tbuckley/cabot-search huggingface dataset:
Phase I trial of gemcitabine plus trastuzumab and pertuzumab in previously treated metastatic HER2+ breast cancer.
Authors: Hatem Hussein Soliman, Fatema Khambati, Hyo S. Han, Roohi Ismail-Khan, Loretta S. Loftus, Susan E. Minton
Journal: Journal of Clinical Oncology (2016)

595 Background: In HER2+ breast cancers, HER2 forms heterodimers with HER3 to activate its signaling cascade. Dual HER2 blockade with trastuzumab (T) + pertuzumab (P) prevents heterodimerization and is superior to trastuzumab alone. Prior trials suggest a role for continued T beyond progression, so a study was proposed to assess the role of T+P in the salvage setting. A phase 1/2 trial is ongoing to assess the safety and efficacy of gemcitabine (G) + TP in metastatic HER2+ pretreated patients. (NCT02139358) Here we report the data for the completed phase 1 cohort. Methods: The phase 1 trial used a 3+3 design with 3 dose levels (DL), starting at DL0. DL0 used G 1200mg/m2 IV D1, 8 + T 6 mg/kg IV D1, P 420mg IV D1 q21 days (after loading doses on C1D1). DL-1 is identical to DL0 but used G at 1000mg/m2 and DL -2 used G at 850mg/m2. Primary endpoint(s) were recommended phase 2 dose (RP2D) and safety/toxicity. DLT definition was any 1stcycle unexpected ≥ G3 non-hematologic or ≥ G4 hematologic toxicity leading to a dose delay of > 3 weeks. Patients were evaluated q3 weeks with physical exam, CMP, and CBC + echocardiogram/MUGA q 3 months. Response scans were obtained every 2 cycles. Patients who had progressed on any prior HER2 directed therapy, had adequate organ function, PS 0-2, no untreated active CNS mets were eligible. Results: Six female patients were accrued to DL0 from 9/2014 to 4/2015. Median age = 55. # of prior lines of therapy ranged from 2-7. A DLT did not occur at DL0 so this was declared the RP2D. Dose reductions of G to 1000mg/m2 were required in 2/6 pts after the DLT period. Significant toxicities included grade 3 anemia, diarrhea, fatigue, infection, leukopenia, dehydration, hypotension, and one grade 4 respiratory failure (due to disease progression). No treatment related deaths occurred. Best responses were 1 PR, 4 SD, 1 PD. Median PFS for cohort was 3.75 months (2-9.1). Conclusions: The GTP regimen was safe and feasible to administer at DL0, establishing it as the RP2D. In this small, pretreated group of patients the regimen demonstrated signs of clinical activity with 1 PR out of six patients. This regimen is being evaluated in a single arm phase 2 to determine efficacy of this combination in the salvage setting. Clinical trial information: NCT02139358.
Final results of the international randomized PORTEC-3 trial of adjuvant chemotherapy and radiation therapy (RT) versus RT alone for women with high-risk endometrial cancer.
Authors: Stephanie M. de Boer, Melanie E. Powell, Linda R. Mileshkin, Dionyssios Katsaros, Paul Bessette, Christine Haie-Meder, Petronella B Ottevanger, Jonathan A. Ledermann, Pearly Khaw, Alessandro Colombo, Anthony W. Fyles, Marie-Helene Baron, Henry C. Kitchener, Hans Nijman, Roy F.P.M. Kruitwagen, Ina M. Jurgenliemk-Schulz, Remi A. Nout, Vincent T.H.B.M. Smit, Hein Putter, Carien L. Creutzberg
Journal: Journal of Clinical Oncology (2017)

5502 Background: Women with high-risk endometrial cancer (HREC) are at increased risk of distant metastasis and endometrial cancer-related death. The randomized PORTEC-3 intergroup trial was initiated to investigate the benefit of adjuvant chemotherapy during and after radiotherapy (CTRT) versus pelvic radiotherapy (RT) alone for women with HREC. Methods: Women with HREC (FIGO stage I grade 3 with deep myometrial invasion and/or LVSI; stage II or III; or serous/clear cell histology) were randomly allocated (1:1) to RT (48.6 Gy in 1.8 Gy fractions) or CTRT (two cycles of cisplatin 50 mg/m² in week 1 and 4 of RT, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m² at 3-week intervals) with stratification for participating center, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival (OS) and failure-free survival (FFS). The Kaplan-Meier method, log-rank test and Cox regression analysis were used for final analysis according to intention-to-treat. PORTEC-3 is registered with ISRCTN (ISRCTN14387080) and ClinicalTrials.gov (NCT00411138). Results: 686 women were enrolled between 2006 and 2013. 26 women were excluded; 13 withdrew consent early and 13 were ineligible, which left 660 patients in the analysis, with a median follow up time of 60.2 months (IQR 47.1–72.9): 330 CTRT and 330 RT. Three- and five-year OS for CTRT vs. RT was 84.4% versus 83.9%, and 81.8% versus 76.7%; overall HR 0.79 [95% CI 0.57-1.12, p=0.183]. Three-year FFS was 79.7% (CTRT) versus 71.8% (RT), and at 5 years 75.5% versus 68.9%, overall HR for FFS 0.77 [0.58-1.03, p=0.078]. Patients with stage III EC had lower 5-year FFS and OS compared to stage I-II (FFS 63.9% vs 78.9%, p&lt;0.001, and OS 74.3% vs 83.1%, p=0.003). They also had greatest benefit of CTRT: 5-year FFS for stage III was 69.3% for CTRT vs 58.0% for RT [95% CI 0.45-0.97, p=0.032], and 5-year OS for stage III was 78.7 % vs 69.8% (p=0.114). Conclusions: Adjuvant chemotherapy given during and after pelvic radiotherapy for treatment of HREC did not significantly improve 5-year FFS and OS, compared with RT alone. For women with stage III EC FFS was however significantly improved with CTRT by 11% at 5 years. Follow-up will continue to evaluate long-term outcomes. Clinical trial information: NCT00411138.
Predictive value of circulating tumor cells in patients with breast and colon cancer.
Authors: Siegfried Hauch, Silke Lankiewicz, Winfried Albert, Sabine Kasimir-Bauer, Tim Greten
Journal: Clinical Cancer Research (2007)

B19  Background: Metastasized breast and colon cancer patients were analyzed during therapy for presence of circulating tumor cells (CTC) to determine the usefulness of this diagnostic approach for the prediction of therapy response.  Materials and Methods: 5 ml blood was obtained from M1 patients with either breast cancer (n=22) or colon cancer (n=29) and tested for CTC by multiplex analysis of GA733-2, MUC-1 and HER-2 expression with the AdnaTest BreastCancer and for GA733-2, CEA and EGFR expressionwith the AdnaTest ColonCancer according to the manufacturer’s instruction (AdnaGen AG, Langenhagen, Germany).  Results:The detection rate for CTC in metastatic breast cancer before therapy was 54% (12/22) and in colon cancer patients 59% (17/29), respectively. 4 of the initially CTC negative breast cancer patients became CTC positive during therapy. One patient died and the remaining 15 breast cancer patients, CTC positive either before or during therapy, showed in 13 cases a correlation between presence, persistence or early disappearance of CTC with therapy response, corresponding to a prediction rate of 87%. In M1 colon cancer patients 31% progressed under therapy, 41% showed a remission and 28% had stable disease. In patients, positive for CTC either before or after treatment, CTC disappeared immediately in 75% (6/8) of the responders whereas in 83% (5/6) of the non-responders CTC persisted during therapy. CTC were detected in 50% (2/4) of the patients diagnosed with stable disease after therapeutic intervention.  Discussion: Although the prognostic value of CTC in primary cancer still has to be proven in prospective studies, it could be shown, that the presence of CTC in metastatic disease is a predictor of therapy response. Early identification of responders and non-responders may help do improve therapy efficacy and may increase disease free and overall survival of metastasized breast and colon cancer patients.
MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer
Authors: Surendra K. Shukla, Vinee Purohit, Kamiya Mehla, Venugopal Gunda, Nina V. Chaika, Enza Vernucci, Ryan J. King, Jaime Abrego, Gennifer D. Goode, Aneesha Dasgupta, Alysha L. Illies, Teklab Gebregiworgis, Bingbing Dai, Jithesh J. Augustine, Divya Murthy, Kuldeep S. Attri, Oksana Mashadova, Paul M. Grandgenett, Robert Powers, Quan P. Ly, Audrey J. Lazenby, Jean L. Grem, Fang Yu, José M. Matés, John M. Asara, Jung-whan Kim, Jordan H. Hankins, Colin Weekes, Michael A. Hollingsworth, Natalie J. Serkova, Aaron R. Sasson, Jason B. Fleming, Jennifer M. Oliveto, Costas A. Lyssiotis, Lewis C. Cantley, Lyudmyla Berim, Pankaj K. Singh
Journal: Cancer Cell (2017)
Acute coronary syndrome in new-onset rheumatoid arthritis: a population-based nationwide cohort study of time trends in risks and excess risks
Authors: Marie Holmqvist, Lotta Ljung, Johan Askling
Journal: Annals of the Rheumatic Diseases (2017)

Acute coronary syndrome (ACS) and other cardiovascular diseases are the main drivers of the increased morbidity and preterm mortality in rheumatoid arthritis (RA). ACS in RA has been linked to inflammation and RA severity. During recent years and with new therapeutic options and treat-to-target strategies, increasing efforts have been made to reach RA remission as soon as possible after diagnosis, and the average level of RA disease activity has declined. Whether this has resulted in declining excess risks for RA comorbidities remains unclear.We performed a nationwide population-based cohort study of patients with new-onset RA from 1997 to 2014, and matched general population comparators. In the Swedish healthcare system, all residents have equal access to healthcare services. Healthcare is monitored using high-quality population-based registers that can be linked together. 15 744 patients with new-onset RA, identified from the Swedish Rheumatology Quality Register, and 70 899 general population comparator subjects were included.Seven hundred and seventy two patients with RA developed an ACS during 103 835 person-years of follow-up (crude incidence, 7.4 per 1000), corresponding to an overall HR versus the general population of 1.41 (95% CI 1.29 to 1.54). Whereas the ACS incidence declined over calendar time in both the RA and the general population cohort, the excess and the relative risks of ACS remained the same.Despite improved disease control in new-onset RA, the elevated risk of ACS in RA remains a concern.
Phase I study of IGF-methotrexate conjugate in the treatment of refractory malignancies expressing IGF-1R.
Authors: Rozina A. Chowdhery, Arkadiusz Z. Dudek, Rajyasree Emmadi, Robert J. Cabay, Hui Xie, Yang Lu, Frederick Behm, Sujata Gaitonde, Hugh McTavish, Neeta K. Venepalli
Journal: Journal of Clinical Oncology (2014)

TPS2635 Background: The insulin-like growth factor 1 receptor (IGF-1R) is overexpressed in multiple malignancies, including breast, prostate, lung, colorectal, CLL, T-ALL, and mantle cell lymphoma. Activation of IGF-1R through binding of IGF-1 and IGF-2 induces activation of the MAPK and PIRK/ATK/mTOR pathways, resulting in inhibition of cell differentiation, resistance to apoptosis, chemotherapy resistance, and metastasis. Serum IGF binding proteins (IGFBP1-6) regulate IGF-1 and IGF-2 bioavailability. IGF-IR down-regulation leads to massive apoptosis; in vitro and in vivo IGF-IR inhibition leads to anti-proliferative effects and appears synergistic with chemotherapy. IGF-Methotrexate (IGF-MTX) is a novel conjugate of methotrexate (MTX) and 765IGF, a variant of IGF-1 with high affinity for IGF-1R and reduced affinity for IGFBP; in vivo studies confirmed tumor control at lower doses than free MTX. Targeting IGF-MTX towards malignancies overexpressing IGF-1R is a novel therapeutic strategy. Methods: This is a single center Phase I dose escalation study with a modified toxicity probability interval design to determine the MTD of 765IGF-MTX in patients with previously treated advanced malignancy expressing IGF-1R. Primary objectives: establish the MTD, safety and toxicity. Secondary objectives: pharmacokinetics (PK) / pharmacodynamics (PD) /biomarker profiles, and preliminary antitumor activity in patients with refractory malignancies expressing IGF-1R. Inclusion criteria: IGF-1R expression > 10% on tumor tissue via IHC or IGF-1R density > 0.1% on flow cytometry, ECOG PS 0-2, good organ function and a rest period of 2-6 weeks from their last treatment (duration based on previous therapy). Exclusion criteria: previous MTX use, or uncontrolled chronic illness. Administration and design: 765IGF-MTX is given IV over 1 hour on days 1, 8 and 15 of a 28 day cycle. This study has two components: first, an initial dose finding component with up to 7 cohort dose levels (0.05, 0.10, 0.20, 0.40, 0.80, 1.6, 2.5 µeq/kg), and second, an expansion cohort of 9 patients at MTD, with PK/PD/biomarker profile. The study is currently enrolling patients. Clinical trial information: NCT02045368.
Allogeneic Hematopoietic Stem Cell Transplantation Is Underutilized in Patients with Myelodysplastic Syndromes
Authors: Bartlomiej Getta, Ashwin Kishtagari, Patrick Hilden, Sean Devlin, Molly A. Maloy, Patrick K. Gonzales, Brian C. Shaffer, Doris M Ponce, Boglarka Gyurkocza, Juliet N. Barker, Esperanza B. Papadopoulos, Hugo Castro-Malaspina, Ann A. Jakubowski, James W. Young, Martin S. Tallman, Miguel-Angel Perales, Sergio A. Giralt, Roni Tamari, Virginia M. Klimek
Journal: Blood (2016)
Large Perivascular Spaces Visible on Magnetic Resonance Imaging, Cerebral Small Vessel Disease Progression, and Risk of Dementia
Authors: Jie Ding, Sigurður Sigurðsson, Pálmi V. Jónsson, Gudny Eiriksdottir, Andreas Charidimou, Oscar L. Lopez, Mark A van Buchem, Vilmundur Guðnason, Lenore J. Launer
Journal: JAMA Neurology (2017)

With advancing age, an increased visibility of perivascular spaces (PVSs) on magnetic resonance imaging (MRI) is hypothesized to represent impaired drainage of interstitial fluid from the brain and may reflect underlying cerebral small vessel disease (SVD). However, whether large perivascular spaces (L-PVSs) (>3 mm in diameter) visible on MRI are associated with SVD and cognitive deterioration in older individuals is unknown.To examine whether L-PVSs are associated with the progression of the established MRI markers of SVD, cognitive decline, and increased risk of dementia.The prospective, population-based Age, Gene/Environment Susceptibility-Reykjavik Study assessed L-PVSs at baseline (September 1, 2002, through February 28, 2006) on MRI studies of the brain in 2612 participants. Participants returned for additional MRI from April 1, 2007, through September 30, 2011, and underwent neuropsychological testing at the 2 time points a mean (SD) of 5.2 (0.2) years apart. Data analysis was conducted from August 1, 2016, to May 4, 2017.The presence, number, and location of L-PVSs.Incident subcortical infarcts, cerebral microbleeds, and progression of white matter hyperintensities detected on MRI; cognitive decline defined as composite score changes between baseline and follow-up in the domains of memory, information processing speed, and executive function; and adjudicated incident dementia cases diagnosed according to international guidelines.Of the 2612 study patients (mean [SD] age, 74.6 [4.8] years; 1542 [59.0%] female), 424 had L-PVSs and 2188 did not. The prevalence of L-PVSs was 16.2% (median number of L-PVSs, 1; range, 1-17). After adjusting for age, sex, and interval between baseline and follow-up scanning, the presence of L-PVSs was significantly associated with an increased risk of incident subcortical infarcts (adjusted risk ratio, 2.54; 95% CI, 1.76-3.68) and microbleeds (adjusted risk ratio, 1.43; 95% CI, 1.18-1.72) and a greater 5-year progression of white matter hyperintensity volume. The presence of L-PVSs was also associated with a steeper decline in information processing speed and more than quadrupled the risk of vascular dementia. All associations persisted when further adjusted for genetic and cerebrovascular risk factors. The associations with cognitive outcomes were independent of educational level, depression, and other SVD MRI markers.Large PVSs are an MRI marker of SVD and associated with the pathogenesis of vascular-related cognitive impairment in older individuals. Large PVSs should be included in assessments of vascular cognitive impairment in the older population and as potential targets for interventions.
Timed Delivery of Therapy Enhances Functional Muscle Regeneration
Authors: Christine A. Cezar, Praveen Arany, Sarah A. Vermillion, Bo Ri Seo, Herman H. Vandenburgh, David J. Mooney
Journal: Advanced Healthcare Materials (2017)

Abstract Cell transplantation is a promising therapeutic strategy for the treatment of traumatic muscle injury in humans. Previous investigations have typically focused on the identification of potent cell and growth factor treatments and optimization of spatial control over delivery. However, the optimal time point for cell transplantation remains unclear. Here, this study reports how myoblast and morphogen delivery timed to coincide with specific phases of the inflammatory response affects donor cell engraftment and the functional repair of severely injured muscle. Delivery of a biomaterial‐based therapy timed with the peak of injury‐induced inflammation leads to potent early and long‐term regenerative benefits. Diminished inflammation and fibrosis, enhanced angiogenesis, and increased cell engraftment are seen during the acute stage following optimally timed treatment. Over the long term, treatment during peak inflammation leads to enhanced functional regeneration, as indicated by reduced chronic inflammation and fibrosis along with increased tissue perfusion and muscle contractile force. Treatments initiated immediately after injury or after inflammation had largely resolved provided more limited benefits. These results demonstrate the importance of appropriately timing the delivery of biologic therapy in the context of muscle regeneration. Biomaterial‐based timed delivery can likely be applied to other tissues and is of potential wide utility in regenerative medicine.
Health-Related Quality of Life of Patients with Newly Diagnosed Multiple Myeloma Receiving Any or Lenalidomide Maintenance after Autologous Stem Cell Transplant in the Connect® MM Disease Registry
Authors: Rafat Abonour, Brian G.M. Durie, Sundar Jagannath, Jatin J. Shah, Mohit Narang, Howard R. Terebelo, Cristina J. Gasparetto, Kathleen Toomey, James W. Hardin, Amani Kitali, Craig Gibson, Shankar Srinivasan, Arlene S. Swern, Robert M. Rifkin
Journal: Blood (2016)
The Ras-related Rho GTPases, Rac1 and Rac2 regulate the homing, engraftment and mobilization of hematopoietic stem cells and progenitor cells
Authors: J. A. Cancelas, Y. Gu, M. D. Filippi, R. Prabhakar, A. W. Lee, J. E. Siefring, D. A. Williams
Journal: Blood (2003)
Lycorine Downregulates HMGB1 to Inhibit Autophagy and Enhances Bortezomib Activity in Multiple Myeloma
Authors: Mridul Roy, Long Liang, Xiaojuan Xiao, Yuanliang Peng, Yuhao Luo, Weihua Zhou, Ji Zhang, Lugui Qiu, Shuaishuai Zhang, Feng Liu, Xiuli An, Mao Ye, Wen Zhou, Jing Liu
Journal: Blood (2016)
In moderate-to-severe sciatica, pregabalin did not reduce leg pain intensity or improve quality of life
Authors: Eyad Al-hihi, Robert G. Badgett
Journal: Annals of Internal Medicine (2017)

ACP Journal Club18 July 2017In moderate-to-severe sciatica, pregabalin did not reduce leg pain intensity or improve quality of lifeEyad Al-hihi, MD, Robert G. Badgett, MDEyad Al-hihi, MDUniversity of Kansas School of Medicine, Kansas City, Kansas, USA (E.A.)Search for more papers by this author, Robert G. Badgett, MDUniversity of Kansas School of Medicine, Wichita, Kansas, USA (R.G.B.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2017-167-2-004 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationMathieson S, Maher CG, McLachlan AJ, et al. Trial of pregabalin for acute and chronic sciatica. N Engl J Med. 2017;376:1111-20. https://pubmed.ncbi.nlm.nih.gov/28328324Clinical Impact RatingsGIM/FP/GP: Neurology: References1 Ostelo RW, Deyo RA, Stratford P, et al. Interpreting change scores for pain and functional status in low back pain: towards international consensus regarding minimal important change. Spine (Phila Pa 1976). 2008;33:90-4. [PMID: 18165753] Google Scholar2 Qaseem A, Wilt TJ, McLean RM, Forciea MA; Clinical Guidelines Committee of the American College of Physicians. Noninvasive treatments for acute, subacute, and chronic low back pain: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2017;166:514-30. [PMID: 28192789] Google Scholar3 Deyo RA, Mirza SK. Clinical practice. Herniated lumbar intervertebral disk. N Engl J Med. 2016;374:1763-72. [PMID: 27144851] Google Scholar Author, Article, and Disclosure InformationAffiliations: University of Kansas School of Medicine, Kansas City, Kansas, USA (E.A.)University of Kansas School of Medicine, Wichita, Kansas, USA (R.G.B.)This article was published at Annals.org on 4 July 2017. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited bySecond-Order Peer Reviews of Clinically Relevant Articles for the Physiatrist 18 July 2017Volume 167, Issue 2Page: JC4KeywordsAdverse eventsDisabilitiesLower back painNeuropathic painPainQuality of lifeQuestionnairesSedativesSerious adverse eventsSurgery ePublished: 18 July 2017 Issue Published: 18 July 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Ado-Trastuzumab Emtansine for Patients With <i>HER2</i>-Mutant Lung Cancers: Results From a Phase II Basket Trial
Authors: Bob T. Li, Ronglai Shen, Darren Buonocore, Zachary T. Olah, Ai Ni, Michelle S. Ginsberg, Gary A. Ulaner, Michael Offin, Daniel Feldman, Todd Hembrough, Fabiola Cecchi, Sarit Schwartz, Nick Pavlakis, Stephen Clarke, Helen H. Won, Edyta B. Brzostowski, Gregory J. Riely, David B. Solit, David M. Hyman, Alexander Drilon, Charles M. Rudin, Michael F. Berger, José Baselga, Maurizio Scaltriti, Maria E. Arcila, Mark G. Kris
Journal: Journal of Clinical Oncology (2018)

Purpose Human epidermal growth factor receptor 2 ( HER2, ERBB2)-activating mutations occur in 2% of lung cancers. We assessed the activity of ado-trastuzumab emtansine, a HER2-targeted antibody-drug conjugate, in a cohort of patients with HER2-mutant lung cancers as part of a phase II basket trial. Patients and Methods Patients received ado-trastuzumab emtansine at 3.6 mg/kg intravenously every 3 weeks until progression. The primary end point was overall response rate using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A Simon two-stage optimal design was used. Other end points included progression-free survival and toxicity. HER2 testing was performed on tumor tissue by next generation sequencing, fluorescence in situ hybridization, immunohistochemistry, and protein mass spectrometry. Results We treated 18 patients with advanced HER2-mutant lung adenocarcinomas. The median number of prior systemic therapies was two (range, zero to four prior therapies). The partial response rate was 44% (95% CI, 22% to 69%), meeting the primary end point. Responses were seen in patients with HER2 exon 20 insertions and point mutations in the kinase, transmembrane, and extracellular domains. Concurrent HER2 amplification was observed in two patients. HER2 immunohistochemistry ranged from 0 to 2+ and did not predict response, and responders had low HER2 protein expression measured by mass spectrometry. The median progression-free survival was 5 months (95% CI, 3 to 9 months). Toxicities included grade 1 or 2 infusion reactions, thrombocytopenia, and elevated hepatic transaminases. No patient stopped therapy as a result of toxicity or died on study. Conclusion Ado-trastuzumab emtansine is an active agent in patients with HER2-mutant lung cancers. This is the first positive trial in this molecular subset of lung cancers. Further use and study of this agent are warranted.