tbuckley/cabot-search huggingface dataset:
Identification of effective therapy in Langerhans cell histiocytosis in the adult population.
Authors: Jennifer Ma, James Laird, Karen Chau, Monica Chelius, Andrew C. Bell, Benjamin H. Lok, Joachim Yahalom
Journal: Journal of Clinical Oncology (2017)

7065 Background: Langerhans cell histiocytosis (LCH) is a rare disorder of histiocytic proliferation most commonly observed in children. LCH in adults is less characterized and a standard of care has not been established. Here we review clinical outcomes of adult LCH patients (pts) treated with various therapies at a large referral center. Methods: We identified 108 pts over 18 years of age with histologically confirmed LCH presenting to our center between 1990-2015. Clinical and treatment characteristics were examined and classified by single or multi-system involvement (SSI or MSI, respectively) and risk-organ involvement (ROI; liver, spleen, hematopoietic system and CNS). Overall survival (OS) and freedom from first progression (FFFP) were calculated by the Kaplan-Meier method. Univariate analysis was performed with the Cox proportional hazards model. Results: Median age at diagnosis was 44 years (range 18-89) with a median follow-up of 3.9 years (0.1-9.1). Median OS was 16.1 years and FFFP was 5.6 years, with 94 (87%) pts alive at last follow-up. Eighty-three (77%) had SSI and 13 (12%) had ROI. The most common sites of disease were bone (52 pts; 48%), lung (28; 26%), and skin (24; 22%). Only 11 pts (9%) experienced progression of disease (POD) after first treatment. Twenty-four (22%) received radiotherapy, 42 (39%) underwent excision, and 26 (24%) received systemic therapy at any point during treatment. The most common systemic agents were vinblastine, 6-mercaptopurine (6-MP), methotrexate (MTX), and cladribine. Eight received combination vinblastine, 6-MP, and MTX (VMM), 4 of which had MSI. Median progression-free survival (PFS) of VMM pts was 6 months, compared with 2.8 for all other systemic agents (p = 0.1). For OS, lack of ROI was the only significant variable upon univariate analysis (HR .22, 95%CI 0.06-0.75, p = 0.016). No variables were significant for PFS. Conclusions: Effective therapy for adult LCH has not been clearly identified. In our cohort of both low and high risk patients, the low POD rate observed is encouraging. VMM, a regimen previously studied in pediatric pts, is also effective in adults and may be considered the combination of choice for treatment of adult LCH. Further prospective study is warranted.
The impact of pre-cancer (Ca) diagnosis (Dx) psychiatric utilization (PU) on survival in patients with solid organ ca: A population analysis in Ontario, Canada.
Authors: Zachary William Abraham Klaassen, Christopher J.D. Wallis, Hanan Goldberg, Thenappan Chandrasekar, Rashid K. Sayyid, Neil Eric Fleshner, Antonio Finelli, Robert Nam, Stephen Bentley Williams, Paul Kurdyak, Girish S. Kulkarni
Journal: Journal of Clinical Oncology (2018)

e22144 Background: Patients with Ca have an increased risk of psychiatric disorders leading up to Ca Dx and may have disruptions in care following Dx. We sought to assess the impact of pre-Ca Dx PU on survival outcomes for patients with solid organ Ca. Methods: Patients Dx with one of the top 10 prevalent Ca in Canada (prostate, breast, colorectal, melanoma, lung, bladder, endometrial, thyroid, kidney, oral; 1997-2014) were identified. Using physician/hospital billing codes in the 5 yrs prior to Dx, patients were assigned a PU gradient (PUG) score: 0 – no PU, 1 – outpatient PU, 2 – emergency department PU, 3 – hospital admission PU. The primary exposure was PUG score (categorical). The primary outcome was cancer-specific survival (CSS) assessed using a multivariable competing risks model. The secondary outcome was overall survival (OS) assessed using a multivariable Cox PH model. Results: There were 676,125 patients included in the analysis, including 359,465 (53.2%) with PUG0, 304,559 (45.0%) with PUG1, 7,901 (1.2%) with PUG2, and 4,200 (0.6%) with PUG3. Patients with increasing PUG score were younger at Dx, more often female, had more comorbidities, lower income, lived in non-rural communities, and were Dx in recent years (all p < 0.0001). Increasing PUG score was independently associated with worse CSS, with an effect gradient across the intensity of pre-diagnosis PU (Table). The association between increasing PUG and worsening CSS was strongest in patients with bladder and colorectal Ca. The findings persisted when limiting the analysis to the remaining 8 Ca. In a subgroup analysis adjusting for stage (n = 111,620), the association between increasing PUG score and worse CSS persisted. Finally, increasing PUG score was also associated with worse OS. Conclusions: Pre-Ca Dx PU is independently associated with worse CSS and OS following Dx among patients with solid organ Ca. The specific factors underlying the observed association remain to be elucidated. Variable CSS OS HR 95%CI HR 95%CI PUG Score PUG0 Ref Ref PUG1 1.05 1.04-1.06 1.04 1.03-1.05 PUG2 1.36 1.30-1.43 1.44 1.39-1.49 PUG3 1.73 1.63-1.84 1.94 1.86-2.02 Adjusted for age, gender, comorbidity, income, rural, Dx year
Phase 3, randomized, placebo-controlled trials evaluating glasdegib in combination with intensive or nonintensive chemotherapy in patients with untreated acute myeloid leukemia.
Authors: Jorge E. Cortes, Hervé Dombret, Akil Abid Merchant, Tetsuzo Tauchi, Christine DiRienzo, Mirjana Zeremski, Barbara Sleight, Xiaoxi Zhang, Mohammed Naveed Shaik, Timothy Bell, Geoffrey Chan, Mikkael A. Sekeres
Journal: Journal of Clinical Oncology (2018)

TPS7073 Background: Glasdegib is an oral Hedgehog pathway inhibitor with clinical activity in patients (pts) with untreated AML or higher-risk MDS, and improved survival when combined with low-dose cytarabine (AraC) in unfit pts with AML. BRIGHT AML1019 comprises two Phase 3, randomized (1:1), double-blind trials evaluating glasdegib 100 mg once daily (QD) or placebo (PBO) + chemotherapy in untreated adult AML (NCT03416179). The protocol includes 2 parallel, simultaneous trials: 1 with intensive chemotherapy (IC) and 1 with nonintensive chemotherapy (nIC). Methods: Both trials include pts aged ≥18 y with untreated AML (WHO 2016), including AML evolved from MDS or antecedent hematologic disease, or secondary AML. Key exclusions: inadequate organ function, acute promyelocytic leukemia, active CNS leukemia. Assignment to IC or nIC trial is per Investigator. In the IC trial, 400 pts are randomized (1:1) to glasdegib 100 mg QD or PBO on Day 1 and continue for up to 2 y or until post consolidation minimal residual disease (MRD)-negative status. Glasdegib or PBO are administered with 7+3 induction (AraC 100 mg/m2 IV for 7 days + daunorubicin 60 mg/m2 for 3 days); induction 2, if needed, will use 7+3 or 5+2. Consolidation consists of single-agent AraC 1 or 3 g/m2 IV over 3 h twice daily on Days 1, 3 and 5 every 28 days for ≤4 cycles; eligible patients may receive hematopoietic stem cell transplant. In the nIC trial, 320 pts are randomized (1:1) to glasdegib 100 mg QD or PBO, each with azacitidine 75 mg/m2 daily SC or IV for 7 days, in 28-day cycles. Treatments continue until disease progression, unacceptable toxicity, withdrawal or death. In both trials, glasdegib and PBO continue regardless of chemotherapy dose modifications/delays. The primary endpoint is overall survival. Secondary endpoints include response, time to and duration of response, event-free survival, safety, patient-reported outcomes and pharmacokinetics. Clinical trial information: NCT03416179.
Prognostic Value of the Residual SYNTAX Score After Functionally Complete Revascularization in ACS
Authors: Yuhei Kobayashi, Jacob Lønborg, Andy Jong, Takeshi Nishi, Bernard De Bruyne, Dan Eik Høfsten, Henning Kelbæk, Jamie Layland, Chang-Wook Nam, Nico H.J. Pijls, Pim A.L. Tonino, Julie Warnøe, Keith G. Oldroyd, Colin Berry, Thomas Engstrøm, William F. Fearon
Journal: Journal of the American College of Cardiology (2018)
Daratumumab-based combination therapies (DCT) in heavily-pretreated patients (pts) with relapsed and/or refractory multiple myeloma (RRMM).
Authors: Arjun Lakshman, Jithma P. Abeykoon, Shaji Kumar, S.Vincent Rajkumar, Taxiarchis Kourelis, Francis Buadi, David Dingli, Martha Lacy, Wilson I. Gonsalves, Angela Dispenzieri, Robert A. Kyle, Yi Lin, Ronald S. Go, Rahma M. Warsame, Suzanne R. Hayman, Stephen Russell, Nelson Leung, Morie A. Gertz, Prashant Kapoor
Journal: Journal of Clinical Oncology (2017)

8038 Background: Daratumumab-based Combination Therapies (DCT) with bortezomib (V)/ lenalidomide (R)/ pomalidomide (P) and dexamethasone (d) showed exceptional activity in RRMM in trials. Experience outside of trials since the approval of Daratumumab (D) in 2015 is limited. Methods: RRMM pts seen at Mayo Clinic, MN from 12/2015 -12/2016 were reviewed. Pts who received ≥ 1cycle of DCT were included. Time-to-event analyses were done from date of starting DCT. Common terminology criteria for adverse events v4.0 were used to grade toxicities. Results: Of 130 pts, 59% were males and median age at DCT initiation was 67 (43-93) years, ECOG performance score was ≥2 in 29%. Pts were classified as mSMART high (22%), intermediate (22%) or standard (56%) risk. Median time from diagnosis to initiation of DCT was 51.3 (5-156) months (m), and median number of prior therapies was 4 (1-14). 14% of pts were refractory to prior D monotherapy. Fifty-three (41%), 34 (26%) and 25 (19%) received DPd, DRd and DVd respectively. Eighteen (14%) pts received ‘other’ DCT. Median time to first response (≥ PR) was 3.1 m (95% CI 2.1-4.6). Overall response rate was 46%, [CR-2%, VGPR-18%, PR-26%]. Minimal response was seen in 17%, with clinical benefit rate of 62%. Median estimated follow up from initiation of DCT was 5.5 m (CI 4.2-6.1). The median duration of response was 6.1 m [CI 5.1- not reached (NR)]. Median progression free survival (PFS) was 5.5 m (CI 4.1-7.8) and median time to next therapy (TTNT) was 5.9 m (CI 4.6-9.4). Median PFS for DPd, DRd, DVd and other DCTs were 4.6 (CI 2.7-NR), 7.8 (CI 5-NR), 3.9 (CI 2.1-NR) and 3.9 (CI 2.8-8.2) m, respectively (p = 0.3). Median PFS for quadruple refractory (n = 28) MM was 2.8 m (CI 2.2-5.3) vs 5.9 m (CI 4.9-NR) for the rest (p &lt; 0.01). Median overall survival (OS) from DCT was NR (CI 11.4-NR). Grade 3 or higher hematological toxicities were seen in 42% of pts. Other toxicities included infections (37%), fatigue (31%), infusion reactions (16%) and diarrhea (10%). Conclusions: DCT are effective in RRMM, but the PFS remains short particularly in quadruple refractory pts, reflecting the challenges encountered in managing heavily-pretreated, and often less fit patients, in routine practice.
State-Level Population Estimates of Individuals Subject to and Not Meeting Proposed Medicaid Work Requirements
Authors: David M. Silvestri, Margaret L. Holland, Joseph S. Ross
Journal: JAMA Internal Medicine (2018)

Anna L. Goldman, MD, MPH; Steffie Woolhandler, MD, MPH; David U. Himmelstein, MD; David H. Bor, MD; Danny McCormick, MD, MPH
Characterization of first local and metastatic relapse modalities in patients with soft tissue sarcoma.
Authors: Céline Blaye, Véronique Brouste, Michèle Kind, Eberhard Stoeckle, Guy Kantor, Jean-Michel Coindre, Antoine Italiano, Maud Toulmonde
Journal: Journal of Clinical Oncology (2016)

11041 Background: No consensus exists on how to follow patients (pts) after complete remission (CR) of a primary Soft Tissue Sarcoma (STS). A better characterization of relapse modalities (RM) could help tailor guidelines for follow up. We aimed to describe RM in a cohort of pts treated and followed homogeneously at a single institution after CR of a primary STS. Methods: We retrospectively searched our database for pts in CR after initial management of a localized STS who presented a first locoregional (LR) and/or metastatic (M) relapse between January 1995 and July 2015. Pt medical charts were retrieved to collect RM. Results: 360 pts met our inclusion criteria, 202 and 188 pts presented a LR and/or a m relapse as first event, respectively. In pts with LR relapse, relapse was diagnosed on clinical symptoms in 63% of cases, first detected by the pt in 51% of cases, and outside a planned visit in 52% of cases. In patient with m relapse, diagnosis was made by imaging in 58% of cases, and during a planned visit in 61% of cases. Median follow up was 59 months (m) [95%CI: 50-69]. Median time to relapse was 22m (2-223). Median survival after LR and m relapse was 48m [36-70] and 29m [23-35], respectively (p < 0.0001). Overall, median survival after relapse when relapse was diagnosed during a planned follow-up visit was 41m [32-52] vs 27m [23-36] if not (p = 0.1). Median survival after relapse was not significantly different whether first LR relapse was diagnosed clinically (44m [28-70]) or by imaging (57m [33-84], p = 0.5) but was significantly shorter in pts with m relapse diagnosed clinically (21m [11-34]) than by imaging (33m [26-40], p = 0.05), and longer if diagnosis was made on chest CT scan (35m [28-42]) than chest Xray (20m[11-25], p = 0.002). Subgroup analyses were made according to primary location and histology. Conclusions: Half of LR relapses were diagnosed out of planned follow up, and a significant proportion was detected by pts themselves. Pt’s education and clinical assessment should be recommended for monitoring LR relapse. A significant proportion of m relapses were diagnosed on symptoms despite regular imaging. The unbiased impact of follow up with chest CTscan compared to chest Xray on pts management and survival remains to be determined.
Accelerated vs. regular approval: Lessons learned from U.S. FDA oncology approvals.
Authors: Ihid Carneiro Leao, Gideon Michael Blumenthal, Gregory H. Reaman, Richard Pazdur, Ke Liu
Journal: Journal of Clinical Oncology (2018)

2540 Background: This work categorizes the justifications for accelerated and regular approvals (AA and RA) of oncology products granted by U.S. FDA, based on endpoints other than overall survival (OS) that supported RA and pathways for AA conversion to RA. Methods: We reviewed FDA databases for approved oncology products for specific indications from January 2006 to November 2017. For each product and its indication, we reviewed the trial that supported its approval with respect to study population, trial design, endpoints, magnitude of the treatment effect and benefit-risk assessment. Results: Two hundred twenty-six new indications were granted, 159 (70%) received RA and 67 (30%) AA. OS was the primary endpoint supporting 40% of RAs. Non-OS endpoints that supported RA (60%, n = 95) included PFS (n = 51), response and response rate (n = 34), TTP (n = 4), DFS (n = 2), RFS (n = 2) and EFS (n = 2). The disease settings where non-OS endpoints were used included advanced breast cancer, multiple myeloma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, advanced solid tumors such as thyroid, renal cancer, NSCLC and rare cancers. Of the 67 indications granted under AA, response including hematologic response endpoints and pathological complete response was the basis for most of AA (88%, n = 59). Eight approvals were based on a time to event endpoint (12%; PFS, n = 7 and DFS, n = 1). We identified two pathways for AA to RA conversion based on 33 out of 67 AAs converted: (1) longer follow-up of the same trial that supported the AA demonstrating the sustained treatment effect (18%) and (2) additional confirmatory trial with primary endpoint that represented clinical benefit in the intended indication (82%). Conclusions: Our results provide clarity of FDA oncology approvals and useful information to stakeholders for efficient development of oncologic products.
Association of immune related adverse events with improved progression-free survival in patients receiving anti-PD-1 / PD-L1 therapy irrespective of corticosteroid use.
Authors: Hammad Shafqat, Theodore Stewart Gourdin, Amy Marie Sion
Journal: Journal of Clinical Oncology (2018)

e15088 Background: Immune-related adverse events (irAEs) are commonly encountered when using anti-PD-1/PD-L1 therapy and are often managed with corticosteroids. The effect of irAEs, particularly when steroids are required, on patient survival is not well established. Methods: In this retrospective analysis, data for 157 patients with multiple tumor types treated with anti-PD-1/PD-L1 therapy between April, 2012 and October, 2016 at Medical University of South Carolina were obtained. Objectives of this analysis were to determine the overall effect(s) of corticosteroid use on progression free survival (PFS). Multivariate Cox regression analysis was performed to analyze the effects of irAEs and corticosteroid use on PFS. Analysis was performed for all patients, as well as
Safety of tumor treating fields and concomitant radiotherapy for newly diagnosed glioblastoma.
Authors: Rachel Grossman, Felix Bukstein, Deborah T. Blumenthal, Carmit Ben Harush, Dror Limon, Zvi Ram
Journal: Journal of Clinical Oncology (2018)

e14078 Background: Tumor Treating Fields (TTFields) are a non-invasive, loco- regional, anti-mitotic treatment based on low intensity alternating electric fields. Efficacy of TTFields in newly diagnosed glioblastoma (ndGBM) has been shown in the EF14 study of TTFields plus maintenance temozolomide (TMZ) (Stupp R., et al., JAMA 2017). TTFields/TMZ showed significant survival improvement versus TMZ alone (HR, 0.63; p < 0.001). Preclinical data show that TTFields increase proportion of glioma cells undergoing cellular death after radiotherapy (RT) by inhibiting DNA-damage repair through the homologous recombination pathway. This suggests that TTFields may have a radiosensitizing effect. The current study tested TTFields concomitant to RT in ndGBM patients. Methods: Patients with ndGBM (n = 10, KPS ≥70) enrolled in this single-arm trial between April and December 2017 had all recovered from maximal debulking surgery or biopsy. Patients started TTFields prior to or at the time of RT, and were on stable or decreasing doses of corticosteroids for 7 days pre-enrollment. TTFields (200 kHz) were delivered 18 hours/day with daily removal of the transducer arrays during RT delivery. TMZ (75 mg/m2 daily) was given for 6 weeks and RT at a total dose of 60 Gy. The primary endpoint was safety of the combined therapies. Results: Median age was 59 (range 42-71 years), median KPS was 90 (range 80-100) and 8 (80%) of patients were male. Five patients (50%) underwent gross total resection while rest had biopsy only. Median dose of RT was 60 Gy (range 52-60 Gy). Six patients (60%) reported adverse events (AEs) to-date. The most common AE was TTFields-related skin toxicity, reported in 4 (40%) patients. These were not severe. All other AEs occurred in a single patient possibly due to underlying disease or chemotherapy. Two serious AEs reported (seizures and general deterioration) were assessed as unrelated to TTFields. Conclusions: TTFields-related skin toxicity (40%) reported was similar to that for the 466 patients treated with TTFields in the phase III study (52%), where patients started TTFields > 4 weeks after RT. No other TTFields-related toxicities were reported. There was no increase in RT- or TMZ-related toxicities when combined with TTFields. Clinical trial information: IRB ID- 0412-08 TLV.
Single-center experience with metastatic leiomyosarcoma: Survival, prognostic factors and outcome of chemotherapy.
Authors: Thomas Van Cann, Jasmien Cornillie, Raf Vandeweyer, Agnieszka Wozniak, Maria Debiec-Rychter, Raf Sciot, Daphne Hompes, Patrick Schöffski
Journal: Journal of Clinical Oncology (2016)

e22531 Background: Leiomyosarcoma (LMS) is a common subtype of soft tissue sarcoma originating from smooth muscle. We evaluated the clinical course and treatment outcome of patients (pts) with metastatic (met) LMS seen in our tertiary referral center. Methods: Using our institutional sarcoma database (LECTOR), we identified all pts with met LMS diagnosed and/or treated at the University Hospitals Leuven between 2000-2014. The log-rank test and Cox’s proportional-hazard models were used to evaluate prognostic factors for survival. Hazard ratios (HR) and 95% confidence intervals (CI) are listed. Results: We identified 123 pts (77 female), median age 60 (range 19-84). Median survival from diagnosis of met disease (OS) was 20.1 months (mo) (range 0.4-116). Synchronous met disease was an independent predictive factor of worse OS [p = 0.002; HR 2.14 (CI 1.32-3.46)] as compared to metachronous disease. Age > 60 had a worse OS compared to younger pts (median 19.7 vs. 24.7 mo, p = 0.01, log-rank), but this was not significant in the multivariate analysis. Primary tumor site or number of met sites did not impact OS. Most pts (76.4%) received systemic therapy with most common first line treatments being single agent doxorubicin (n = 47) and an anthracycline with an alkylator (n = 28). Best response to first line systemic therapy was complete/partial response (CR/PR), stable disease (SD) or progressive disease (PD) in 24.5%, 40.4% and 31.9% of pts. Pts who underwent metastasectomy resulting in macroscopic R0/1 resection [median 82.6 vs 17.5 mo, p = 0.007; HR 0.35 (CI 0.16-0.75)] and pts with PR/CR/SD compared to pts with PD [median 26.0 vs 13.3 mo, p = 0.001; HR 0.45 (CI 0.28-0.74)] had better OS. Type of anthracycline containing regimen was not a relevant prognostic factor. Conclusions: Met LMS has poor prognosis and objective responses to first line systemic therapy are rare. Response rates and survival in our series are in line with data reported previously. Synchronous met disease is a poor prognostic factor, while pts qualifying for R0/1 metastasectomy and pts with PR/CR/SD to first line therapy have better OS. The retrospective nature of this analysis does not allow to draw definitive conclusion due to potential bias.