the literature, loss of the chromosomal region 1p and loss of chromosome 10 have the strongest influence on meningioma recurrence among the chromosomes that were analyzed in this study. Besides that, loss of chromosome 17 was detected in a high frequency among the aberration patterns of the meningiomas in this study. Therefore, loss of chromosome 17 might be a potential marker for malignancy and a higher risk for recurrence in meningiomas. This phenomenon is by the time not mentioned in the literature.
CAMKK2 Promotes Prostate Cancer Independently of AMPK via Increased Lipogenesis
Authors: Lucy Penfold, Angela Woods, Phillip Muckett, Alexander Yu. Nikitin, Tera R. Kent, Shuai Zhang, Rebecca Graham, Alice Pollard, David Carling
Journal: Cancer Research (2018)

Abstract New targets are required for treating prostate cancer, particularly castrate-resistant disease. Previous studies reported that calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) expression is increased in human prostate cancer. Here, we show that Camkk2 deletion or pharmacologic inhibition protects against prostate cancer development in a preclinical mouse model that lacks expression of prostate-specific Pten. In contrast, deletion of AMP-activated protein kinase (Ampk) β1 resulted in earlier onset of adenocarcinoma development. These findings suggest for the first time that Camkk2 and Ampk have opposing effects in prostate cancer progression. Loss of CAMKK2 in vivo or in human prostate cancer cells reduced the expression of two key lipogenic enzymes, acetyl-CoA carboxylase and fatty acid synthase. This reduction was mediated via a posttranscriptional mechanism, potentially involving a decrease in protein translation. Moreover, either deletion of CAMKK2 or activation of AMPK reduced cell growth in human prostate cancer cells by inhibiting de novo lipogenesis. Activation of AMPK in a panel of human prostate cancer cells inhibited cell proliferation, migration, and invasion as well as androgen-receptor signaling. These findings demonstrate that CAMKK2 and AMPK have opposing effects on lipogenesis, providing a potential mechanism for their contrasting effects on prostate cancer progression in vivo. They also suggest that inhibition of CAMKK2 combined with activation of AMPK would offer an efficacious therapeutic strategy in treatment of prostate cancer. Significance: These findings show that CAMKK2 and its downstream target AMPK have opposing effects on prostate cancer development and raise the possibility of a new combined therapeutic approach that inhibits CAMKK2 and activates AMPK.
不均衡型房室中隔欠損の心エコー判定基準と手術適応決定 Congenital Heart Surgeons’ Societyの多施設共同研究
Authors: Jegatheeswaran Anusha, Pizarro Christian, A Caldarone Christopher, S Cohen Meryl, M Baffa Jeanne, B Gremmels David, Mertens Luc, O Morell Victor, G Williams William, H Blackstone Eugene, W Mccrindle Brian, M Overman David
Journal: Circulation (2010)
Promoter bivalency favors an open chromatin architecture in embryonic stem cells
Authors: Glòria Mas, Enrique Blanco, Cecilia Ballaré, Miriam Sansó, Yannick G. Spill, Deqing Hu, Yuki Aoi, François Le Dily, Ali Shilatifard, Marc A. Marti-Renom, Luciano Di Croce
Journal: Nature Genetics (2018)
Economic impact of next generation sequencing vs sequential single-gene testing modalities to detect genomic alterations in metastatic non-small cell lung cancer using a decision analytic model.
Authors: Nathan A. Pennell, Alex Mutebi, Zheng-Yi Zhou, Marie Louise Ricculli, Wenxi Tang, Helen Wang, Annie Guerin, Tom Arnhart, Kenneth W. Culver, Gregory Alan Otterson
Journal: Journal of Clinical Oncology (2018)

9031 Background: Metastatic non-small cell lung cancer (mNSCLC) patients (pts) should be tested for genomic alterations (GA) to inform treatment decisions. This study assesses the economic impact of next generation sequencing (NGS) vs sequential single-gene testing modalities for Center for Medicare and Medicaid Services (CMS) Medicare and US commercial payers. Methods: In a decision analytic model, newly diagnosed mNSCLC pts were modeled to receive PD-L1 and GA tests (EGFR, ALK, ROS1, BRAF, MET, HER2, RET, NTRK1) using 1) sequential tests, 2) exclusionary mutation (KRAS) test followed by sequential tests 3) panel test or 4) upfront NGS, including all GAs and KRAS. Pts in modalities 1-3 were tested for GAs with currently approved treatment (EGFR, ALK, ROS1, BRAF) followed by single-gene tests or NGS for other GAs (e.g., HER2); a proportion were assumed to need rebiopsy. Inputs included turnaround time, unit costs and mNSCLC prevalence based on literature, public data and expert opinion. Time to receive results and total cost (test + rebiopsy) were calculated for each modality and compared with NGS. Results: For hypothetical 1 million-member plans, an estimated 2,066 CMS Medicare and 156 commercially insured mNSCLC pts would be tested for GA. Estimated time to receive results was 2.0 weeks for NGS and panel, 2.7 and 2.8 weeks faster than exclusionary and sequential, respectively. Using CMS reimbursement, NGS represented savings of $1,393,678 vs exclusionary, $1,530,869 vs sequential and $2,140,795 vs panel. For commercial payers, NGS remained the least expensive by $3,809 (vs exclusionary) to $250,842 (vs panel). Conclusions: Our model estimated that upfront NGS leads to the same (as panel) or shorter (vs exclusionary and sequential testing) wait time for results and the lowest payer cost to establish GA status for newly diagnosed mNSCLC pts to inform treatment decisions. Sequential Exclusionary Panel NGS CMS Medicare N = 2 066 Total cost 3 721 368 3 584 177 4 331 295 2 190 499 Savings with NGS 1 530 869 1 393 678 2 140 795 Commercial N = 156 Total cost 747 771 624 178 871 211 620 369 Savings with NGS 127 402 3 809 250 842
TCT-683 Long-term prognosis of complete percutaneous coronary revascularization in patients with chronic total occlusion: a comparison between preserved and impaired renal function
Authors: Maria Grazia De gregorio, Eleonora Gabrielli, Andrea Bernardini, Martina Berteotti, Angela Migliorini, Lucia Martinese, Ruben Vergara, Renato Valenti
Journal: Journal of the American College of Cardiology (2018)
What’s hot that the other lot got
Authors: Lucy E Maddocks
Journal: Thorax (2018)

Serum procalcitonin is associated with infection severity and is more specific for bacterial rather than viral infections. Huang et al. ( NEJM 2018;379:236) investigated whether procalcitonin-guided use of antibiotics in lower respiratory tract infections (LRTI) reduces the number of total antibiotic days over a 30 day period. This randomised control multi-centred clinical trial focused on patients admitted to emergency departments from 14 U.S hospitals with suspected LRTI and divided them into two groups: the usual care group (n=834) and the procalcitonin group (n=830). Prior to study initiation the trial sites had educational updates on best practice for LRTI management. Clinicians in the procalcitonin group were provided with initial and/or serial procalcitonin results alongside a procalcitonin-guided antibiotic guideline. There was no significant difference between the two groups in mean number of antibiotic days (4.2 days for the procalcitonin group vs 4.3 days for the usual care group; difference −0.05 days, 95% CI −0.6 to 0.5 days, P=0.87). Patients with lower levels of procalcitonin had fewer infective symptoms and therefore the impact of measuring procalcitonin on treatment decisions was negligible. The study …
A feasibility study to determine T cell responses to neoantigens following treatment with ipilimumab in men with metastatic castration-resistant prostate carcinoma (mCRPC).
Authors: Sumit Kumar Subudhi, Ana Aparicio, Patricia Troncoso, Jianhua Zhang, Curtis Gumbs, Chang-jiun Wu, Luis M Vence, Christopher Logothetis, Andrew Futreal, James Patrick Allison, Padmanee Sharma
Journal: Journal of Clinical Oncology (2016)

e14506 Background: Ipilimumab (anti-CTLA-4) promotes durable antitumor responses in a subset of patients with mCRPC. We designed a clinical trial (NCT02113657) to test the hypothesis that the induction of an effective antitumor response by ipilimumab is mediated, at least in part, by lymphocyte responses to prostate cancer neoantigens. Methods: All patients (pts) enrolled into this clinical trial have tumor tissue biopsied or resected prior to receiving intravenous ipilimumab (3 mg/kg) every 21 days for a total of 4 doses. Mutations will be identified using whole-exome sequencing and RNA-seq. Peptides covering the expressed mutations will be synthesized and evaluated in in vitro studies for T cell responses prior to and after ipilimumab therapy. As target antigens for T cell assays, we will use synthetic 25mer peptides containing the given mutation derived from sequencing in its center, so that it is included at any position within a core epitope potentially recognized. Peptides containing putative mutated epitopes can be pooled and used to stimulate CD4 and CD8 T cells, following processing into naturally selected epitopes by CD4/CD8-depleted PBMCs, without the need to predefine alleles of HLA restriction. CD8 and CD4 T cell responses against mutant epitopes will be analyzed independently from peripheral blood mononuclear using IFN-gamma ELISPOT and intracellular multi-cytokine staining for functional recognition of antigen. Results: We have enrolled 14 of a total of 20 pts in this ongoing clinical trial, and 8 (57%) pts have received all 4 doses of ipilimumab. Ipilimumab was prematurely discontinued in 2 pts (14%) due to progression of disease and in 6 pts (43%) due to treatment-related toxicities including 2 pts (14%) who experienced grade 3 immune-related adverse events (irAEs). We have collected tumor tissues and PBMCs from 15 patients. Our studies are ongoing and data will be provided at the meeting. Conclusions: Identification of potential neoantigens in prostate tumors may facilitate future combination therapy studies with personalized vaccines and immune checkpoint agents for the effective treatment of patients with prostate cancer.
Metformin effect on clinical course of non-small cell lung cancer (NSCLC) in patients (pts.) with concomitant diabetes mellitus (DM) after radical resection.
Authors: Igor A. Leyman, Oleg Ivanovich Kit, Gennadiy Z. Sergostyants, Yury N. Lazutin, Liubov Yu Vladimirova, Anna Pavlovna Kharitonova, Tamara G. Ayrapetova, Anna V. Chubaryan, Sergey P. Pyltsin, Pavel A. Anistratov
Journal: Journal of Clinical Oncology (2016)

e20072 Background: Metformin is a drug prescribed for the treatment of type II diabetes, a widespread disease worldwide. Ability of metformin to inhibit the growth of malignant tumors in tissue cultures in vitro and in experimental models in vivo has been shown in recent years. The aim of this work was to study the effect of metformin on the clinical course of NSCLC in patients with type II DM. Methods: Retrospective clinical trial included pts. with stages II-IIIA NSCLC who underwent radical surgery followed by adjuvant platinum-based chemotherapy. Group A included 31 pts. with concomitant type II DM receiving metformin 1000-1500 mg. a day. Group B included 34 pts. without DM. The groups were comparable clinically and pathologically. EFS was investigated by the method of Kaplan-Meier, the comparison was performed using the log rank test. Results: Intrathoracic disease recurrence in 12 mon. was observed in 2 (6.5%) of 31 pts. in group A and 3 (9%) of 34 in group B, in 24 mon. - only in 5 (16.1%) pts. vs.7 (23.2%), respectively. Distant metastases in 12 mon. were found in 1 (3.1%) pts. in group A and 4 (13.6%) in group B, in 24 mon. - in 3 (9.3%) vs. 7 (23.2%). Thus, recurrent NSCLC was registered in 8 (24.8%) pts. in group A and in 14 (47, 6%) in group B (p = .052). With a median follow-up of 26 months, the median survival in the two groups was not achieved. 2-year EFS in group A was 75% vs. 52% in group B (p = . 069). Conclusions: The tendency to improvment in the survival of patients with NSCLC with concomitant type II DM is probably associated with the continuous use of metformin. The data demonstrate expediency of prospective clinical trials for evaluation of the effectiveness of metformin as a component of adjuvant therapy.
P01.040 Identification of a predictive biomarker of response to regorafenib in relapsed glioblastoma patients <REGOMA trial>
Authors: G Lombardi, S Indraccolo, G de Salvo, M Verza, G Magni, M Eoli, R Rudà, E Franceschi, M Faedi, I Lolli, S Rizzato, M Caccese, M Gardiman, V Zagonel
Journal: Neuro-Oncology (2018)

There is currently no predictive biomarker for anti-angiogenic drugs which could be used for patient selection purposes. Pre-clinical studies show that anti-angiogenic therapy exacerbates tumor hypoxia and activatesliver kinase B1 (LKB1)/AMP kinase (AMPK), a pathway involved in the regulation of tumor metabolism. Inspired by these findings, we investigated whether certain angiogenesis- and metabolism-related in situ biomarkers could predict response to regorafenib in the context of the phase 2 randomized REGOMA trial. Immunohistochemistry was used to investigate expression in tumor sections of vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor β (PDGFRβ), fibroblast growth factor receptor (FGFR), the angiopoietin receptor (Tie2),monocarboxylate transporter 1 and 4 (MCT1, MCT4), phosphorylated AMPK (pAMPK) and phosphorylated acetyl-CoA carboxylase(pACC), which is a canonical target of AMPK activity.Positivity for the markers was independently assessed by two analists blinded to clinical data and results of the REGOMA trial. The status of each biomarker was associated with clinical endpoints, including overall survival (OS) and progression free survival (PFS) in patients (PTS) with relapsed GBM treated either with regorafenib or lomustine. Radiological assessment was performed by RANO criteria. Between November 2015 and February 2017, 119 PTS were enrolled ﴾n=59 REG; n=60 LOM﴿ and stratified for surgery at recurrence; baseline characteristics were balanced. Biomarker analysis was performed in 85 PTS (71%), including 43 PTS of the REG arm and 42 PTS of the LOM arm. Among all markers analyzed, only pACC showed predictive value. In fact, median OS was 8.0 months (m) (95% CI 5.6-) for REG and 5.3m (95% CI 4.2–6.6) for LOM for pACC positive patients. HR 0.44 (95% CI 0.22–0.87), log rank p-value = 0.012; Test for interaction = 0.0419. In this randomized, controlled study we report for the first time a predictive impact of pACC expression in patients with relapsed GBM treated with regorafenib. These results suggest that integrity of the AMPK pathway is associated with clinical benefit from treatment with regorafenib.
Factors affecting the concordance of radiologic and pathologic tumor size in breast carcinoma.
Authors: Ameer Hamza, Ramen Sakhi, Sidrah Khawar, Shelby Miller, Ahmed Alrajjal, Warda Ibrar, Sajad Salehi, Jacob Edens, Uqba Khan, Daniel Ockner
Journal: Journal of Clinical Oncology (2018)

e12568 Background: Radiologic assessment of tumor size is an essential work up for breast carcinoma. Concordance between radiologic and pathologic tumor size helps surgical decision. A variety of factors affect this concordance. Methods: This study is a retrospective review of surgical pathology breast specimens. Data were collected for 470 cases. Concordance was defined as a size difference within ± 2mm. Results: The difference between radiologic and pathologic tumor size was within ±2mm in 39.8% cases. The mean radiologic size was 1.74±1.07cm. The mean pathologic size was 1.83±1.33cm. A paired t-test showed a significant difference between radiologic and pathologic sizes (p = 0.016). Despite the size difference, stage classification was same in 59.6% cases. Radiologic size overestimated stage in 14.5% cases and underestimated stage in 25.9% cases. The concordance was significantly higher for tumors less than or equal to 2cm as compared to those greater than 2cm (50.2 % vs. 19.7%, p < 0.0001). A significantly higher proportion of lumpectomy specimens (46.6%) were concordant compared to mastectomy specimens (29.5%) (p < 0.0001). Invasive ductal carcinoma had better concordance compared to other tumors (p = 0.007). 44% cases without neoadjuvant therapy were concordant as compared to only 9.5% cases with neoadjuvant therapy (p < 0.0001). Cases with a time gap of no more than two months between imaging and surgery had better concordance as compared to those where the time gap was more than two months (43.1% vs. 29.4%, p = 0.02). Tumor site (quadrant of breast), radiologic characteristics of the tumor (circumscription, homogeneity versus heterogeneity and presence of calcifications), specimen weight and formalin fixation time had no significant effect on the concordance. Conclusions: We found a significant mean difference between radiology and pathology measurements. Radiology and pathology tumor measurements were concordant in about 60% of cases. A high level of concordance between radiology and pathology measurements is essential in determining the correct surgical plan for the patient. Knowledge of factors influencing this concordance can be useful in regards to surgical planning.
Correlation of constitutive PD-1 resistance in HNC with GM-CSF expression and presence of myeloid derived suppressor cells (MDSCs).
Authors: Tanguy Y. Seiwert, Riyue Bao, Y-H Carol Tan, Rajesh Acharya, Ryan J. Brisson, Sara Kochanny, Saba Arshad, Zhixiang Zuo, Vassiliki Saloura, Nishant Agrawal, Zhen Gooi, Elizabeth A. Blair, Mark W. Lingen, Everett E. Vokes, Thomas Gajewski, Peter A Savage, Arun Khattri
Journal: Journal of Clinical Oncology (2017)

6049 Background: PD-1 checkpoint blockade is active in head and neck squamous cell carcinomas (HNC) with a response rate of ~18% and significant impact on survival. However, only a subset of patients benefits (Seiwert, Lancet Oncol). Biomarkers such as PD-L1 IHC and the Interferon-Gamma gene expression profile (INF-G GEP) identify inflamed tumors with a higher chance of response (~35-40%). However, it remains unclear why the majority of INF-G inflamed tumors still do not respond, or how to overcome constitutive resistance. Methods: 50 anti-PD-1 treated recurrent/metastatic HNC patients were included. Tumor RNA was analyzed using a 638-gene immune panel on the Nanostring nCounter. HPV status was assessed by HPV E6/E7 mRNA. T-cell inflamed phenotype was calculated using the 6-gene INF-G GEP (geometric mean) using both a low (6) and a high cutpoint. Differential gene expression was determined between inflamed-benefitting (IB) patients (defined as OS ≥ 250days), and inflamed-non-benefitting (INB) patients. Candidate biomarkers were evaluated in the entire cohort. Results: CD8 correlated highly with INF-G GEP (R = 0.80), suggesting T cell-driven inflammation. Comparing inflamed benefitting with inflamed non-benefitting tumors, the most differentially expressed gene was CSF-2, encoding GM-CSF, with 4-fold higher expression in inflamed non-benefitting (INB) tumors (with both cutpoints). In the overall anti-PD-1 treated cohort of 50 patients, CSF-2/GM-CSF correlated strongly with poor overall survival (P = 0.02), outperforming both HPV status, or PD-L1 expression in cox PH multivariate analysis. GM-CSF expression has been linked to myeloid derived suppressor cells (MDSC); MDSC marker CD34, as well as JAK2/IL10 were significantly elevated in inflamed non-benefitting (INB) tumors. There was no difference in M2 macrophage marker CD163 between the two groups. Conclusions: Constitutive resistance to PD-1 checkpoint blockade in inflamed HNC associates with expression of GM-CSF and Myeloid Derived Suppressor Cell (MDSC) markers. Strategies to deplete MDSCs, such as chemotherapy, should be considered in combination or sequentially with anti-PD-1.
Clinical benefit and tolerability of adjuvant intraperitoneal chemotherapy in patients who received neoadjuvant treatment for advanced ovarian cancer.
Authors: Trishala Meghal, Vivek Kumar, Vishangi Dave, Yiqing Xu
Journal: Journal of Clinical Oncology (2016)

e17054 Background: Adjuvant chemotherapy using intraperitoneal (IP) treatment has demonstrated survival benefit over intravenous (IV) therapy alone in patients treated with upfront debulking surgery for advanced stage ovarian cancer. Neoadjuvant chemotherapy followed by interim surgery and adjuvant chemotherapy has demonstrated the same benefit as adjuvant treatment alone; IP treatment was not part of the regimen. Additionally, IP treatment has not been well adopted due to treatment toxicities. In this study, we evaluated the clinical benefit and tolerability of incorporating IP chemotherapy in patients who received neoadjuvant treatment and compared the data with those who received IP after upfront surgery. Methods: We retrospectively evaluated our patients with stage III and IV ovarian cancer who received intraperitoneal chemotherapy after optimal cytoreductive surgery (group 1) or after neoadjuvant chemotherapy followed by interim surgery (group 2) between 07/2005 and 07/2015. Results: Thirty one patients were identified, median age was 50.3 years and range was 38.6 to 73 years. Twenty and 11 were treated in group 1 or 2, respectively. The dose reduction rates and OS data are tabulated below. There is no statistically significant difference in the tolerability, DFS or OS when IP was used in the setting after neoadjuvant therapy or in the adjuvant setting after upfront surgery. Of note, the OS and DFS were numerically much longer in the group who received neoadjuvant chemotherapy followed by IP adjuvant chemotherapy than reported in the EORTC trial wherein they were 30 and 12 months, respectively. Conclusions: Administrating IP chemotherapy in patients who received neoadjuvant chemotherapy and interim debulking is feasible with tolerable toxicities. The clinical benefit of this approach appears to be comparable to patients receiving IP treatment after upfront surgery and should warrant further prospective studies. Treatement Approach Overall Adjuvant (group 1) Neoadjuvant (group 2) Number 31 20 11 Cycles of IP 3 3.5 3 Dose reduction rate 45% 50% 36% OS 79.8m (61 - 98.4) 79.8m* 63.9m* DFS 25.8m (10 - 41) 25.8m* 13.3m* *CI not calculated due to small sample size