tbuckley/cabot-search huggingface dataset:
Rapid progression of disease following ibrutinib discontinuation in patients with chronic lymphocytic leukemia.
Authors: Paul Joseph Hampel, Kari G. Chaffee, Wei Ding, Timothy Call, Saad Kenderian, Eli Muchtar, Jose Francisco Leis, Asher Alban Akmal Chanan-Khan, Deborah Bowen, Amie L. Fonder, Susan M. Schwager, Susan L. Slager, Tait D. Shanafelt, Neil E. Kay, Sameer Ashok Parikh
Journal: Journal of Clinical Oncology (2018)

7525 Background: The clinical characteristics, management, and outcomes of patients (pts) with chronic lymphocytic leukemia (CLL) who develop rapid progression of disease following ibrutinib discontinuation are not well described. Methods: We identified all CLL pts at Mayo Clinic who discontinued ibrutinib therapy. Clinical symptoms, exam and radiographic findings, and laboratory changes associated with discontinuation were ascertained. Results: Of 281 ibrutinib treated pts, 82 (29%) discontinued therapy. Reasons for discontinuation and the median time to discontinuation include: toxicity (n = 30, 37%, 8 months), CLL progression (n = 18, 22%, 25 months), Richter’s transformation (n = 9, 11%, 6 months), other (n = 11, 13%), and death (n = 14, 17%). In total, 61 pts had adequate records for review within 4 weeks after discontinuing ibrutinib. Among these, 15 (25%) had progressive worsening in > 2 clinical domains (i.e., symptoms, exam/imaging, labs) post discontinuation, including 13 pts who discontinued due to progression or transformation and 2 pts who discontinued due to toxicity or other. Clinical findings included sudden worsening of constitutional symptoms (n = 14, 93%), worsening lymphadenopathy or splenomegaly (n = 10, 67%), and increasing lactate dehydrogenase or lymphocytosis (n = 12, 80%). We defined these clinical symptoms as ibrutinib stop sequela. Next line therapy was started the next day after ibrutinib discontinuation for 6 pts, after gap in treatment in 4 pts (median 13 days, range 5-36), and overlapped with ibrutinib in 2 pts. Three pts did not receive subsequent therapy. Next line therapy included idelalisib (n = 3), venetoclax (n = 3), steroids with anti-CD20 therapy (n = 2), pembrolizumab (n = 1) and multi-agent chemotherapy (n = 3). Age, sex, TP53 disruption, and IGHV mutation status did not predict the occurrence of the described worsening on univariate analysis. The median overall survival for the entire group was 35 months. Conclusions: Multiple ibrutinib stop sequela were seen in 1 out of 4 patients after stopping ibrutinib, occurring despite prompt next line salvage therapy. Parameters to better define the post-ibrutinib interval and optimal ways for its management are required.
Phosphatidylinositol-4, 5-biphosphate 3-kinase, catalytic subunit alpha (<i>PI3KCA)</i> and microsatellite instability in ovarian clear cell carcinoma, clinical correlation.
Authors: Mariana de Paiva Batista, Raquel López Reig, Ignacio Romero, Carmen Illueca Ballester, Fernando Chaud, Pedro Mallol, Guilherme Urano Machado, Cristiane Alves Mendes, Antonio Cesar Mendes Santiago, Eduardo Magalhaes Rego, Jose Antonio Lopez-Guerrero, Andres Poveda
Journal: Journal of Clinical Oncology (2016)

e17061 Background: Ovarian carcinoma represents a heterogeneous group of disease. Clear cell carcinoma (CCC), an infrequent subtype, presents particular clinical characteristics and genetic profiles. PIK3CA mutations (PIK3CAmut) in CCC represent the highest frequency among all of the cancer types and a potential target treatment. High microsatellite instability (MSI-H) is reported in around 14%. Methods: From a retrospective two-institutional CCC database with cases ranging from 1997 to 2015, 24 ovarian CCCs were analyzed for PIK3CAmut and MSI status and correlated with clinical outcome. A central pathology review ofHematoxylin-Eosin stained sections from tissue specimens confirmed the diagnosis of pure ovarian CCCs. MSI analysis was performed using a conventional PCR method with specific primers for NR27, NR21, NR24 BAT26 and BAT25 mononucleotidic markers and fragment analysis. The PIK3CAmut were detected by real time PCR, using COBAS platform and a specific detection kit. Results: Twenty-four cases were analyzed for PIK3CAmut and MSI-H, two of them were not evaluable. Main characteristics included: median age of 50 years, FIGO stages I-II in 70.8% of the cases and FIGO III-IV in 29.2%. Molecular features analyzed were present in 45.5% of cases: 13.6% (3) had MSI-H and 31.8% (7) had PIK3CA mutations. Both events were mutually exclusive. Type of PIK3CA mutations included: five H1047X, one E545X and one C420R. MSI-H was more frequently identified in stage I-II: 7.1% compared to 40% in advanced stages without statistical significance. With a median follow up of 46 months, there was no correlation between MSI-H or PIK3CA mutation and relapse or survival. PIK3CA mutation was only identified in early stages with a significant correlation among FIGO I-II (p: 0.029). Conclusions: In our series, around one third (31.8%) of CCC had a PI3KCA mutation. PIK3CA mutation was correlated with initial stage disease (I-II). Even if MSI-H was infrequent, both molecular events were mutually exclusive.
Inflamm-aging and the need to consider age in cytokine-patient-reported outcome (PRO) relationships: The case of acute myeloid leukemia (AML).
Authors: Shabbir M.H. Alibhai, Henriette Breunis, John Matelski, Narhari Timilshina, Arjun Kundra, Chieh-Hsin Lee, Madeline Li
Journal: Journal of Clinical Oncology (2018)

10047 Background: Cancer-related fatigue (CRF) and poor quality of life (QOL) remain major problems in adults with AML during and after active treatment. Prior studies have linked cytokines to these PROs but have not examined age as a modifier. Ageing is associated with chronic inflammation which may alter the cytokine-PRO relationship. Methods: 213 patients age 18 or older who underwent intensive chemotherapy for AML were assessed at up to 4 time points (pre-treatment, 1 month, 6 months, 12 months). PROs were assessed with validated self-report questionnaires (FACT-F, EORTC QLQ-C30 global health) and blood was analyzed in duplicate for a panel of 32 cytokines using multiplexed protein immunoassays (Meso Scale Diagnostics). Log-transformed and centred cytokine values were regressed in models against CRF and QOL in separate models adjusting for age, gender, time, remission status, and haemoglobin. Models were stratified by age ( < 60, 60+) and model and partial R2 values were calculated. Results: 498 sets of cytokine measurements were available for analysis. For CRF, the model R2 was 20.6%, with cytokines explaining 7.8% of the variance. For QOL, the model R2 was 25.7%, and cytokines accounted for 7.8% of the variance. When stratified by age ( < 60 versus 60+ years or older), the proportion of variance in CRF explained by the multivariable model and by cytokines collectively was greater in younger patients (34.1% for the entire model and 17.9% for cytokines) than older adults (21.7% and 14.4%, respectively). The interaction term was significant (p = 0.002). The three most influential cytokines were TNF-α, MCP-4, and IL-15 in younger adults and MIP-1a, TARC, and IL-7 in older adults. Similar differential results by age group were seen for global QOL (interaction term p < 0.001). Conclusions: Cytokines explain a significantly larger amount of variation in both CRF and QOL in younger patients with AML compared to older patients. Specific culprit cytokines also appear to be different. This suggests that cytokine-targeted therapies (drug or non-drug) may need to differ in younger versus older adults but requires verification in other tumour types.
TCT-841 Baseline characteristics and 3-month outcomes of the EVOLVE Short DAPT Trial: A prospective investigation of abbreviated antiplatelet therapy in high bleeding risk patients treated with a thin-strut bioabsorbable polymer-coated, everolimus-eluting coronary stent
Authors: Ajay Jayant Kirtane, Laura Mauri, Robert Stoler, Robert Feldman, Franz-Josef Neumann, Loukas Boutis, Naeem Tahirkheli, Ralph Toelg, Islam Othman, Bernardo Stein, Stephan Windecker, Robert Yeh, Harold Dauerman, Matthew Price, Paul Underwood, Dominic Allocco, Ian Meredith, Dean Kereiakes
Journal: Journal of the American College of Cardiology (2018)
Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease
Authors: Marc S. Sabatine, Gaetano M. De Ferrari, Robert P. Giugliano, Kurt Huber, Basil S. Lewis, Jorge Ferreira, Julia F. Kuder, Sabina A. Murphy, Stephen D. Wiviott, Christopher E. Kurtz, Narimon Honarpour, Anthony C. Keech, Peter S. Sever, Terje R. Pedersen
Journal: Circulation (2018)

The FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) recently showed that the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab significantly reduced major vascular events in patients with stable atherosclerotic cardiovascular disease, including patients with prior myocardial infarction (MI). Within the broad group of patients with prior MI, we hypothesized that readily ascertainable features would identify subsets who derive greater clinical risk reduction with evolocumab.The 22 351 patients with a prior MI were characterized on the basis of time from most recent MI, number of prior MIs, and presence of residual multivessel coronary artery disease (≥40% stenosis in ≥2 large vessels). The relative and absolute risk reductions in major vascular events, including the primary end point (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) and the key secondary end point (cardiovascular death, MI, or stroke), with evolocumab in these subgroups were compared.A total of 8402 patients (38%) were within 2 years of their most recent MI; 5285 patients (24%) had ≥2 prior MIs; and 5618 patients (25%) had residual multivessel coronary artery disease. In a multivariable-adjusted model that simultaneously included all 3 high-risk features and other baseline covariates, more recent MI, multiple prior MIs, and residual multivessel coronary disease remained independent predictors of cardiovascular outcomes, with adjusted hazard ratios (HRs) for the primary end point of 1.37 (95% confidence interval [CI],1.22-1.53), 1.78 (95% CI, 1.59-1.99), and 1.39 (95% CI, 1.24-1.56; all P<0.001). The relative risk reductions with evolocumab for the primary end point tended to be greater in the high-risk subgroups and were 20% (HR, 0.80; 95% CI, 0.71-0.91), 18% (HR, 0.82; 95% CI, 0.72-0.93), and 21% (HR, 0.79; 95% CI, 0.69-0.91) for those with more recent MI, multiple prior MIs, and residual multivessel coronary artery disease, whereas they were 5% (HR, 0.95; 95% CI, 0.85-1.05), 8% (HR, 0.92; 95% CI, 0.84-1.02), and 7% (HR, 0.93; 95% CI, 0.85-1.02) in those without, respectively. Given the higher baseline risk, the respective absolute risk reductions at 3 years exceeded 3% in the high-risk groups (3.4%, 3.7%, and 3.6%) versus ≈1% in the low-risk groups (0.8%, 1.3%, and 1.2%).Patients closer to their most recent MI, with multiple prior MIs, or with residual multivessel coronary artery disease are at high risk for major vascular events and experience substantial risk reductions with low-density lipoprotein cholesterol lowering with evolocumab.URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.
Rational identification of a Cdc42 inhibitor presents a new regimen for long-term hematopoietic stem cell mobilization
Authors: Wei Liu, Wei Du, Xun Shang, Lei Wang, Chris Evelyn, Maria Carolina Florian, Marnie A. Ryan, Ahmad Rayes, Xueheng Zhao, Kenneth Setchell, Jarek Meller, Fukun Guo, Nicolas Nassar, Hartmut Geiger, Qishen Pang, Yi Zheng
Journal: Leukemia (2018)
Fludarabine/cyclophosphamide (Flu/Cy) non-myeloablative allogeneic stem cell transplant for aplastic anemia and hypoplastic myelodysplasia: A single institution experience.
Authors: Michelle Alison Levy, Muhammad Rizwan-ul-Haq Khawaja, David Claxton, Shin Mineishi
Journal: Journal of Clinical Oncology (2018)

e19021 Background: Allogeneic hematopoietic stem cell transplant (HSCT) is a potentially curative option for severe aplastic anemia (SAA) or hypoplastic myelodysplasia (h-MDS). However, there is no standard conditioning regimen for adults undergoing this treatment. Methods: We performed a retrospective study of adult patients with SAA and h-MDS (defined as MDS with marrow cellularity < 10%) who underwent non-myeloablative HSCT between January 2006 and March 2017. The conditioning regimen involved fludarabine 25mg/m2 for five doses (days -7 to -3) and cyclophosphamide 1000mg/m2 for two doses (days -7 and -6). Patient demographics, disease, and HSCT-related characteristics and outcomes were recorded. Results: Thirteen patients with SAA (n = 11) and hypoplastic MDS (n = 2) received HSCT from matched related (MRD, n = 6) or unrelated (MUD, n = 7) donors. Stem cell source was peripheral blood (n = 10) or bone marrow (n = 3). Nine patients were older than 50 years (median age: 54 years). Twelve patients were transfusion dependent at the time of HSCT. Ten of 11 patients with SAA had received prior immunosuppression, and one patient with hypoplastic MDS had received prior hypomethylation therapy. GVHD prophylaxis consisted of tacrolimus (n = 6), tacrolimus and sirolimus (n = 7), and methotrexate (n = 12). Patients achieved neutrophil engraftment at a median of 13 days (range 9-21), and platelet engraftment at a median of 20 days (range 8-241). Median time to > 95% total donor chimerism was 29 days (range 13-42). At five-year follow up, three patients died: day 5 (respiratory failure), day 34 (sepsis), and day 414 (sepsis). Two patients experienced acute GVHD (skin grade 2), and six patients had evidence of chronic GVHD. Conclusions: Based on this retrospective single-institution study, non-myeloablative HSCT with Flu/Cy conditioning is feasible for adults with AA and hypoplastic MDS. These findings need to be confirmed with a prospective clinical trial.
Is more surgery better for patients with gallbladder cancer? A survival analysis of extended versus simple cholecystectomy.
Authors: Christos Fountzilas, Marcela Mazo- Canola, Brian Hernandez, Michelle Janania Martinez, Ruchi Hamal, Paromita Datta, Devalingam Mahalingam, Joel Michalek, Sukeshi Patel Arora
Journal: Journal of Clinical Oncology (2017)

e15615 Background: Gallbladder cancer (GBC) is a rare cancer; the minority of patients have resectable tumor at diagnosis. Based on retrospective, single-institution data, extended cholecystectomy (EXT) has been recommended over simple cholecystectomy (CHOL) in &gt;T1 tumors; however, effect of EXT on survival is unclear. Thus, we evaluated the survival of patients with resectable GBC at our institution. Methods: Retrospective analysis from 1/1/2005 to 1/1/2016 for patients with GBC. Patients with advanced or metastatic disease were excluded. The Recurrence-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Results: 68 patients with GBC; 26 (38%) with early disease. Twelve patients had EXT. Patient/tumor characteristics are shown in Table. Median RFS was 22 months (95% CI: 9-not reached) and OS was 25 months (95% CI: 15-not reached) for the entire cohort. Median RFS was increased in CHOL (30 months) relative to EXT (9 months); p=0.73. OS appeared similar between the two groups (25 vs. 23 months for CHOL and EXT group, respectively). Conclusions: EXT appears to improve RFS with no effect on OS in patients with early GBC. Due to the limitations of small sample size and retrospective analysis, multi-institutional collaborations are necessary to better identify optimal management. [Table: see text]
Use of Inpatient Palliative Care Services in Patients With Advanced Cancer Receiving Critical Care Therapies
Authors: Kah Poh Loh, Maya Abdallah, Meng-Shiou Shieh, Mihaela S. Stefan, Penelope S. Pekow, Peter K. Lindenauer, Supriya G. Mohile, Dilip Babu, Tara Lagu
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: Invasive mechanical ventilation (IMV), dialysis for acute kidney failure, and other critical care therapies (CCTs) are associated with a high risk for complications in patients with metastatic cancer. Inpatient palliative care (IPC) can assist in assessing patients' preferences for life-prolonging treatment at the end of life. This study investigated the use pattern of IPC, outcomes (in-hospital mortality, length of stay [LOS], discharge destination, and cost of care), and predictors of IPC use in patients with metastatic cancer who received CCTs. We hypothesized that IPC services are underused in this cohort. Methods: In this retrospective cohort study, we used the 2010 California State Inpatient Databases to identify adults with metastatic cancer who received CCTs that are common and reliably coded (IMV, tracheostomy, percutaneous endoscopic gastrostomy tube, dialysis for acute kidney failure, and total parenteral nutrition). We determined IPC use in all patients, in those who received IMV, and across 4 cancer subtypes (lung, breast, colorectal, and genitourinary). Outcomes were assessed based on IPC use. Multivariable analyses were used to investigate factors associated with IPC use. Results: We identified 5,862 hospitalizations, 19.8% of which used IPC services. IPC use varied across cancer subtypes (lung, 28.3%; breast, 22.4%; colorectal, 12.8%; genitourinary, 16.1%; P<.01). Patients who received and did not receive IPC services had high in-hospital mortality rates (63.9% and 29.8%, respectively), and costs of care and LOS were lower in survivors who received IPC compared with those who did not. Predictors of IPC use were lung cancer (vs colorectal or genitourinary cancer), higher comorbidity score, do-not-resuscitate status on admission or within 24 hours of admission, infections (vs cancer-related diagnoses), and higher hospital bed count. Conclusions: Use of IPC was low in the cohort who received CCTs with poor outcomes, although data on outpatient palliative care services is lacking. Predictors of IPC use may be used to identify patients who may benefit from these services.
HDAC and PD-1 inhibition in humanized triple-negative breast cancer xenografts.
Authors: Anna Capasso, Julie Lang, Todd M. Pitts, Paul Francoeur, Sarah Lindsey Davis, Christopher Hanyoung Lieu, Stacey M Bagby, John J. Tentler, Anthony d Piscopio, Jennifer Robinson Diamond, Roberta Pelanda, S. Gail Eckhardt
Journal: Journal of Clinical Oncology (2017)

e14604 Background: There is great interest in investigating immune checkpoint inhibition in combination with novel agents, however, preclinical studies are limited by the lack of immune-competent human cancer cell line xenograft models. We developed a “hematopoietic” humanized mouse model to address this unmet need. HDAC inhibitors (HDACi) induce T-cell chemokine expression and enhance response to PD1 inhibitors in lung cancer models. We evaluated the combination of OKI-179, a novel Class I HDACi and nivolumab in our humanized mouse model. Methods: BRGS newborn pups were transplanted with CD34+ cells purified from umbilical cord blood. At 16 weeks, MDA-MB-231 cells were implanted in the flanks of the mice. When the average tumor size reached ~150-300 mm3, the mice were randomized into vehicle, nivolumab, OKI-179, or the combination treatment according to % chimerism. At the end of the treatment, mice were euthanized and tissues were collected for further analysis. Results: We observed a statistically significant improvement in tumor growth inhibition with the combination of OKI-179 and nivolumab (%TGI = 77%) as compared to single agent nivolumab (45%TGI). Nivolumab treatment led to a significant decrease in PD-1 expression on T cells. We also observed an increased number of TILs (CD8+ T cells) and T cells in the lymph nodes of treated mice suggesting T cell expansion. All mice were highly chimeric and responding tumors exhibited an increase in CD44 high IFN+ T cells. We observed a higher CD8% and a higher effector memory % (HLADR+, CD45RO+) in these mice. Conclusions: We successfully established a humanized TNBC human cancer cell line xenograft model, with tumor engraftment occurred in all humanized mice. Mice treated with nivolumab demonstrating the development of lymph nodes that were populated by activated T cells. The combo resulted in superior tumor growth inhibition. These preliminary results demonstrate that human immunity and PD-1 expressing T cells exist in these models and provide the basis for planned immunotherapy combination studies.
The efficacy and safety of apatinib in patients with metastatic colorectal cancer refractory to standard therapies.
Authors: Wangxia Lv, Meiqin Yuan, Yunshan Yang, Zhong Shi, Haijun Zhong
Journal: Journal of Clinical Oncology (2017)

e15003 Background: Colorectal cancer is the third most frequent cancer and the fourth most frequent cause of cancer-related death worldwide.25% of patients with colorectal cancer have metastatic disease which leads a clinically significant detrimental effect on prognosis. After failure of standard treatments, regorafinib will be recommended to patients, but it has not been approved in China now. Apatinib is a novel, small-molecule tyrosine kinase inhibitor of VEGFR-2 which has shown a survival benefit in gastric cancer in a Phase III trial. This study is an initial clinical experience about the efficacy and safety of apatinib in patients with metastatic colorectal cancer refractory to standard therapies. Methods: Patients with refractory metastatic colorectal cancer received apatinib 500mg once daily. A treatment cycle was defined as 28 days (4 weeks). Response was assessed using RECIST 1.1 criteria. Toxicity was recorded using CTCAE version 4.0. Results: Between August 2015 to October 2016, seventeen patients were enrolled. One patient had PR (5.9%),twelve patients had SD (70.6%), and four had PD (23.6%). The ORR was 5.9% and DCR was 76.5%. The median PFS was 125 days (4.0months, 95%,CI = 1.1-6.9). The grade3/4 adverse events were hypertension (2/17;11.8%), proteinuria (2/17;11.8%), Hand-foot syndrome (2/17;11.8%), leukopenia(1/17;5.9%), neutropenia(1/17;5.9%), hyperbilirubinemia(1/17;5.9%), and diarrhea(1/17;5.9%),respectively.There were no treatment-related deaths. Conclusions:Apatinib is active for the treatment of refractory metastatic colorectal cancer with a manageable tolerability profile. Further investigations of apatinib in mCRC are needed.