tbuckley/cabot-search huggingface dataset:
Long-term survival of de novo stage IV human epidermal growth factor receptor 2 (HER2)-positive breast cancers treated with HER2 targeted therapy.
Authors: Yao Wong, Akshara Singareeka Raghavendra, Christos Hatzis, Javier Perez Irizarry, Teresita Vega, Carlos Hernando Barcenas, Mariana Chavez-Mac Gregor, Vicente Valero, Debu Tripathy, Lajos Pusztai, Rashmi Krishna Murthy
Journal: Journal of Clinical Oncology (2017)

1021 Background: An increasing number of metastatic HER2 positive cancers represent de novo stage IV disease as fewer early stage patients relapse. We hypothesize that a subset of these has long progression free survival (PFS) after initial combined modality HER2-targeted therapies. Methods: 483 patients with de novo stage IV HER2 positive breast cancer diagnosed between 1998-2015 were identified through the medical records at Yale and MD Anderson Cancer Centers, respectively. Treatment, clinical variables and survival were extracted and compared between those who achieved “no evidence of disease” (NED) status with initial therapy and those who did not. Results: All patients received trastuzumab and 94 (20%) also received pertuzumab as first line therapy.The median OS was 5.5 years (95% Cl: 4.8-6.2); OS rates at 5 and 10 years were 54% (95% CI: 48%-60.4%) and 18% (95% Cl: 11.4%-28.3%), respectively and PFS were 41% (95% CI: 35%-48%) and 41% (95% CI: 35%-48%). Sixty-three patients (13.0%; 95% CI: 10.2% -16.4%) achieved NED. The PFS and OS at 5 and 10 years were the same 100% and 98% (95% CI: 94.6%-100%), respectively. For patients with no-NED (n = 420), the median OS was 4.7 years (95% Cl: 4.2-5.3), the PFS and OS rates at 5 and 10 years were 12% (95% CI: 4.5%-30.4%) and 0% and 45% (95% CI: 38.4%-52.0%) and 4% (95% CI: 1.3%-13.2%), respectively. NED patients had significantly longer progression free survival (log-rank test p≤0.001) and overall survival (log-rank test p≤0.001), more frequently had single organ site metastasis (76% vs 57%, p = 0.005), and more frequently had surgery for primary tumor (59% vs. 25%, p ≤0.001) than no-NED patients, but there was no significant difference in age, grade, race, year of diagnosis, ER status, treatment distribution, or radiation between the groups. Conclusions: About 13% of de novo, stage IV, HER-2 positive MBC patients achieved NED with HER-2 targeted therapies, all of these patients were progression free at 5 years and overall survival at 10-years was 98% compared to 4% among those with no-NED in our data sets. These results suggest that aggressive multimodality therapy of newly diagnosed stage IV HER2 positive cancers to render them NED may be warranted.
Vandetanib-eluting Radiopaque Beads: <i>In vivo</i> Pharmacokinetics, Safety and Toxicity Evaluation following Swine Liver Embolization
Authors: Alban Denys, Peter Czuczman, David Grey, Zainab Bascal, Rhys Whomsley, Hugh Kilpatrick, Andrew L. Lewis
Journal: Theranostics (2017)

To evaluate the plasma and tissue pharmacokinetics, safety and toxicity following intra-arterial hepatic artery administration of Vandetanib (VTB)-eluting Radiopaque Beads (VERB) in healthy swine.In a first phase, healthy swine were treated with hepatic intra-arterial administration of VERB at target dose loading strengths of 36 mg/mL (VERB36), 72 mg/mL (VERB72) and 120 mg/mL (VERB120). Blood and tissue samples were taken and analysed for VTB and metabolites to determine pharmacokinetic parameters for the different dose forms over 30 days. In a second phase, animals were treated with unloaded radiopaque beads or high dose VTB loaded beads (VERB100, 100 mg/mL). Tissue samples from embolized and non-embolized areas of the liver were evaluated at necropsy (30 and 90 days) for determination of VTB and metabolite levels and tissue pathology. Imaging was performed prior to sacrifice using multi-detector computed tomography (MDCT) and imaging findings correlated with pathological changes in the tissue and location of the radiopaque beads.The peak plasma levels of VTB (Cmax) released from the various doses of VERB ranged between 6.19-17.3 ng/mL indicating a low systemic burst release. The plasma profile of VTB was consistent with a distribution phase up to 6 h after administration followed by elimination with a half-life of 20-23 h. The AUC of VTB and its major metabolite N-desmethyl vandetanib (NDM VTB) was approximately linear with the dose strength of VERB. VTB plasma levels were at or below limits of detection two weeks after administration. In liver samples, VTB and NDM VTB were present in treated sections at 30 days after administration at levels above the in vitro IC50 for biological effectiveness. At 90 days both analytes were still present in treated liver but were near or below the limit of quantification in untreated liver sections, demonstrating sustained release from the VERB. Comparison of the reduction of the liver lobe size and associated tissue changes suggested a more effective embolization with VERB compared to the beads without drug.Hepatic intra-arterial administration of VERB results in a low systemic exposure and enables sustained delivery of VTB to target tissues following embolization. Changes in the liver tissue are consistent with an effective embolization and this study has demonstrated that VERB100 is well tolerated with no obvious systemic toxicity.
3D printed lattices as an activation and expansion platform for T cell therapy
Authors: Bahman Delalat, Frances Harding, Batjargal Gundsambuu, Elena M. De-Juan-Pardo, Felix M. Wunner, Marie-Luise Wille, Marek Jasieniak, Kristen A.L. Malatesta, Hans J. Griesser, Antonio Simula, Dietmar W. Hutmacher, Nicolas H. Voelcker, Simon C. Barry
Journal: Biomaterials (2017)
Abstract MIP-043: OVARIAN CARCINOMA CDK12 MUTATIONS IMPAIR GENE-SPECIFIC POL II ELONGATION AND FAITHFUL REPAIR OF DNA DOUBLE STRAND BREAKS
Authors: Kingsley M. Ekumi, Hana Paculova, Tina Lenasi, Vendula Pospichalova, Christian A. Bösken, Jana Rybarikova, Vitezslav Bryja, Matthias Geyer, Dalibor Blazek, Matjaz Barboric
Journal: Clinical Cancer Research (2017)

Abstract The Cdk12/CycK complex is a novel transcription elongation-associated kinase that promotes expression of a subset of RNA polymerase II (Pol II) genes, including those of the DNA damage response (DDR) network. CDK12 is mutated in many cancers, particularly in high-grade serous ovarian carcinoma (HGS-OvCa), where it is one of only nine genes with statistically recurrent somatic mutations. However, the influence of these mutations on the kinase and their link to cancerogenesis remain ill-defined. Here, we show that most CDK12 mutations interfere with formation of the complex, rendering the kinase inactive. By examining the mutations within the Cdk12/CycK structure, we find that they likely provoke structural rearrangements detrimental to Cdk12 activation. Our mRNA expression analysis of the patient samples containing the CDK12 mutations identifies coordinated down-regulation of key DDR genes, particularly those of the homologous recombination (HR) repair pathway. Moreover, we note that production of nascent HR gene transcripts is compromised significantly upon CDK12 and CYCK knockdown. Indeed, Cdk12 occupies these genes and promotes phosphorylation of the Pol II's C-terminal domain (CTD) at Serine 2 (Ser2-P), the hallmark of effective transcription elongation, indicating that the down-regulated genes are directly controlled by Cdk12/CycK. Functionally, we demonstrate that the mutant Cdk12 proteins fail to stimulate the faithful repair of DNA double strand breaks via HR. In summary, we provide molecular basis of how mutated CDK12 ceases to function in ovarian carcinoma. We propose that CDK12 is a tumor suppressor of which the loss-of-function mutations could elicit defects in HR-mediated and possibly other DNA repair pathways, leading to genomic instability underlying the genesis of HGS-OvCa. Citation Format: Kingsley M. Ekumi, Hana Paculova, Tina Lenasi, Vendula Pospichalova, Christian A. Bösken, Jana Rybarikova, Vitezslav Bryja, Matthias Geyer, Dalibor Blazek and Matjaz Barboric. OVARIAN CARCINOMA CDK12 MUTATIONS IMPAIR GENE-SPECIFIC POL II ELONGATION AND FAITHFUL REPAIR OF DNA DOUBLE STRAND BREAKS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-043.
Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma
Authors: Mark W Kieran, Julia Chisholm, Michela Casanova, Alba A Brandes, Isabelle Aerts, Eric Bouffet, Simon Bailey, Sarah Leary, Tobey J MacDonald, Francoise Mechinaud, Kenneth J Cohen, Riccardo Riccardi, Warren Mason, Darren Hargrave, Stacey Kalambakas, Priya Deshpande, Feng Tai, Eunju Hurh, Birgit Geoerger
Journal: Neuro-Oncology (2017)

Sonidegib (LDE225) is a potent, selective hedgehog (Hh) inhibitor of Smoothened. This study explored the safety and pharmacokinetics of sonidegib in children with relapsed/recurrent tumors followed by a phase II trial in pediatric and adult patients with relapsed medulloblastoma (MB) to assess tumor response.
Immune-Related Tumor Response Dynamics in Melanoma Patients Treated with Pembrolizumab: Identifying Markers for Clinical Outcome and Treatment Decisions
Authors: Mizuki Nishino, Anita Giobbie-Hurder, Michael P. Manos, Nancy Bailey, Elizabeth I. Buchbinder, Patrick A. Ott, Nikhil H. Ramaiya, F. Stephen Hodi
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Characterize tumor burden dynamics during PD-1 inhibitor therapy and investigate the association with overall survival (OS) in advanced melanoma. Experimental Design: The study included 107 advanced melanoma patients treated with pembrolizumab. Tumor burden dynamics were assessed on serial CT scans using irRECIST and were studied for the association with OS. Results: Among 107 patients, 96 patients had measurable tumor burden and 11 had nontarget lesions alone at baseline. In the 96 patients, maximal tumor shrinkage ranged from −100% to 567% (median, −18.5%). Overall response rate was 44% (42/96; 5 immune-related complete responses, 37 immune-related partial responses). Tumor burden remained &amp;lt;20% increase from baseline throughout therapy in 57 patients (55%). Using a 3-month landmark analysis, patients with &amp;lt;20% tumor burden increase from baseline had longer OS than patients with ≥20% increase (12-month OS rate: 82% vs. 53%). In extended Cox models, patients with &amp;lt;20% tumor burden increase during therapy had significantly reduced hazards of death [HR = 0.19; 95% confidence interval (CI), 0.08–0.43; P &amp;lt; 0.0001 univariate; HR = 0.18; 95% CI, 0.08–0.41; P &amp;lt; 0.0001, multivariable]. Four patients (4%) experienced pseudoprogression; 3 patients had target lesion increase with subsequent response, which was noted after confirmed immune-related progressive disease (irPD). One patient without measurable disease progressed with new lesion that subsequently regressed. Conclusions: Tumor burden increase of &amp;lt;20% from the baseline during pembrolizumab therapy was associated with longer OS, proposing a practical marker for treatment decision guides that needs to be prospectively validated. Pseudoprogressors may experience response after confirmed irPD, indicating a limitation of the current strategy for immune-related response evaluations. Evaluations of patients without measurable disease may require further attention. Clin Cancer Res; 23(16); 4671–9. ©2017 AACR.
Beyond triple-negative breast cancer and African ancestry: Tumor phenotypes among internationally diverse patient populations.
Authors: Evelyn Mawunyo Jiagge, Aisha Jibril, George Divine, Kofi K. Gyan, Jessica Miley Bensenhaver, Joseph Kwaku Oppong, Baffour Awuah, Ernest Adjei, Sofia Merajver, Max Wicha, Lisa A. Newman
Journal: Journal of Clinical Oncology (2017)

1101 Background: Population-based incidence rates of breast cancers that are negative for estrogen receptor (ER), progesterone receptor (PR), and HER2/ neu(triple negative breast cancer {TNBC}) are higher among African American (AA) compared to White American (WA) women. Several studies show higher TNBC frequency among selected populations of African patients. The colonial-era trans-Atlantic slave trade resulted in shared West African ancestry between contemporary AA and Ghanaian (Gh) populations. The extent to which TNBC susceptibility is related to East African versus West African ancestry, and whether these associations extend to expression of other biomarkers such as Androgen Receptor (AR) and mammary stem cell marker ALDH1 is unknown. Methods: We used immunohistochemistry to assess ER, PR, HER2/ neu, AR and ALDH1 among WA (n = 153); AA (n = 76); Ethiopian (Eth)/East African (n = 90) and (Gh)/West African (n = 286) breast cancers through an IRB-approved international research program. Results: Mean age at breast cancer diagnosis was 43; 49; 60; and 57 years for the Eth; Gh; AA; and WA patients, respectively. Frequency of TNBC was significantly higher for AA and Gh patients (54% and 41%, respectively) compared to WA and Eth patients (23% and 15%, respectively); p &lt; 0.001. These associations were unchanged when limited to patients age 50 and younger (47% and 49% for AA and Gh, respectively; versus 18% and 16% for WA and Eth, respectively); p &lt; 0.001. Frequency of ALDH1 positivity was also higher for tumors from AA and Gh patients (32% and 36%, respectively) compared to those from WA and Eth patients (23% and 17%, respectively); p = 0.007. Significant differences were observed for distribution of AR positivity, which was 71%; 55%; 42% and 50% for the WA; AA; Gh; and Eth cases, respectively (p = 0.008). Conclusions: We found a correlation between extent of African ancestry and risk of particular BC phenotypes. West African ancestry was associated with increased risk of TNBC and breast cancers that are positive for ALDH1. Future studies of hereditary TNBC susceptibility among women with African ancestry are warranted.
Comparing prognoses of male and female breast cancers based on molecular subtypes: A retrospective study from a single center.
Authors: Xingfei Yu, Maio lu Lu
Journal: Journal of Clinical Oncology (2015)

e11524 Background: In our previous study (published in The Breast 2013), we concluded that the molecular subtypes of male breast cancer (MBC) play important role in prognoses. The aim of this study was to investigate whether there are any differences in prognoses between MBC and FBC based on the molecular subtypes. Methods: We identified MBC cases diagnosed between Sep 2001 and Aug 2011. Each male case was paired with four FBC cases from the same period (within one month). We compared overall survival (OS) across the different subtypes between males and females using the Kaplan-Meier method and a Cox proportional hazard regression model. We also evaluated the clinical characters that were associated with each molecular subtype using t-tests and chi-square tests. Results: After ten years of following up, we identified 72 MBC cases that were paired with 288 female patients. Follow-ups were not possible for eight female cases; thus, a total of 352 patients were included in the study with 92 months of median follow-up time. MBC was much more frequently hormone receptor-positive than FBC (91.67% vs. 50.36%). The proportion of the luminal A subtype was much higher among the male patients than among the female patients (55.56% vs. 34.28%); however, the 10-years OSs were similar between males and females (p > 0.05) in the luminal A, luminal B and non-luminal A subtypes (consist of luminal B, triple-negative and HER2 over express). The Cox proportional hazard regression model indicated that molecular subtype had a significant influence on prognoses (p < 0.05) in both male and female breast cancer. Conclusions: The prognosis of MBC is similar to that of FBC, regardless of molecular subtype.
Precision Medicine in Pediatric Oncology: Translating Genomic Discoveries into Optimized Therapies
Authors: Thai Hoa Tran, Avanthi Tayi Shah, Mignon L. Loh
Journal: Clinical Cancer Research (2017)

Survival of children with cancers has dramatically improved over the past several decades. This success has been achieved through improvement of combined modalities in treatment approaches, intensification of cytotoxic chemotherapy for those with high-risk disease, and refinement of risk stratification incorporating novel biologic markers in addition to traditional clinical and histologic features. Advances in cancer genomics have shed important mechanistic insights on disease biology and have identified "driver" genomic alterations, aberrant activation of signaling pathways, and epigenetic modifiers that can be targeted by novel agents. Thus, the recently described genomic and epigenetic landscapes of many childhood cancers have expanded the paradigm of precision medicine in the hopes of improving outcomes while minimizing toxicities. In this review, we will discuss the biologic rationale for molecularly targeted therapies in genomically defined subsets of pediatric leukemias, solid tumors, and brain tumors. Clin Cancer Res; 23(18); 5329-38. ©2017 AACR.
Abstract MIP-068: TUMOR–PROMOTING EFFECTS OF THE OVARIAN CANCER MUCIN, MUC16, ARE ASSOCIATED WITH SUPPRESSION OF INNATE IMMUNITY
Authors: Mildred Felder, Arvinder Kapur, Alexander L. Rakhmilevich, Xiaoyi Qu, Joseph Connor, Manish S. Patankar
Journal: Clinical Cancer Research (2017)

Abstract The membrane-spanning mucin MUC16 promotes proliferation and metastasis of ovarian cancer cells. Here, we demonstrate that mice implanted with MUC16-knockdown human ovarian tumors show greater than two-fold increase in survival as compared to controls with tumors that express this mucin. While the lower survival of mice bearing MUC16-positive tumors is reportedly attributable to the ability of MUC16 to increase proliferation and metastasis, we also show that murine NK cells and macrophages are more efficient at lysing MUC16-knockdown cells. Macrophages showed infiltration in the MUC16-knockdown tumors but were restricted to the surrounding stroma in MUC16-positive tumors. In vitro cytotoxicity assays with NK cells and macrophages isolated from mice stimulated with agonistic anti-CD40 antibody showed 2-3-fold increased activity against the MUC16-knockdown cells as compared to matching target cells expressing this mucin. Finally, knockdown of MUC16 increased the susceptibility of cancer cells to ADCC and lysis by KS-IL2, an immunocytokine investigated as a treatment for ovarian cancer. Collectively our results support a role for MUC16 in promoting tumor growth. The ability of murine innate cells to selectively target MUC16-knockdown cells indicates that in vivo experiments investigating the biology of this mucin should be interpreted taking into account its immunomodulating activity as well as its growth promoting properties. Citation Format: Mildred Felder, Arvinder Kapur, Alexander L. Rakhmilevich, Xiaoyi Qu2, Joseph Connor, and Manish S. Patankar. TUMOR–PROMOTING EFFECTS OF THE OVARIAN CANCER MUCIN, MUC16, ARE ASSOCIATED WITH SUPPRESSION OF INNATE IMMUNITY [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-068.
Re: Daniel E. Spratt, Herbert A. Vargas, Zachary S. Zumsteg, et al. Patterns of Lymph Node Failure after Dose-escalated Radiotherapy: Implications for Extended Pelvic Lymph Node Coverage. Eur Urol 2017;71;37–43
Authors: Andrei Fodor, Claudio Fiorino, Maria Picchio, Nadia Di Muzio
Journal: European Urology (2017)
Independent validation of stromal uPA in archived tumor samples from the prospectively randomized ABCSG8 trial to provide level 1b evidence for a prognostic value of uPA immunohistochemistry in endocrine-treated postmenopausal breast cancer patients.
Authors: Christian F. Singer, Stephan W Jahn, Margaretha Rudas, Zsuzsanna Bago-Horvath, Florian Fitzal, Richard Greil, Brigitte Mlineritsch, Manfred Schmitt, Martin Filipits, Michael Gnant
Journal: Journal of Clinical Oncology (2017)

536 Background: We have recently demonstrated that urokinase Plasminogen Activator (uPA), together with its inhibitor PAI-1, have prognostic value in hormone-receptor positive early breast cancer, and can be measured in FFPE archived tumor samples. We have now aimed to validate the prognostic role of uPA protein expression in FFPE archived tumor samples in an independent cohort of endocrine-treated breast cancer patients. Methods: 303 postmenopausal women with hormone receptor–positive, early breast cancer who had received 5 years of endocrine therapy in the prospectively designed ABCSG-08 trial, and in whom FFPE tumor tissue was available, were included in this analysis. Stromal uPA and PAI-1 protein expression was evaluated by immunohistochemistry and correlated with distant recurrence-free survival (DRFS) and overall survival (OS). Results: Stromal uPA was detected in 132 of 297 tumors (44.4%), and 74 out of 269 samples (27.5%) exhibited stromal PAI-1, while co-expression of both proteins was found in 48 of 294 (16.3%) samples. Neither uPA nor PAI-1 expression were associated with tumor size, age, nodal status, grading, or receptor status. Patients whose tumor stroma expressed uPA protein were more likely to have a shorter DRFS (adjusted HR for relapse: 2.78; 95% CI 1.31-5.93; p=0.008 Cox regression analysis) and OS (adjusted HR for death: 1.29; 95% CI 0.86-12.50; p=0.161) than women without uPA expression. No such association was observed for PAI-1 and for the uPA/PAI1 ratio. After a median follow-up of 5.6 years women with uPA-positive tumors experienced a significantly shorter DRFS (93.3% vs 84.8%; p&lt;0.013 log rank test) and tended to have a worse OS (83.0.4% vs 77.3%; p=0.106) compared to women with uPA negative tumors. Conclusions: By confirming the clinical utility of stromal uPA IHC in archived breast cancer samples from an independent prospective randomized trial, we now provide level 1b evidence for a prognostic role of stromal uPA in women with endocrine-responsive early breast cancer.
Making Conscious the Unconscious
Authors: Jessica W. Tsai
Journal: JAMA Pediatrics (2017)

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Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study
Authors: Claire N Harrison, Nicolaas Schaap, Alessandro M Vannucchi, Jean-Jacques Kiladjian, Ramon V Tiu, Pierre Zachee, Eric Jourdan, Elliott Winton, Richard T Silver, Harry C Schouten, Francesco Passamonti, Sonja Zweegman, Moshe Talpaz, Joanne Lager, Zhenming Shun, Ruben A Mesa
Journal: The Lancet Haematology (2017)