tbuckley/cabot-search huggingface dataset:
Long-term responders with metastatic breast cancer (MBC) receiving eribulin: Real life experience.
Authors: Vera Gorbunova, Ludmila Manzyuk, Elena Kovalenko, Larisa Bolotina, Tatiana Semiglazova, Larisa Zhilyaeva, Elena Karabina, Dmitry Ponomarenko, Alfia Khasanova, Irina Evstigneeva, Guzel Mukhametshina
Journal: Journal of Clinical Oncology (2018)

e13065 Background: Recently developed microtubule dynamics inhibitor eribulin mesylate (eribulin) differs from taxanes and vinca alkaloids by another mechanism of action. Here, we describe eribulin-treated MBC patients who achieved a long duration of response (DoR) in Russian clinical practice. Methods: Data for 168 MBC pts treated with eribulin between January 1 2014 and January 1 2018 were collected from different Russian centers. All these health records were retrospectively analyzed by the central institution, the Russian Oncology Research Center. Results: Our primary analysis revealed 32 (19%) pts with long DoR (8 months and more). Median age of these patients was 52 (32-67) yrs. ECOG status 0-1 was defined in 97% cases. Most of the pts (78%) had visceral metastases, median number of metastatic sites was 2 (1-5). Eighteen (56%) pts were ER/PR-positive, 7 (22%) – triple-negative, 7 (22%) – HER2-positive (eribulin was given in combination with trastuzumab). Eribulin was prescribed in the 2nd and 3rd lines of MBC treatment in 15 (47%) pts, in the 4th and later lines in 17 (53%) pts. Treatment continued until progression or intolerable toxicity. The median number of cycles was 10 (range 8-42). Complete and partial responses were achieved in 17 (53%) pts, stable disease in 15 (47%) pts, according to RECIST v.1.1. Median PFS was 9.56 months (95% CI 8.16-14.0). No unusual side effects were observed during the eribulin treatment. The main toxicity included neutropenia: Gr 2 in 6 (19%) pts and Gr 3-4 in 5 (16%) pts and peripheral neuropathy: Gr 2 in 2 (6%) pts. Conclusions: This is a real-life description of clinical characteristics and outcomes of eribulin-treated MBC patients who achieved a long DoR in the Russian Federation. Further investigation is needed for identification of any specific patterns for long term response with eribulin, which may be associated with mechanism of action of eribulin.
P01.120 Importance of systematic TERT promoter and IDH mutations screening in non-diagnostic biopsies from patients​ with a suspected glioma
Authors: M Barritault, T Picart, D Poncet, T Fenouil, J Guyotat, E Jouanneau, B Joubert, A Vasiljevic, J Honnorat, D Meyronet, F Ducray
Journal: Neuro-Oncology (2018)

Non-diagnostic biopsies are a recurrent issue in patients with a suspected brain tumor. Herein, in order to explore the utility of molecular testing in this setting, we determined whether IDH and TERT promoter (pTERT) mutations can be detected in non-diagnostic biopsies from glioma patients. Using Snapshot PCR, we retrospectively assessed IDH and pTERT mutation status in 28 adult glioma patients in whom a first non-diagnostic biopsy had led to perform a second biopsy. Median age at diagnosis was 65 years and median delay between the first and second biopsy 21 days. The first biopsy consisted of non characterizable infiltrated glial cells (n=19), hemorrhage (n=4), necrosis (n=2) or normal tissue (n=3). The second biopsy demonstrated an IDH-wildtype glioblastoma (n=22), an IDH-wildtype astrocytoma (n=4), an IDH-mutant oligodendroglioma (n=1) and an IDH-mutant astrocytoma (n=1). A pTERT mutation was present in 21 cases. Retrospectively, the same IDH and pTERT mutations were identified in the non-diagnostic biopsies of the 2 patients with an IDH-mutant glioma and of 12 out of 21 patients with a pTERT-mutant glioma (57%). Overall an IDH and/or a pTERT mutation were detected in the non-diagnostic biopsies of 13 out of the 22 IDH-mutant and/or pTERT-mutant gliomas (59%) and in 13 out of the 28 cases included in the present series (46%). IDH and pTERT mutations can be detected in a high percentage of non-diagnostic biopsies from glioma patients supporting a role for molecular testing in the interpretation of non-diagnostic biopsies from patients with a suspected brain tumor
P04.69 Differential microglia - glioma cell interaction during tumor progression
Authors: J Grosch, M Osswald, A S Berghoff, W Wick, F Winkler
Journal: Neuro-Oncology (2018)

Microglia cells resemble the innate immune system of the brain, which makes them prime candidates for interactions with glioma cells, and thus potential targets for therapeutic interventions. Their role in glioma invasion and progression is contradictory, implying heterogeneous actions of this cell type. An impact on the formation and function of the recently discovered progression- and resistance-promoting long cellular processes of glioma cells, tumor microtubes (TMs), has not been assessed. Patient-derived glioblastoma stem-like cell (GBMSC) lines with an invading growth pattern were implanted under a cranial window in CX3Cr1-EGFP knock-in mice. Further, a syngeneic model (GL261) was used to validate the findings in an immunocompetent glioma mouse model. Repetitive in vivo two-photon laser scanning microscopy was used to gain dynamic insights into how microglia and glioma cells interact during brain colonization. Microglia cells form a dense network of inter-connected cells resting in the brain parenchyma as well as in the perivascular space that is invaded by glioma cells after cortical injection. Microglia density was stable during the process of glioma cell infiltration (8666 cells/mm3 before infiltration vs. 8590 cells/mm3 densely infiltrated region). A diverse pattern of microglia - glioma cell interactions was observed, with direct cell-to-cell connections, as well as co-localization of cell processes of microglia cells and TMs of glioma cells. Direct somatal microglia - glioma cell interactions were more frequently observed in the perivascular niche compared to the brain parenchyma (64.2% vs. 37.0%; p=0.05, t-test). Inhibiting the function of microglia cells by using CX3Cr1-EGFP +/+ mice with a functional loss of the chemokine receptor lead to a higher invasion speed of the glioma cells in contact with microglia cells in the perivascular space vs. +/- mice (6.0 µm/h vs. 3.5 µm/h; p=0.036, Mann-Whitney U test) but not in the other brain parenchyma. Inhibition of the CSF-1 pathway by PLX3397 profoundly reduced microglia cell function, again with a pro-invasive effect on glioma cells in the perivascular space (10.2 µm/h vs. 3.7µm/h, treatment vs. control; p=0.021, Mann-Whitney U test). In all experimental paradigms, there was no apparent impact of microglia interactions on TM formation and dynamics, and TM-dependent tumor cell invasion and proliferation outside the perivascular niche. Tracing invading tumor cells in a syngeneic GL261 tumor model confirmed the specific importance of microglia interactions for perivascular niche invasion. Functional microglia cells inhibit the perivascular route of glioma cell invasion in vivo, but have no apparent impact on TM formation and function. In consequence, microglia inhibition appears counterproductive when the invasive nature of the disease is the therapeutic target.
A Randomized Trial Comparing Bilateral Lateral Rectus Recession versus Unilateral Recess and Resect for Basic-Type Intermittent Exotropia
Authors: Sean P. Donahue, Danielle L. Chandler, Jonathan M. Holmes, Brian W. Arthur, Evelyn A. Paysse, David K. Wallace, David B. Petersen, B. Michele Melia, Raymond T. Kraker, Aaron M. Miller
Journal: Ophthalmology (2018)
Phase 2 trial of the novel multi-receptor tyrosine kinase inhibitor sitravatinib in well-differentiated/dedifferentiated liposarcoma.
Authors: Matthew Ingham, Shing Mirn Lee, Parag Patwardhan, Edwin Choy, Isan Chen, Shahnaz Singh-Kandah, Lauren Taiclet, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2017)

TPS11082 Background: Well-differentiated/dedifferentiated liposarcoma (WD/DD LPS) is a sarcoma subtype of adipocytic origin characterized by amplification of cyclin dependent kinase 4 (CDK4) and MDM2. WD/DD LPS is resistant to chemotherapy and success with CDK4 inhibitors is limited. We recently characterized the landscape of activated receptor tyrosine kinases (RTKs) and intracellular signaling pathways finding marked heterogeneity by sarcoma subtype [Patwardhan et al. Oncotarget 2016;7(4)]. In WD/DD LPS cell lines, phosphorylated (p) IGF1-R, MET and PDGFRb are strongly expressed. Selective siRNA knockdown of expression of 1 or more of these RTKs inhibited growth of WD/DD LPS cell lines. Sitravatinib (S) is a novel inhibitor of a broad panel of related RTKs. We showed that S abrogates expression of p-RTKs, including IGF1-R, MET and PDGFRb, at low nanomolar concentrations and potently inhibits proliferation of WD/DD LPS cell lines, where anti-proliferative effects of S were superior to other RTK inhibitors including imatinib, crizotinib and pazopanib. S suppressed tumor growth in vivo in WD/DD LPS . A phase 1 trial of S in solid tumors showed clinical activity in WD/DD LPS. Recommended phase 2 dose was 150 mg/day. As there are no approved RTK inhibitors for adipocytic sarcomas, and based on these findings, we initiated a phase 2 trial of S in WD/DD LPS. Methods: This is a single-arm open-label multi-center Simon 2 stage phase II trial of S in 29 patients (pts) with advanced WD/DD LPS who failed 1 prior therapy and show disease progression before enrollment. Pts receive S 150 mg orally daily continuously. Primary endpoint is the progression free rate at 12 weeks (PFR 12 ) versus historical controls. The design has power of 85% to show improvement in PFR 12 from 20% (inactive) to 40% (active) with α = 0.10. Secondary endpoints are ORR, PFS and safety. A subset of pts undergo baseline and on-treatment biopsies and reverse phase protein array used to measure changes in expression of p-RTKs and signaling pathway proteins with confirmation by immunoblot. Genomic landscape of these tumors will be analyzed by next generation sequencing. The study opened in 1/2017. Clinical trial information: NCT02978859.
Safety and efficacy of metronomic eltrombopag prophylaxis (MEP) in the prevention of chemotherapy-induced thrombocytopenia (CIT) in cancer patients.
Authors: Francesco Iuliano, Alessia Perricelli, Eleonora Iuliano, Maria Luci, Angelo Pomillo, maria Aquila Santoro, Sisto Milito, Salvatore Palazzo
Journal: Journal of Clinical Oncology (2018)

e14566 Background: CIT is provided with a platelet count < 100×109/μL with or without bleeding in cancer patients receiving chemotherapy .CIT can prevent the administration of the optimal dose and schedule of anticancer treatment. Eltrombopag selectively binds to the trans-membrane domain of the receptor by allowing a synergistic action with endogenous TPO. The aim of the study is to prevent CIT in patients for whom the maintenance of dose intensity was crucial for remission or survival. Methods: A total of 28 consecutive adult patients, female (60 %), median age 47 years (range 28 - 68) were enrolled in the study. The reason of chemotherapy has been ovary cancer in 5 patients, colon cancer in 8 patients, relapsed DLBC lymphoma in 6 patients, breast cancer in 6 patients, pancreatic cancer in 3 pts. In two patients with platelet counts below 120000 μL, a medullary evaluation was performed before the start of chemotherapy. Patients with platelet counts below 80000 /μL before chemotherapy or with medullary disease were excluded from the study. The homocysteine dosage was done in all patients at the time of enrolment. All patients received eltrombopag 25 mg by mouth twice a week as soon as the platelet count fell below 80000 mmc, and continued on treatment until completion of cycles of chemotherapy. Results: The mean platelet count nadir was 60000/µL ; the number of days with platelet count < 80000/µL was 4 days; the maximum value reached was 270,000/µL. No treatment related toxicity was observed. 1 out of 28 pts , did not respond to the planned dose and received 50 mg for eight consecutive days before each course of chemotherapy. In another patient the scheduled dose was doubled to 50 mg twice per week. Both of these patients showed qualitative dysplastic morphological alterations of bone marrow.The principal endpoints of the study - nadir platelet counts < 50,000/µL avoidance,platelet transfusions, bleeding events, chemotherapy dose reductions , chemotherapy delays - were achieved in all patients. Conclusions: In our opinion MEP can be an effective and safe strategy for preventing CIT
Pre-treatment evaluation of LVEF for breast cancer patients receiving anthracyclines: Is it necessary?
Authors: Prakash Peddi, Samip R. Master, Hari P Ravipati, Abhishek H Patel, Ashish Dutta Dwary, Avinash Pasam, Quyen Chu, Runhua Shi, Gary Von Burton
Journal: Journal of Clinical Oncology (2016)

6608 Background: Anthracycline containing adjuvant chemotherapy is widely used for breast cancer treatment and, despite lack of clinical evidence, obtaining pre-chemotherapy left ventricular ejection fraction (LVEF) measurement is widely practiced. We completed a retrospective review of breast cancer patients who had LVEF measurement in anticipation of chemotherapy to determine if defined cardiac risk factors predicted for poor cardiac function. Methods: 482 female breast cancer patients, in whom LVEF was measured before chemotherapy, were analyzed for demographics and risk factors associated with congestive heart failure (CHF). The cardiac risk factors actually associated with abnormal LVEF were identified using logistic regression. The frequency of anthracycline omission based on LVEF findings was also determined. Results: The Median age was 52 years. The original chemotherapy plan was changed in only 8 patients (1.65%) based on LVEF findings; all had asymptomatic LV dysfunction with LVEF ranging 40-51%. In 32 patients, despite normal LVEF results, anthracyclines were omitted secondary to prior cardiac issues. In 17 patients where LVEF was reported normal, anthracyclines were skipped based on patient’s preference, tumor characteristics or upstaging of the cancer based on imaging studies. 27 possible risk factors for CHF were defined, with no patients with ≤ 2 risk factors having an abnormal LVEF (N = 350). Factors that were associated with abnormal LVEF on logistic regression analysis were hypertension (2.2 relative risk), CHF (4.9), pulmonary hypertension (5.3), family history of premature heart disease (7.7), smoking (9.4) and heart failure symptoms (15.9). Conclusions: The probability of finding an abnormal LVEF in patients without any cardiac risk factors is extremely rare. Our study questions the ongoing practice of obtaining routine pre-chemotherapy echocardiograms for measurement of LVEF in breast cancer patients undergoing anthracycline chemotherapy.
A phase Ib study of atezolizumab (atezo) alone or in combination with lenalidomide or pomalidomide and/or daratumumab in patients (pts) with multiple myeloma (MM).
Authors: Hearn J. Cho, Craig Cole, Thomas G. Martin, Jeffrey A. Zonder, Joseph W. Fay, Ravi Vij, John CH Byon, A. Keith Stewart, Madhav V. Dhodapkar
Journal: Journal of Clinical Oncology (2017)

TPS8053 Background: The advent of proteasome inhibitors and immunomodulatory drugs (IMiDs) have significantly improved outcomes in MM, and the first monoclonal antibodies for MM have been recently approved (daratumumab, elotuzumab). Despite novel therapies and improved disease management, MM is still considered incurable and most pts relapse, confirming the need for additional treatment options. MM cells express PD-L1, with higher levels observed after relapse and with advanced disease. Additionally, PD-L1–expressing immune cells in the microenvironment promote MM cell survival and potential immune escape. However, anti–PD-1 monotherapy did not result in objective responses in the MM cohort of a Ph I study, suggesting that MM pts need combination therapy. Daratumumab has activity as a single agent, as well as in combination with IMiDs plus dexamethasone and bortezomib plus dexamethasone in R/R MM. Immunomodulatory activity for daratumumab has also been reported. Thus, disruption of the PD-L1/PD-1 pathway may be additive or synergistic. The safety and efficacy of atezo (anti–PD-L1) alone or with lenalidomide or pomalidomide and/or daratumumab will be evaluated in a Ph Ib study of MM pts. NCT02431208. Methods: R/R MM pts with ≤ 3 prior therapies will be enrolled in Cohorts A (atezo), B (atezo + lenalidomide), D (atezo + daratumumab) and E (atezo + daratumumab + lenalidomide); MM pts with measurable disease after ASCT (Cohort C: atezo) or ≥ 3 prior therapies (Cohort F: atezo + daratumumab + pomalidomide) will also be enrolled. Cohorts B, D, E and F include a safety run-in (D) or dose escalation phase (B, E, F) and an expansion. Lenalidomide and pomalidomide will be dose escalated and the MTD evaluated in expansion phases. Atezo will be given at 1200 mg IV (A, B, C) or 840 mg IV (D, E, F); pts will get daratumumab at 16 mg/kg IV (D, E, F). All pts will be ECOG PS ≤ 2. Primary endpoints are ORR and the RP2D of lenalidomide and pomalidomide with atezo and daratumumab and the RP2D of lenalidomide with atezo. DOR and PFS are secondary endpoints; safety, PK and the relationship between biomarkers and other endpoints, including efficacy, will be assessed. Pts will be enrolled at 19 US sites. Clinical trial information: NCT02431208.
Colorectal surgery in the elderly: Does the extreme age determine the odds ratio of complications?
Authors: Gemma Soler, Miguel Martinez-Vilalta, Josep Vallet, Albert Sueiras, Juan Antonio Marín, Raquel Legido, Mercedes Martinez Villacampa, Cristina Santos, Nuria Mulet, Alexandre Teule, Jose Carlos Ruffinelli, Juana Saldana, Idoia Morilla, Beatriz Pardo-Burdalo, Lucia Heras, Silvia Vazquez, Sabela Recalde, Maria Plana, Ramon Salazar
Journal: Journal of Clinical Oncology (2018)

e22046 Background: The human aging is an ongoing process, expressing a functional worsening, subjective or objective. Before to consider colorectal surgery in the elderly we have to assess the need of surgery, the ethical guidelines, the risk/benefit and the expected survival.The aim of the study is to assess if age, Charlson Comorbidity (CC) and ASA determine the odds ratio (OR) of global, surgical and medical complications, anastomotic leakages and reoperations in colorectal elective surgery. Methods: A clinical series reviewing the period 2004-2013 in which we performed 643elective colectomies. We selected groups and subgroups according to age: Group 1: < 75 years (Subgroup 1.1: < 65 ; Subgroup 1.2: 65-75 ); Group 2: > 75 (Subgroup 2.1: 75-85 ; Subgroup 2.2: > 85 ). Age, CC and ASA were included as predictor variables in the multivariate analysis. Results: The OR of global complications in patients between 75 and 85 compared with under 75 is 1.89. However in patients over 85 compared with under75 is 1.143 . This OR increases 1.317 times per each increased grade of ASA .The OR of surgical complications in patients between 75 and 85 compared with under 75 is 2. However in patients over 85 compared with patients under 75 is 1.494. This OR increases 1.315 times per each increased grade of ASA.The OR of medical complications increases 1.736 times per each increased grade of ASA. The OR of anastomotic leakages increases 1.596 times per each increased grade of ASA.The OR of reoperations in patients between 75 and 85 compared with under 75 is 2.367. However in patients over 85 compared with under 75 is 1.385. Conclusions: The risk of global and surgical complications is determined by age and ASA . The risk of medical complications and anastomotic leakages is just determined by ASA .The risk of reoperations is just determined by the age . Thus, in patients over 85 , those who have achieved a successful aging and with a right selection of surgery candidates, we didn´t show a major percentage of global and surgical complications, neither reoperations compared with patients under 75 . Despite that patients over 75 have a higher CCI, we didn´t demonstrate any statistical significant relationship between postoperative complications and this scale.
Acalabrutinib in patients (pts) with Waldenström macroglobulinemia (WM).
Authors: Roger Owen, Helen McCarthy, Simon Rule, Shirley D'Sa, Sheeba K. Thomas, Francesco Forconi, Thomas C. Anderson, Marie Jose Kersten, Pier Luigi Zinzani, Sunil Iyengar, Jaimal Kothari, Monique Minnema, Efstathios Kastritis, Raquel Izumi, J. Greg Slatter, Diana Mittag, Helen Wei, Dih-Yih Chen, Priti Patel, Richard R. Furman
Journal: Journal of Clinical Oncology (2018)

7501 Background: Bruton tyrosine kinase (BTK) is a clinically validated target in WM. Acalabrutinib is a highly selective, potent, covalent BTK inhibitor that we evaluated in a Phase 2 study of pts with treatment-naive (TN) or relapsed/refractory (R/R) WM. Methods: Pts with TN or R/R WM received 100 mg acalabrutinib BID (or 200 mg QD [n=6], later switched to 100 mg BID) in 28-day cycles until progressive disease (PD) or intolerance. The primary endpoint was investigator-assessed overall response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety and PK. Results: One hundred six pts (14 TN and 92 R/R) were treated; median age was 69 y (range 39-90); 94% had ECOG PS ≤1; median serum IgM was 3615 mg/dL (range 291-9740). R/R pts had a median of 2 prior therapies (range 1-7). At a 25-mo median follow-up, 7 (50%) TN and 70 (76%) R/R pts remain on treatment. Discontinuations were primarily due to PD (TN 0 pts; R/R 9 pts), adverse events (AEs; TN 3; R/R 3), and investigator decision (TN 2; R/R 4). BTK occupancy and PK parameters were consistent with previous acalabrutinib studies. Efficacy outcomes are listed in the Table. Common AEs (any grade) were headache (39%), diarrhea (31%), contusion (29%), and dizziness (25%). Common Gr 3/4 AEs were neutropenia (16%), pneumonia (7%), anemia, increased ALT, and hyponatremia (each 5%). Atrial fibrillation occurred in 3 pts (1 Gr 3). Bleeding events occurred in 57% of pts (commonly contusion [29%] and epistaxis [13%]); 4 events were Gr 3/4: epistaxis, hematuria, dysfunctional uterine bleeding, and retinal hemorrhage. There were 5 Gr 5 events: pneumonia, glioblastoma multiforme, esophageal carcinoma, myocardial ischemia, and intracranial hematoma. Conclusions: Acalabrutinib is a highly effective treatment for WM with durable responses and limited toxicity. Clinical trial information: NCT02180724.Modified 3rd Intl workshop on WM criteria (Kimby 2006). TN (n=14) R/R (n=92) ORR (≥ minor response [MR]), n (%) 13 (93) 86 (94) 95% CI 66, 100 86, 98 Major response rate (≥ partial response [PR]) 11 (79) 72 (78) 95% CI 49, 95 68, 86 Complete response 0 0 Very good PR 1 (7) 29 (32) PR 10 (71) 43 (47) MR 2 (14) 14 (15) 24-mo rate, % (95% CI) DOR 90 (47, 99) 84 (73, 90) PFS 90 (47, 99) 82 (72, 88) OS 92 (54, 99) 89 (80, 94)