tbuckley/cabot-search huggingface dataset:
Genetic Characterization and Prognostic Relevance of Acquired Uniparental Disomies in Cytogenetically Normal Acute Myeloid Leukemia
Authors: Christopher J. Walker, Jessica Kohlschmidt, Ann-Kathrin Eisfeld, Krzysztof Mrózek, Sandya Liyanarachchi, Chi Song, Deedra Nicolet, James S. Blachly, Marius Bill, Dimitrios Papaioannou, Christopher C. Oakes, Brian Giacopelli, Luke K. Genutis, Sophia E. Maharry, Shelley Orwick, Kellie J. Archer, Bayard L. Powell, Jonathan E. Kolitz, Geoffrey L. Uy, Eunice S. Wang, Andrew J. Carroll, Richard M. Stone, John C. Byrd, Albert de la Chapelle, Clara D. Bloomfield
Journal: Clinical Cancer Research (2019)

Uniparental disomy (UPD) is a way cancer cells duplicate a mutated gene, causing loss of heterozygosity (LOH). Patients with cytogenetically normal acute myeloid leukemia (CN-AML) do not have microscopically detectable chromosome abnormalities, but can harbor UPDs. We examined the prognostic significance of UPDs and frequency of LOH in patients with CN-AML.Experimental Design: We examined the frequency and prognostic significance of UPDs in a set of 425 adult patients with de novo CN-AML who were previously sequenced for 81 genes typically mutated in cancer. Associations of UPDs with outcome were analyzed in the 315 patients with CN-AML younger than 60 years.We detected 127 UPDs in 109 patients. Most UPDs were large and typically encompassed all or most of the affected chromosome arm. The most common UPDs occurred on chromosome arms 13q (7.5% of patients), 6p (2.8%), and 11p (2.8%). Many UPDs significantly cooccurred with mutations in genes they encompassed, including 13q UPD with FLT3-internal tandem duplication (FLT3-ITD; P < 0.001), and 11p UPD with WT1 mutations (P = 0.02). Among patients younger than 60 years, UPD of 11p was associated with longer overall survival (OS) and 13q UPD with shorter disease-free survival (DFS) and OS. In multivariable models that accounted for known prognostic markers, including FLT3-ITD and WT1 mutations, UPD of 13q maintained association with shorter DFS, and UPD of 11p maintained association with longer OS.LOH mediated by UPD is a recurrent feature of CN-AML. Detection of UPDs of 13q and 11p might be useful for genetic risk stratification of patients with CN-AML.
Oxidative stress and α-synuclein conspire in vulnerable neurons to promote Parkinson’s disease progression
Authors: Kelvin C. Luk
Journal: Journal of Clinical Investigation (2019)

Patients with Parkinson's disease (PD) show selective degeneration of dopaminergic neurons in the substantia nigra and cholinergic neurons in the dorsal motor nucleus (DMnX), but the drivers of this specific susceptibility are unknown. In this issue of the JCI, Musgrove et al. report on their use of an impressive array of in vivo and ex vivo tools for interrogating DMnX neurons and demonstrate that this population exhibits enhanced sensitivity to oxidative stress. Remarkably, this sensitivity was amplified by the overexpression of α-Synuclein (α-Syn), a pathological protein in PD. They further show that oxidative stress augments cell-cell transfer of α-Syn, which may be an important mechanism underlying the development and progression of PD.
Can neoadjuvant gemcitabine plus carboplatin followed by immediate cystectomy improve survival in patients with cisplatin-ineligible muscle-invasive bladder cancer?
Authors: Takuya Koie, Yuichiro Suzuki, Yuki Tobisawa, Tohru Yoneyama, Kazuyuki Mori, Akiko Okamoto, Hayato Yamamoto, Atsushi Imai, Shingo Hatakeyama, Takahiro Yoneyama, Yasuhiro Hashimoto, Chikara Ohyama
Journal: Journal of Clinical Oncology (2013)

e15565 Background: Standard neoadjuvant chemotherapy has not yet been established for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin based chemotherapy. In the present study, we conducted a propensity score analysis to elucidate the clinical significance of neoadjuvant gemcitabine and carboplatin chemotherapy (GCarbo) for cisplatin-ineligible patients with MIBC. Methods: The cohort of the neoadjuvant group consisted of 51 patients with MIBC, treated between March 2005 and June 2011, who were ineligible for cisplatin. Patients received 2 courses of GCarbo consisting of 800 mg/m 2 gemcitabine on days 1, 8, and 15, and carboplatin with an AUC of 4 on day 2. After GCarbo, radical cystectomy (RC) and bilateral pelvic lymph node dissection (PLND) were performed at an interval of 1 month. The cohort of RC alone included 59 cisplatin-ineligible MIBC patients treated with RC and bilateral PLND between June 1998 and February 2010. Propensity score matching was used to adjust for potential selection biases associated with treatment type. The endpoints were overall (OS) and disease-free survival (DFS). Results: Of the 51 patients who received GCarbo and RC, 6 (11.8%) RC specimens were found to be cancer free. Grade 3/4 neutropenia occurred in 17 patients (33.3%) and thrombocytopenia in 11 patients (21.6%). There were no patients who experienced grade3/4 nephrotoxicity or nausea. Propensity score-matched analysis indicated 45 matched pairs from both groups. The median follow-up period was 35.3 months. The 3-year OS rate was 86.5% for neoadjuvant GCarbo vs. 50.6% for the RC alone group (P &lt; 0.0001). The DFS rate was 78.8% for neoadjuvant GCarbo vs. 44.8% for RC alone (P= 0.001). Multivariate analysis revealed that the neoadjuvant GCarbo regimen was an extremely strong and independent predictor of the longer OS and DFS. Conclusions: Although the present study is non-randomized, neoadjuvant GCarbo chemotherapy followed by immediate RC achieved significantly longer OS and DFS than cystectomy alone. The clinical usefulness of the present treatment for cisplatin-ineligible patients with MIBC should be verified by further trials.
Feasibility study comparing docetaxel-cisplatin versus docetaxel-carboplatin as first-line chemotherapy for ovarian cancer
Authors: J. Kigawa, M. Shimada, Y. Minagawa, Y. Kanamori, H. Itamochi, F. Kitada, M. Okada, N. Terakawa
Journal: Journal of Clinical Oncology (2006)

15055 Background: The carboplatin-paclitaxel combination therapy is a gold standard regimen for patients with ovarian cancer. However, combination chemotherapy continues to produce significant neurotoxicity, a serious adverse effect. We conducted the present study to determine the feasibility of docetaxel-cisplatin combination therapy compared with docetaxel-carboplatin combination therapy as first-line chemotherapy for patients with ovarian cancer. Methods: Fifty patients with International Federation of Gynecology and Obstetrics stage Ic-IV ovarian cancer who underwent primary surgery were randomly assigned to receive treatment with docetaxel-cisplatin (n = 23) or docetaxel-carboplatin (n = 27). Docetaxel 70 mg/m 2 and cisplatin 60 mg/m 2 or carboplatin to an area under the curve = of 5 were administered consecutively on Day 1 of a 3-week cycle, for 3 cycles in patients with stage Ic-II cancer and for over 5 cycles in patients with stage III-IV cancer. Patients were evaluated for treatment-related toxicity in each cycle using the National Cancer Institute Common Toxicity Criteria version 2.0. Results: Five patients (2 in the docetaxel-cisplatin arm and 3 in the docetaxel-carboplatin arm) discontinued the treatment at the end of the second course of chemotherapy because of apparent disease progression; however, no patients came off the protocol therapy because of treatment-related toxicity. Overall, 103 cycles of docetaxel-cisplatin treatment and 130 cycles of docetaxel-carboplatin treatment were delivered. The major toxicity was neutropenia in both regimens. The total incidence of grades 3 and 4 neutropenia was 83% (19/23) in the docetaxel-cisplatin arm and 96% (26/27) in the docetaxel-carboplatin arm. The incidence of grade 4 neutropenia was significantly lower in the docetaxel-cisplatin arm [39% (9/23) vs. 74% (20/27)]. Conclusions: Docetaxel-cisplatin combination therapy may be feasible as first-line chemotherapy for patients with ovarian cancer. No significant financial relationships to disclose.
Abstract 21013: Impaired Postischemic Neovascularization in Sickle Cell Disease
Authors: Derick Okwan-Duodu, Laura Hansen, Alicia Lyle, Gigi Joseph, David Archer, W Robert Taylor
Journal: Circulation (2017)

Objectives: The adaptive response to vascular injury is the formation of collateral vessels to maintain organ function. Many of the clinical complications associated with sickle cell disease (SCD), such as strokes, retinopathy, sudden cardiac death and recalcitrant leg ulcers, can be attributed to repeated bouts of vascular insufficiency, yet the detailed mechanisms of collateral vessel formation following injury are largely unknown in SCD. Here, we characterize post-ischemic neovascularization in SCD, with a focus on the cellular source and contribution of H 2 O 2 , given our previous work showing the critical importance of this reactive oxygen species (ROS) in collateral vessel formation. Methods and Results: To evaluate post-ischemic neovascularization, we performed hind limb ischemia (HLI) by ligation of the femoral artery in the humanized Townes sickle cell (SS) mice, and compared them to their wildtype (AA) mice. Our results showed significant diminution in functional collateral vessel formation in SS mice following HLI as evaluated by LASER Doppler perfusion imaging (76 ±13 % recovery in AA vs 34±10 % recovery in SS by day 28, p &lt; 0.001 n=8 per group). The rate of amputation after HLI was significantly increased in the SS compared to AA mice (25% vs 5%), as was the rate of foot necrosis (80% vs 15%, P &lt;0.001, 8 mice per group). Spontaneous motor function recovery evaluation by the running wheel assay was also significantly impaired in SS mice (36% vs 97% at 28 days post HLI, p &lt; 0.001, n=6 mice per group). The phenotype was associated with persistent neutrophils in the hind limb muscle for up to 28 days in the SS, a time point by which all neutrophils were cleared in AA mice. Consequently, there was a 2.45 fold increased production of H 2 O 2 in SS mice at day 28, compared to AA mice (p&lt; 0.05). Importantly, both in vivo depletion of neutrophils and treatment with the anti-oxidant N-acetylcysteine (NAC) significantly reduced oxidative stress and improved functional collateral formation in the SS mice. Conclusions: Our data suggest dysfunctional collateral vessel formation in SS mice after vascular injury, and provide mechanistic basis for the multiple vascular complications of SCD. Targeting neutrophils and excessive ROS may improve vascular dysfunction in SCD.
Efficacy of Albumin Treatment for Patients with Cirrhosis and Infections Unrelated to Spontaneous Bacterial Peritonitis
Authors: Javier Fernández, Paolo Angeli, Jonel Trebicka, Manuela Merli, Thierry Gustot, Carlo Alessandria, Niels Kristian Aagaard, Andrea de Gottardi, Tania M. Welzel, Alexander Gerbes, German Soriano, Victor Vargas, Agustin Albillos, Francesco Salerno, Francois Durand, Rafael Bañares, Rudolf Stauber, Verónica Prado, Mireya Arteaga, María Hernández-Tejero, Fátima Aziz, Filippo Morando, Christian Jansen, Barbara Lattanzi, Christophe Moreno, Daniela Campion, Henning Gronbaek, Rita Garcia, Cristina Sánchez, Elisabet García, Alex Amorós, Marco Pavesi, Joan Clària, Richard Moreau, Vicente Arroyo
Journal: Clinical Gastroenterology and Hepatology (2019)
Epitope mapping of epidermal growth factor receptor (EGFR) in lung cancer using immunohistochemistry: Fine tuning the protocols
Authors: J. TIMAR, K. Derecskei, B. Dome, J. Moldvay
Journal: Journal of Clinical Oncology (2007)

21162 Background: Until now, immunohistochemistry was not able to become a reliable diagnostic approach for EGFR targeted therapies. The golden standard of the determination of EGFR protein expression in paraffin embedded cancer tissues is the EGFRpharmDXtm kit. Methods: Here we show data based on analysis of 110 lung adenocarcinomas, that the recommended protocol may not be optimal for ideal performance of the immunodetection, since microwave retrieval, extended primary antibody-incubation time and replacement of the developer reagent converted four EGFR-negative tumor into EGFR protein positive out of eight lung adenocarcinoma cases. Protocol modification improved the performance of another widely used EGFR-kit, Ventana's CONFIRM, where replacement of the protease antigen retrieval with microwave cooking converted several EGFR-negative tumors to strongly positive. Meanwhile both EGFR-kits detect EGFR expression (juxtamembrane domain) but do not provide information on the expression of epitopes critical from the point of view of targeted therapy. Results: We have developed two protocols, which can detect the ligand-binding (AB-10, BioMarkers) and C-terminal (AB- 335, Biogenex) cytoplasmic domains of the EGFR protein in paraffin embedded lung cancer tissues. We have shown, based on the analysis of more than 110 lung adenocarcinoma tissues, that the ligand binding domain of EGFR is rarely expressed while the C-terminal domain is ubiquitously expressed in EGFR-PharmDX and CONFIRM-positive cancers. The biological activity of EGFR can be characterized either by autophosphorylation of the receptor or by detection of divers phosphorylated downstream signaling components. We have found that unlike p1086 (detected by a Zymed antibody), the p1173 site of EGFR (identified by a rabbit monoclonal of Epitomics) can be detected 27/110 paraffin embedded lung adenocarcinomas. Conclusions: Using the tested antibody panel we can reliably determine the EGFR protein expression in paraffin embedded (lung)cancer tissues. This work was supported by Ministry of Education (NKFP1a-0024–05). No significant financial relationships to disclose.
CNS-targeting pharmacological interventions for the metabolic syndrome
Authors: Kerstin Stemmer, Timo D. Müller, Richard D. DiMarchi, Paul T. Pfluger, Matthias H. Tschöp
Journal: Journal of Clinical Investigation (2019)

The metabolic syndrome (MetS) encompasses medical conditions such as obesity, hyperglycemia, high blood pressure, and dyslipidemia that are major drivers for the ever-increasing prevalence of type 2 diabetes, cardiovascular diseases, and certain types of cancer. At the core of clinical strategies against the MetS is weight loss, induced by bariatric surgery, lifestyle changes based on calorie reduction and exercise, or pharmacology. This Review summarizes the past, current, and future efforts of targeting the MetS by pharmacological agents. Major emphasis is given to drugs that target the CNS as a key denominator for obesity and its comorbid sequelae.
Detection of EML4-ALK in serum RNA from lung cancer patients using MassARRAY platform.
Authors: Keita Kudo, Makoto Nishio, Kazuko Sakai, Azusa Tanimoto, Toshio Sakatani, Ryota Saito, Kyohei Kaburaki, Noriko Yanagitani, Atsushi Horiike, Fumiyoshi Ohyanagi, Kazuto Nishio
Journal: Journal of Clinical Oncology (2012)

10569 Background: The presence of the transforming fusion gene EML4-ALK in non–small cell lung cancer (NSCLC) is a predictive marker for the efficacy of ALK kinase inhibitors. The break apart fluorescence in situ hybridization (FISH) assay has served as the standard test for identification of NSCLC patients with ALK gene rearrangement. Circulating RNA in plasma/serum is an emerging field for noninvasive molecular diagnosis. We previously developed a MassARRAY assay to detect nine types of EML4-ALK fusion gene (variants 1, 2, 3a, 3b, 4, 5a, 5b, 6, and 7). The assay is based upon region-specific PCR followed by specific single-base primer extension reactions; the extended products are resolved using MALDI-TOF mass spectrometry. In this study, we evaluated whether EML4-ALK fusion RNA could be detected in serum obtained from NSCLC patients. Methods: The RNA was extracted from serum obtained from 12 lung cancer patients with ALK rearrangements by FISH analysis. The extracted RNA was reverse transcribed into cDNA, and the resultant cDNA was amplified by nested PCR. The PCR product was subjected to MassARRAY assay to identify EML4-ALK variants. Results: The EML4-ALK RNA (variant 1 and 3) was detected in serum from 2 of 12 patients. These are confirmed by subcloning and sequencing. Conclusions: The detection of EML4-ALK in serum RNA samples by MassARRAY assay is feasible. This noninvasive assay will be useful in patients with insufficient or unavailable tumor specimens. Additional experiments will reveal the sensitivity and specificity of this detection system.
SM-88 therapy in high risk poor prognosis pancreatic cancer (PDAC).
Authors: Marcus Smith Noel, Andrea Wang-Gillam, Allyson J. Ocean, Sant P. Chawla, Vincent Chung, Giuseppe Del Priore, Vincent J. Picozzi
Journal: Journal of Clinical Oncology (2019)

e15714 Background: Refractory PDAC has no established therapy (JCO 37, 2019 supp 4; 226). SM-88 (D,L-alpha-metyrosine) is a novel oral therapy used with low doses of sirolimus, phenytoin and methoxsalen. Previous studies show safety and efficacy in compromised patients (JCO 37, 2019 supp 4; 200. JCO 37, 2019 supp 4; 310). We now report the dose optimization phase (NCT03512756). Methods: Randomized Phase 2 with dose optimization and expansion cohort of PDAC after 1 prior line, ECOG PS ≤2 and radiographic PD. Subjects randomized to 460 or 920 mg/d SM-88; all received phenytoin 50 mg, methoxsalen 10 mg and sirolimus 0.5 mg. Results: As of Jan 2019, 85 subjects consented, 41 ineligible, 38 randomized and 28 evaluable (1 cycle dosed). Average age 66.9 yrs, BMI 24.1, CA-19.9 median 2,562 (1.2 – 700,000), 2 prior lines 50%, 3 prior 14.3%, &gt; 4 prior 21.4%; 85.7% had prior 5FU, 89.3% Gem, 71.4% taxanes, and 71.4% platinums. In both SM-88 doses, toxicity did not increase on treatment. AEs were not increased among high risk groups (age, sex, low BMI, low albumin, high CA-19.9 and prior radiotherapy). AEs increased with more prior lines of therapy, but were not dose dependent. There were 21 SAEs prior to dosing including 5 deaths among 14 patients. Two SAEs (rash and hypotension) were considered possibly related to SM-88 Therapy. No deaths were drug-related. 9 subjects had either a CEA or CA-19.9 decrease with 2 having both; 96.5% of subjects had CTCs detectable at baseline with 70% experiencing &gt; 30% decline for at least 1 cycle with a median CTC best response decrease of 73%. Prior Lines of Therapy Subjects (n) Current Median OS 2-month Target Lesion Response CTCs Median Best OR % Alive 1 4 +5.7m 1 PR, 2 SD, 1 n/a* -74% 75% 2 14 +4.7m 6 SD, 3 PD, 5 n/a* -84% 79% 3+ 10 +3.5m 1 PR, 4 PD, 5 n/a* -55% 50% Total 28 +4.3m 2 PR, 8 SD, 7 PD, 11 n/a* -73% 68% *Not available RECIST clinical benefit (SD + PR) was 47.1% (8/17). 68% of subjects were alive at a median follow up of +4.3 months. EORTC global health and QOL measures did not deteriorate on treatment. Conclusions: Both doses of SM-88 were well tolerated without clinically significant toxicity. Anti-tumor activity was observed in this heavily pretreated population warranting expansion of the study for further efficacy evaluation. Clinical trial information: NCT03512756.
What lipodystrophies teach us about the metabolic syndrome
Authors: Jake P. Mann, David B. Savage
Journal: Journal of Clinical Investigation (2019)

Lipodystrophies are the result of a range of inherited and acquired causes, but all are characterized by perturbations in white adipose tissue function and, in many instances, its mass or distribution. Though patients are often nonobese, they typically manifest a severe form of the metabolic syndrome, highlighting the importance of white fat in the "safe" storage of surplus energy. Understanding the molecular pathophysiology of congenital lipodystrophies has yielded useful insights into the biology of adipocytes and informed therapeutic strategies. More recently, genome-wide association studies focused on insulin resistance have linked common variants to genes implicated in adipose biology and suggested that subtle forms of lipodystrophy contribute to cardiometabolic disease risk at a population level. These observations underpin the use of aligned treatment strategies in insulin-resistant obese and lipodystrophic patients, the major goal being to alleviate the energetic burden on adipose tissue.
Recurrent somatic JAK3 mutations in NK-cell enteropathy
Authors: Wenbin Xiao, Gaurav K. Gupta, Jinjuan Yao, Yoon J. Jang, Liqiang Xi, Jeeyeon Baik, Allison Sigler, Anita Kumar, Alison J. Moskowitz, Maria E. Arcila, Mark Raffeld, Stefania Pittaluga, Ahmet Dogan, Elaine S. Jaffe
Journal: Blood (2019)
Racial Differences Influence Bariatric Surgery Outcomes—Reply
Authors: Jonathan F. Finks
Journal: JAMA Surgery (2019)

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Response of HER2+ breast cancer patients to allogeneic cell immunotherapy.
Authors: Michael Har-Noy, Wirote Lausoontornsiri, Reuven Or, Emmanual Katsanis
Journal: Journal of Clinical Oncology (2012)

e13013 Background: The immune mechanism of non-myeloablative allogeneic stem cell transplantation has been shown to be effective in debulking chemotherapy-resistant metastatic cancer despite the presence of immunoavoidance mechanisms, but this immune effect is intimately related to GVHD toxicity limiting the clinical application. An allogeneic cell therapy (aCT) with intentionally mismatched, CD3/CD28 microbead-conjugated CD4+ memory cells exhibiting both Th1- and NK-like properties designed to elicit autologous anti-tumor effects in the context of graft rejection was evaluated in a FDA-approved phase I/II clinical trial of 42 refractory metastatic solid tumor patients with a variety of indications. No objective tumor response was observed, however there was evidence of enhanced survival and immune-mediated tumor debulking without GVHD toxicity. RECIST overestimated tumor burden, as responding tumors swelled and appeared larger on CT. Multi-parameter analysis identified serum IL-12 as a predictor of enhanced survival. 50% were IL-12+ and survived a median of 211 days vs. 131 days for IL-12- patients (p&lt;.009). Methods: An analysis of IL-12+ responders was conducted to determine the indication with the highest IL-12 response. Results: 9 of 16 refractory metastatic breast cancer (mBC) patients were IL-12+. The Her2+ subset of mBC were 100% IL-12+ (5 of 5) with a median survival of 416 days, while the 11 Her2- patients had a median survival of only 134 days (p&lt;0.05). Conclusions: Normally, Her2+ tumors are more aggressive and have a poorer prognosis than Her2- tumors. The enhanced response to aCT in Her2+ mBC may be due to high titers of anti-Her2 IgG1 antibodies known to be present in these patients. aCT upregulates host FcgR expression on host monocytes through a CD40L-CD40 mechanism. The FcgR bind IgG1 antibodies and mediate ADCC tumor lysis. We hypothesize that patients expressing tumor-specific IgG1 autoantibodies are more likely to respond to aCT. Serum autoantibodies to tumor-associated antigens thus may be a predictive biomarker for aCT responders. The combination of natural or exogenous tumor-specific IgG1 Abs with aCT may be a platform for refractory metastatic tumor debulking leading to increased overall survival.