tbuckley/cabot-search huggingface dataset:
Prospects of signet ring cell gastric cancer studying (mophoimmunohistochemical study).
Authors: Oleg Ivanovich Kit, Sergey Sergeevich Todorov
Journal: Journal of Clinical Oncology (2014)

e15012 Background: Signet ring cell gastric cancer (SRC) occupies a special place among all malignant neoplasms of the gastrointestinal tract. This is primarily due to the fact that SRC has a fast diffuse aggressive growth, is more common in working-age people, early gives lymphatic and haematogenous cancer spread. Such special biological properties of SRC are based on structural-functional changes in cells of the tumor and stroma, which should certainly be considered when choosing the tactics of preoperative chemotherapy and radiowave treatment, including targeted therapy. In this regard the purpose of this study was comparative comprehensive morphoimmunohistochemical analysis of SRC with the definition of the role of Her-2/neu, E-cadherin, Ki-67, Muc-5A, Muc-2. Methods: 75 biopsies of stomach of SRC patients aged 29-38 years were studied. After usual fixation of biopsy material histological slides were stained with hematoxylin-eosin, PAS-reaction was employed. For immunohistochemical studies antibodies against Her-2/neu, E-cadherin, Ki-67, Muc-5A, Muc-2 by Ventana, Dako in immunosteiner BenchMark Ultra were used. Results: On the basis of morphoimmunohistochemical study three molecular biological types of SRC were identified: 1) PAS-positive, Her-2/neu negative, E-cadherin positive, Ki-67 – 10-15%, Muc-5A negative, Muc-2 positive; 2) PAS-negative, Her-2/neu negative, E-cadherin negative, Ki-67 – 25-35%, Muc-5A negative, Muc-2 negative; 3) PAS-positive, Her-2/neu positive, E-cadherin negative, Ki-67 – 15-20%, Muc-5A positive, Muc-2 positive. Conclusions: Molecular-genetic heterogeneity of SRC shows the important role of various types of mucin in the progression of the tumor, which must be considered when planning further targeted treatment. The “negative” type of SRC with the cells not containing mucus and not having receptors for Her-2/neu, E-cadherin, deserves special attention.
Therapeutic insights for malignant phyllodes from next-generation sequencing.
Authors: Kim M. Hirshfield, Christiaan Devries, Aleksander Lech Chojecki, Siraj M. Ali, Roman Yelensky, Juliann Chmielecki, Jeffrey S. Ross, Philip J. Stephens, Vincent A. Miller, Lorna Rodriguez, Shridar Ganesan
Journal: Journal of Clinical Oncology (2014)

e22069 Background: The unpredictable and sometimes aggressive behavior of phyllodes tumors of the breast has resulted in the primary therapeutic goal of obtaining negative surgical margins. However, disease not amenable to surgical resection is difficult to treat due to limited sensitivity to radiation, hormonal therapy, and chemotherapy. Little is known about underlying genomic alterations in phyllodes tumors. To evaluate the spectrum of genomic alterations in phyllodes tumors of the breast, a genomic profiling assay was performed on formalin-fixed, paraffin-embedded tumor specimens from three different patients representing a spectrum of disease: borderline-malignant localized, malignant localized, and metastatic malignant. Methods: A clinical next generation sequencing (NGS)-based assay of all exons of 236 cancer related genes and 47 introns of 19 genes frequently rearranged in cancer was performed using in-solution capture of libraries constructed from extracted tumor DNA (Foundation Medicine, Cambridge, MA). Results: Up to 5 alterations were identified in each tumor, and both malignant phyllodes tumors harbored PIK3R1 alterations. PTEN and SETD2 alterations were common to the borderline and metastatic phyllodes. The remaining alterations were found in FGFR1, ATM, CDKN2A/B, EGFR, SMARCA4, and MED12. The patients with localized phyllodes are without evidence of disease after surgical resection. The metastatic phyllodes regressed with doxorubicin monotherapy with significant clinical improvement, a treatment initiated prior to genomic testing. Conclusions: Genomic profiling of phyllodes tumors, a rare entity, has identified several clinically meaningful alterations for each patient that can potentially guide targeted treatment decisions. Though current clinical guidelines follow sarcoma regimens for empiric systemic cytotoxic therapy, these phyllodes tumors display unique sets of genomic alterations not typically observed in sarcomas and that support exploring unanticipated avenues for targeted therapy and clinical trials.
Cyclin-dependent kinases as therapeutic targets: Examination of palbociclib (PD 0332991) and flavopiridol in human tumor primary culture microspheroids.
Authors: Robert Alan Nagourney, Eknath A. Deo, Nilesh L. Vora, Milan Rohit Sheth, Paula J Bernard, Federico R Francisco, Steven S Evans
Journal: Journal of Clinical Oncology (2014)

e13504 Background: The cyclin dependent kinases (CDK) are a family of enzymes that mediate cell cycle progression. CDK dysregulation is a common event in human carcinogenesis, making CDK inhibition an attractive target for therapy. Palbociclib (PD) is a selective CDK 4/6 inhibitor, while flavopiridol (FL) is non-specific. CDK inhibitors are now in clinical trials. Methods: To examine the activity and compare the profiles of PD & FL, we used Ex Vivo Analyses of Programmed Cell Death (EVA/PCD) in human tumor primary cultures isolated from surgical specimens. After disaggregation, microspheroids, isolated by precise density centrifugation were exposed to PD or FL for 72 hours and drug induced cell death then measured by delayed-loss-of-membrane integrity and/or ATP content (luciferase).Dose response curves were interpolated to LC50 values. Twenty nine PD, 68 FL and 20-both specimens were studied. Results: PD & FL reveal activity in a broad array of tumors including upper GI, NSCLC, Breast, Ovary & Hematologic. No activity was observed for FL or PD in Head & Neck. Similar profiles were observed except in prostate where FL was more active than PD. Correlations by Pearson Moment revealed an R = 0.58 P<0.01 (2-tailed T). Conclusions: Findings confirm activity for the CDK inhibitors and suggest disease specific profiles. With culture conditions established, further analyses are now comparing PD with other classes of drugs, to examine combinations, synergy & sequence dependence, as will be reported. Supported in part by the Vanguard Cancer Foundation and the Memorial Medical Center Foundation.
Caffeic acid phenethyl ester protects against oxidative stress and dampens inflammation via heme oxygenase 1
Authors: Alexandra Stähli, Ceeneena Ubaidha Maheen, Franz Josef Strauss, Sigrun Eick, Anton Sculean, Reinhard Gruber
Journal: International Journal of Oral Science (2019)

Periodontal disease is associated with chronic oxidative stress and inflammation. Caffeic acid phenethyl ester (CAPE), which is a potent inducer of heme oxygenase 1 (HO1), is a central active component of propolis, and the application of propolis improves periodontal status in diabetic patients. Here, primary murine macrophages were exposed to CAPE. Target gene expression was assessed by whole-genome microarray, RT-PCR and Western blotting. The antioxidative and anti-inflammatory activities of CAPE were examined by exposure of the cells to hydrogen peroxide, saliva and periodontal pathogens. The involvement of HO1 was investigated with the HO1 inhibitor tin protoporphyrin (SnPP) and knockout mice for Nrf2, which is a transcription factor for detoxifying enzymes. CAPE increased HO1 and other heat shock proteins in murine macrophages. A p38 MAPK inhibitor and Nrf2 knockout attenuated CAPE-induced HO1 expression in macrophages. CAPE exerted strong antioxidative activity. Additionally, CAPE reduced the inflammatory response to saliva and periodontal pathogens. Blocking HO1 decreased the antioxidative activity and attenuated the anti-inflammatory activity of CAPE. In conclusion, CAPE exerted its antioxidative effects through the Nrf2-mediated HO1 pathway and its anti-inflammatory effects through NF-κB inhibition. However, preclinical models evaluating the use of CAPE in periodontal inflammation are necessary in future studies.
Continous treatment with bevacizumab in patients with metastatic colorectal cancer.
Authors: Janja Ocvirk, Martina Rebersek, Marko Boc, Neva Volk, Jernej Benedik, Zvezdana Hlebanja
Journal: Journal of Clinical Oncology (2014)

e14642 Background: This is the registry of patients (pts) with metastatic colorectal cancer (mCRC) designed to prospectively evaluate the safety and efficacy of bevacizumab-containing chemotherapy (B-CTX) in routine clinical practice. Methods: Baseline characteristics, pre-specified bevacizumab-related adverse events, and efficacy data were collected from 316 mCRC pts who were treated with B-CTX. Results: First-line B-CTXreceived 210 pts (median age 63, males 61.4%). The Eastern Cooperative Oncology Group (ECOG) performance status (PS) at baseline was 0 in 58%, 1 in 38% and 2 in 4% of pts. Majority of the 210 pts received irinotecan-based chemotherapy (68%) and 105 pts (50%) received bevacizumab maintenance therapy. Complete response (CR) was reported in 6%, partial response (PR) in 35% and stable disease (SD) in 34% of the pts. The median progression-free survival (mPFS) was 10.9 months (95% confidence interval [CI],10.1 - 12.1) and median overall survival (mOS) was 23.7 months (95% CI, 21.6 – 28.9) with 32.2 % patients alive after 3-year follow-up. Liver metastasectomy was performed in 31 (21.1%) pts with liver metastasis. Rates of bevacizumab-related grade 1-2/3-4 adverse events were: proteinuria 21/1 %, hypertension 17/3 %, thromboembolic events 3/4 %, infection 3/2 % and haemorrhage 2/1 %. Second and third line B-CTX received 106 pts (median age 61, males 58.5%), with 57% pts receiving biologic agent in previous regimen. The ECOG PS at baseline was 0 in 54%, 1 in 43%, 2 in 2% and 3 in 1% of patients. Irinotecan-based B-CTX was administered in 53.7% pts and 50 pts (47%) received bevacizumab maintenance therapy. Response rates were: CR - 6%, PR - 27% and SD - 45%. The mPFS was 10.3 months (95% CI,9.0 - 11.7) and mOS was 17.9 months (95% CI, 15.0 – 24.8) with 24.8 % pts alive after 3-year follow-up. Liver metastasectomy was performed in 8 (9.9%) pts with liver metastasis. Rates of bevacizumab-related grade 1-2/3-4 adverse events were: proteinuria 29/0 %, hypertension 20/2 %, thromboembolic events 2/7 %, infection 3/3 % and haemorrhage 1/2 %. Conclusions: We concluded that continued vascular endothelial growth factor inhibition with bevacizumab in patients with mCRC resulted in improved overall success of therapy in routine clinical practice. Clinical trial information: ISRCTN59241668.
Conversion of platinum-taxane resistant to sensitive ovarian cancer with a non-platinum-taxane regimen.
Authors: Shinichi Tate, Kyoko Nishikimi, Hirokazu Usui, Akira Mitsuhashi, Makio Shozu
Journal: Journal of Clinical Oncology (2014)

e16523 Background: Between October, 2008 and May, 2011, We conducted a I/II trial of gemcitabine plus irinotecan in patients with ovarian cancer who had failed to respond to two prior platinum-based regimens. The purpose of the study was to evaluate the efficacy and safety of the combination chemotherapy. We also evaluated weekly paclitaxel-carboplatin for post-progression survival. Methods: A total of 25 patients with a histological diagnosis of ovarian cancer; two prior chemotherapy regimens; and at least one site with measurable disease were included in the study. Patients were treated with irinotecan followed by gemcitabine on days 1 and 8, every 3 weeks. Irinotecan dose was fixed at 50 mg/m2; gemcitabine dose was individualized to the maximum repeatable dose. Gemcitabine starting dose was 500 mg/m2. All patients received the regimen until disease progression. The primary endpoint was time to progression (TTP). As survival post progression (SPP) relates to response to subsequent treatment, patients were stratified in subgroups by TTP. Results: All patients were assessable for response and toxicity. Median TTP was 6.2 months (95% confidence interval [Cl]: 2.7 to 10.7 months) and Median OS was 16.8 months (95% Cl: 9.4 to 30.7 months). DCR was 75% (95% Cl: 58% to 92%). A total of 276 courses were given. Major toxicities were leukocytopenia, granulocytopenia, and anemia: grade 3 to 4 in 9.4%, 11.2% and 9.8% of patients. Major non-hematological toxicities included general fatigue. All patients had tumor progression. Patients were stratified by TTP of more than or less than 6 months. Of 13 patients with TTP less than 6 months, six patients received best supportive care (BSC), four patients pegylated liposomal doxorubicin, and three patients platinum-taxane chemotherapy for subsequent treatment. Of 12 patients with TTP more than 6 months, one patient received BSC and 11 patients platinum-taxane chemotherapy. Median SPP was 5.2 and 15.7months for patients with TTP less than and greater than 6 months, respectively (log-rank p=0.01). Conclusions: The results suggest that for patients who receive non-platinum agents and have a median TTP of greater than 6 months, a change from platinum-taxane resistant to platinum-sensitive disease may occur. Clinical trial information: UMIN000004449.
Outcomes with Subsequent FLT3-Inhibitor (FLT3i) Based Therapies in FLT3-Mutated (mu) Patients (pts) Refractory/Relapsed (R/R) to One or More Prior FLT3 Inhibitor Based Therapies: A Single Center Experience
Authors: Mansour Alfayez, Hagop M. Kantarjian, Farhad Ravandi, Marina Y. Konopleva, Guillermo Garcia-Manero, Tapan M. Kadia, Elias J. Jabbour, Gautam Borthakur, Courtney D. DiNardo, Zeev E. Estrov, Naveen Pemmaraju, Sherry A. Pierce, Musa E. Yilmaz, Nicholas J Short, Koichi Takahashi, Rita Assi, Michael Andreeff, Jorge E. Cortes, Naval G. Daver
Journal: Blood (2018)
Rapid quantification of sputum eosinophil peroxidase on a lateral flow test strip
Authors: M. G. Wolfe, M. Mukherjee, K. Radford, J. D. Brennan, P. Nair
Journal: Allergy (2018)

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Abstract 19589: Bone Marrow Cells Improve Cardiac Function and Remodeling in Patients With Ischemic Heart Disease
Authors: Anweshan Samanta, Muhammad R Afzal, Zubair Shah, Shubha D Roy, Siva S Taduru, Amy Cantilena, Vinodh Jeevanantham, Buddhadeb Dawn
Journal: Circulation (2017)

Introduction: Randomized controlled trials (RCTs) investigating the efficacy of bone marrow cell (BMC) transplantation in patients with ischemic heart disease have provided discordant results. The true benefits of BMMNC therapy in these patients remain unclear. Hypothesis: We hypothesized that injection of BMCs in patients with ischemic heart disease would lead to an improvement in left ventricular (LV) structure and function. Methods: We performed a systemic review and meta-analysis of data from published RCTs that evaluated the efficacy of BMCs in patients with ischemic heart disease. Our literature search yielded 64 trials enrolling 3690 patients. We observed the effects of cell injection on LV ejection fraction (LVEF), LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV) and infarct scar size. BMCs were transplanted in patients with either acute myocardial infarction (AMI) or chronic ischemic heart disease (CIHD). Changes in outcomes of interest were analyzed using random-effects meta-analy...
Novel inhibitors of nicotinamide phosphoribosyl transferase and their evaluation in combination with bortezomib.
Authors: Murali Ramachandra, Anirudha Lakshminarasimhan, Dinesh Chikkanna, Vinayak Khairnar, Sunil Panigrahi, Anuradha Ramanathan, Sumalatha Rani, Narasimha Rao K, Karthikeyan S, Kishore Narayanan, Sreevalsam Gopinath, Raghuveer Ramachandra, Subramanya Hosahalli, Chetan Pandit
Journal: Journal of Clinical Oncology (2014)

e19566 Background: Nicotinamide phosphoribosyl transferase (NAMPT) is the enzyme that catalyzes the rate limiting step in the salvage pathway of Nicotinamide Adenine Dinucleotide (NAD) biosynthesis. NAMPT is reported to be over expressed in a number of cancer and inflammatory indications. NAMPT inhibitors not only exhibit anti-tumor efficacy in preclinical models but also enhance sensitivity to available therapies such as bortezomib resistance in multiple myeloma (MM). In view of the sub-optimal profile of the reported first generation NAMPT inhibitor, we sought to develop NAMPT inhibitors with the “best-in-class” profile for overcoming mechanism-based toxicities and/or resistance to current therapies. Methods: Utilizing structure-guided drug design and SAR-based approaches, we have optimized a novel chemical series of inhibitors of NAMPT. Determination of co-crystal structures with several de novo designed hits greatly aided in the identification of lead compounds that exhibited potent inhibition of NAMPT. Results: Anti-proliferative activity of Lead compounds correlated well with NAD depletion in MM cell lines. Lead compounds exhibited desirable drug-like properties. In a xenograft model of pancreatic cancer and MM, treatment with lead compounds resulted in regression of tumors with no signs of toxicity. Recent reports demonstrating the over expression of NAMPT in bortezomib-resistant cells and a synergistic efficacy with a combination of NAMPT inhibitor and bortezomib against the resistant cells prompted us to evaluate the combination with our optimized leads. The combination of lead NAMPT inhibitors with bortezomib showed synergistic killing of cultured MM cell lines. Evaluation of efficacy of the lead compounds in combination with bortezomib in xenograft models of MM along with determination of therapeutic index based on preclinical models are currently underway. Conclusions: Modulation of NAD levels at lower doses of NAMPT inhibitors in combination with bortezomib could overcome the limitations such as mechanism-based toxicity and/or resistance of both these therapies and provide an effective treatment option for MM.
Chronic Lymphocytic Leukemia Treatment Patterns, Dosing, and Sequencing in the Era of Novel Targeted Therapies: Interim Analysis Results from the Prospective informCLLTM Real-World Registry
Authors: Jeff Sharman, Jacqueline C. Barrientos, Danielle M. Brander, John M. Pagel, Meghan Gutierrez, Karen Kadish, Brian Tomlinson, Nilanjan Ghosh, Nick Giafis, David Ipe, Sandhya Upasani, Murali Sundaram, Lucille Ferrante, Carlos Amaya-Chanaga, Reethi Iyengar, Anthony R. Mato
Journal: Blood (2018)
KD025-208: A Phase 2a Study of KD025 for Patients with Chronic Graft Versus Host Disease (cGVHD) — Pharmacodynamics and Updated Results
Authors: Madan Jagasia, Amandeep Salhotra, Carlos R. Bachier, James Essell, Daniel J. Weisdorf, Behyar Zoghi, Laurie S. Green, Olivier Schueller, Alexandra Zanin-Zhorov, Jonathan M. Weiss, David Eiznhamer, Sanjay K. Aggarwal, Bruce R. Blazar, Stephanie J. Lee
Journal: Blood (2018)
Manufacture of Clinical-Grade Universal Antigen Presenting Cells (UAPC) for the Ex Vivo Expansion and Activation of Natural Killer (NK) Cells
Authors: Enli Liu, Sonny Ang, Yijiu Tong, Li Li, Rafet Basar, Lucila Kerbauy, May Daher, Pinaki P Banerjee, Francesca Lorraine Wei Inng Lim, Indreshpal Kaur, Richard E Champlin, Elizabeth J. Shpall, Katy Rezvani
Journal: Blood (2018)
Gefitinib with concurrent chemoradiation in locally advanced head and neck cancers.
Authors: Charu Singh
Journal: Journal of Clinical Oncology (2014)

6054 Background: Squamous cell carcinomas of Head and Neck express EGFR receptors. We conducted a study to assess the efficacy and toxicity of Gefitinib along with concurrent chemoradiation in comparison to chemoradiation alone in management of locally advanced head and neck cancers. Methods: 86 previously untreated histologically proven patients of squamous cell carcinoma of head and neck cancer were divided into two groups- the study group (n=43) receiving gefitinib 250 mg OD along with weekly cisplatin 30 mg/m2 and radiotherapy , and the control group receiving weekly ciasplatin 30mg/m2along with radiotherapy. The radiotherapy dose was 70 Gy in 35 fractions, 2 Gy / fraction in both the groups. Inclusion criteria were- patients with locally advanced head and neck cancer, biopsy proven squamous cell histology, patients of both genders, between 18 and 70 yearsof age, ECOG PS 0 to 2, life expectancy of 6 months. Patients with poor performance status, known metastatic disease, uncontrolled intercurrent illness, deranged LFT, RFT and complete blood count, and histology other than squamous cell carcinoma were excluded from study. The patients were put on follow up for 6 months after completion of treatment. Results: The analysis was based on intent to treat. In the study group, 34 patients had complete response and 4 had partial response. Overall response was seen in 38 patients (88.37%, p<.05). While in control group 27 patients showed complete response and 3 patients had partial response. Overall response (CR+PR) was seen in 69.76% patients. The most common adverse affects were skin rashes and mucositis. The incidence of dermatitis was 51.16% in the study group and 39.53% in the control group , overall incidence of grade 3 dermatitis being 3%. The incidence of mucositis was 90.69% in the control group and 97.67% in the study group. Conclusions: Chemoradiation remains the mainstay of treatment for head and neck cancer patients. EGFR is most expressed receptor in squamous cell carcinoma of head and neck. The present study shows that targeted therapy with gefitinib and chemoradiation is well tolerated with some enhanced, but manageable toxicities and has shown to improve local control though further studies are needed.
Are the criteria indicating patients to be “medically inoperable” that are used in clinical trials on stereotactic body radiotherapy appropriate for patients with early-stage non-small cell lung cancer?
Authors: Kazuya Takamochi, Shiaki Oh, Kenji Suzuki
Journal: Journal of Clinical Oncology (2014)

7553 Background: The standard treatment for patients with early stage non-small cell lung cancer (NSCLC) is surgical resection. Stereotactic body radiotherapy (SBRT) has recently been investigated as an alternative treatment in place of surgery in clinical trials, especially for medically inoperable (MI) patients. However, no clear rationale for the criteria used to determine whether or not a patient is MI has yet been demonstrated. Methods: Between January 2004 and October 2012, 740 patients underwent surgical resection for clinical stage IA NSCLC. In the present study, MI was defined as patients with FEV1.0≤0.8L, %DLCO<40%, PaO2≤70mmHg, PaCO2>50mmHg, or three or more severe comorbidities, based on the criteria of MI that are frequently used in clinical trials in SBRT for NSCLC patients. The clinicopathological characteristics and surgical outcomes were compared between the MI patients (n = 91) and non-MI patients (n = 649). Results: The proportion of males (P = 0.002), elderly (P < 0.001), smokers (P < 0.001) and those with a non-adenocarcinoma histology (P < 0.001) were higher in MI patients than in non-MI patients. No statistical difference was observed in the proportion of pathological stage IA between the groups (69% in MI vs 77% in non-MI, P = 0.09). Limited operation (wedge lung resection or segmentectomy) was performed for 37 (41%) MI and 227 (35%) non-MI patients (P = 0.3). Mediastinal lymph node dissection was performed for 48 (53%) MI and 413 (64%) non-MI patients (P = 0.05). Although the rates of overall morbidity (39% in MI vs 23% in non-MI, P = 0.002) and 90-day mortality (3% in MI vs 0.5% in non-MI, P = 0.03) were higher in the MI patients, there were no statistical differences in 30-day mortality (1% in MI vs 0.2% in non-MI, P = 0.2), overall survival (P = 0.2) or cancer-specific survival (P= 0.7) between the groups. Conclusions: Surgical resection can be performed in MI patients with an equivalent survival to non-MI patients. The current criteria that are used to determine whether or not a patient is MI for clinical trials in SBRT for NSCLC patients are therefore not considered to be appropriate to evaluate the true operability.