tbuckley/cabot-search huggingface dataset:
P01.125 intraventricular high grade glioma: neuroendoscopy and adjuvant therapy
Authors: P Oppido, F Cattani, C Carapella, V Villani
Journal: Neuro-Oncology (2018)

In ventricular high grade glioma the obstructive hydrocephalus and the subsequent neurological worsening are usually the limit for chemotherapy and radiotherapy. Recently, in ventricular tumours causing obstructive hydrocephalus neuroendoscopy has gained even more appeal as a first choice procedure since it is possible to simultaneously perform tumour biopsy and endoscopic third ventriculostomy (ETV) or septostomy. The immediate relief of intracranial hypertension improve KPS and the availability of specimens for a pathological diagnosis allow time for planning the most suitable treatment strategy based on histological diagnosis and CSF tumour markers. in 24 patients affected by hydrocephalus due to a ventricular tumour the only neuroendoscopy was performed. In all patients (age 17 - 79 yrs) the clinical signs of progressive intracranial hypertension (KPS 50 - 70) at admission were present. In all patients the NMR showed hydrocephalus due to an infiltrating tumour with contrast enhancement: in 9 inside the third ventricle, in 15 inside the lateral ventricle. After neuroendoscopy and histological diagnosis radiotherapy and/or chemotherapy were performed. In 23 patients the biopsy was performed, while in one case of occipital corn tumour was abandoned. The histology was: in 10 GBM, in 1 malignant PNET, in 1 malignant xanthoastrcytoma, in 3 anaplastic ependymoma. During the same neuroendoscopic procedure in 18 cases the third ventricolostomy (ETV) and in 6 the septostomy were realized. In 12 cases the Tu laser for bleeding control and tumour ablation was used to open the CSF pathways. In 22 patients the clinical outcome improved (KPS >70) and radiotherapy and chemotherapy were possible. The median overall survival was 5 months (2 - 14) for progression disease. Based on our experience, the neuroendoscopic biopsy should be considered in the diagnosis and therapy of ventricular tumours, allowing subsequent tumor therapy. Furthermore, CSF pathways can be restored by ETV or septostomy to control intracranial hypertension. By improving the clinical outcome radiotherapy and /or chemotherapy in high grade glioma is possible.
Mental health: 50 organisations vow to win back years of patients’ lost physical health
Authors: Declan C Murphy
Journal: BMJ (2018)

More than 50 organisations have committed to combating disproportionately poorer physical health in people with mental illness.

The signatories of Equally Well UK’s Charter for Equal Health say that they will work towards winning back the 17 years of life that people with long term mental health conditions lose on average.12

“These are the stolen years of life,” says the charter. “And for too many, this means living for many years in pain and with reduced quality of life. We want to win back these stolen years and …
Reduction in hospital visits in patients with chronic myeloid leukemia (CML) with better adherence to tyrosine kinase inhibitors (TKI) and increased molecular monitoring frequency.
Authors: Dominick Latremouille-Viau, Annie Guerin, Patrick Gagnon-Sanschagrin, Katherine Dea, Benjamin Garrett Cohen, George J Joseph
Journal: Journal of Clinical Oncology (2016)

e18539 Background: For patients (pts) with CML, higher frequency of molecular monitoring (qPCR testing) and increased TKI adherence have been associated with fewer hospital visits. More frequent qPCR testing has also been associated with better TKI adherence. This study estimated the overall impact of increased qPCR testing frequency on hospital visits, stratified by the direct and indirect (impact of qPCR testing through TKI adherence on hospital visits) impacts. Methods: Newly diagnosed CML pts were identified from 2 large US claims databases (2010-2015). Adult pts with continuous health plan coverage for ≥ 6 months (mos) before and ≥ 12 mos after (study period) 1st-line TKI (imatinib, nilotinib, or dasatinib) initiation were included. Direct and indirect impacts of qPCR testing frequency through TKI adherence (Medication Possession Ratio [MPR] for any TKIs) on the number of inpatient (IP) days, IP admissions, and emergency room (ER) visits were estimated using multivariate regression models adjusting for potential confounding factors. Results: A total of 1,431 pts (mean age = 54 years; 47% female) were included. During the 12-mo study period 36% of pts had 0 qPCR test, 16% had 1, 15% had 2, 18% had 3, and 16% had 4 tests; with mean MPR: 0.86. Holding TKI adherence and other variables at the mean values, an increase of 1 qPCR test directly reduced the number of IP days by 13.0%. Each increase of 1 qPCR test also increased MPR by 2.2 percentage points. Hence, when considering the indirect impact of qPCR testing frequency through TKI adherence, an increase of 1 qPCR test actually reduced the number of IP days by 15.2%, where the indirect impact accounted for 14.5% of the reduction. Similarly, an increase of 1 qPCR test overall reduced the number of IP admissions by 14.2% and ER visits by 8.6%, where the indirect impact accounted for 18.4% and 2.8% of the reduction, respectively. Conclusions: The direct and indirect impacts of increased qPCR testing frequency and better TKI adherence benefit pts and payers by further reducing hospital visits. Measures aimed at improving both qPCR testing frequency and TKI adherence are likely to have multiplicative benefits.
Efficacy and safety of sonidegib in patients (pts) with locally advanced (la) or metastatic (m) basal cell carcinoma (BCC): BOLT 30-month analysis.
Authors: Reinhard Dummer, Michael Robert Migden, Alexander Guminski, Ralf Gutzmer, Ragini Reiney Kudchadkar, Karl D. Lewis, Luc Dirix, Patrick Combemale, Uwe Trefzer, Carmen Loquai, Martin Kaatz, Anne L. S. Chang, Alexander Stratigos, Elizabeth R. Plummer, Manisha Mone, Henry J. Castro, Tingting Yi, Dalila B. Sellami, John Lear
Journal: Journal of Clinical Oncology (2016)

9538 Background: Sonidegib 200 mg was approved for use in pts with advanced BCC (aBCC; laBCC + mBCC) or laBCC not amenable to surgery/radiotherapy based on results from BOLT (NCT01327053). Updated data from the 30-month analysis (July 10, 2015 cutoff; 38.2-mo median follow-up) are reported. Methods: Pts with laBCC or mBCC received sonidegib 200 or 800 mg daily. Objective response rate (ORR; complete response [CR] + partial response [PR]), duration of response (DOR), and progression-free survival (PFS) were assessed in laBCC (all pts; pts with aggressive [eg, micronodular, infiltrative] and nonaggressive [nodular/superficial] subtypes) per modified RECIST and in mBCC per RECIST v1.1 by central review. Results: Median duration of exposure was 11.0 mo (200 mg) and 6.6 mo (800 mg). In laBCC, ORRs were 56% (200 mg) and 45% (800 mg; Table) and were similar in pts with aggressive vs nonaggressive BCCs (200 mg, 59% [n = 37] vs 52% [n = 29]; 800 mg, 44% [n = 75] vs 47% [n = 53]). Median DOR was > 23 mo; median PFS was ≈ 22 mo. In mBCC, ORRs were 8% (200 mg) and 17% (800 mg); disease control rates (DCRs; CR + PR + stable disease) were 92% (200 mg) and 91% (800 mg). Sonidegib 200 mg continued to have a more favorable safety profile than 800 mg, with fewer grade 3/4 adverse events (AEs; 43% vs 64%) and discontinuations due to AEs (30% vs 40%). The most common AEs (any grade) were muscle spasms (200/800 mg, 54%/69%), alopecia (49%/58%), and dysgeusia (44%/60%). Conclusions: Durable responses and long-term safety were demonstrated with sonidegib in the BOLT 30-month analysis. These data support the use of sonidegib for the treatment of pts with aBCC per local guidelines. Clinical trial information: NCT01327053.Efficacy of sonidegib. laBCC mBCC Daily sonidegib, mg 200 800 200 800 n = 66 n = 128 n = 13 n = 23 ORR, % 56 45 8 17 95% CI 43-68 37-54 0.2-36 5-39 CR, % 5 2 0 0 PR, % 52 44 8 17 DCR, % 91 82 92 91 DOR n/responders 11/37 20/58 1/1 1/4 Median, moa 26.1 23.7 24.0 NR 95% CIa NE 12.2-29.6 NE – PFS n 16 31 8 13 Median, moa 22.1 22.0 13.1 11.1 95% CIa NE 16.7-33.4 5.6-33.1 7.3-16.6 OS Deaths, n 5 11 3 8 Median, moa NR NR NR 36.7 95% CIa – – – NE 2-yr OS, %a 93 91 69 69 95% CIa 80-98 83-95 31-89 43-85 n, Progressive disease/death; NE, not estimable; NR, not reached; OS, overall survival. a Kaplan-Meier estimate.
Cardiac autonomic dysfunction in breast cancer survivors.
Authors: David Payne, Syed Mahmood, Ann H. Partridge, Anju Nohria, John Groarke
Journal: Journal of Clinical Oncology (2017)

10057 Background: Cardiac autonomic dysfunction (AD) has been associated with increased cardiovascular (CV) and all-cause mortality in several diseases. We evaluated the prevalence, functional and prognostic significance of cardiac AD in a cohort of breast cancer (BC) survivors referred for exercise treadmill testing (ETT). Methods: Cardiac AD was defined as the presence of both an elevated resting heart rate (HR ≥ 80 beats per minute) and abnormal HR recovery (HRR ≤ 12 beats per minute if active cool down, or ≤ 18 beats per minute if passive recovery) at 1 minute after peak exercise. Presence of cardiac AD, exercise capacity, and all-cause mortality were assessed in 448 women (age 62.6±10.0 years), 8.7 [range 4.5, 14.3] years from BC diagnosis, compared to 448 cancer-free, age- and sex-matched controls, all of whom were clinically referred for ETT. Results: Elevated resting HR (23.7% vs. 17.0%, p = 0.013), abnormal HRR (25.9% vs. 20.3%, p = 0.048), and cardiac AD (8.0% vs. 4.2%, p = 0.025) were more prevalent in BC survivors than controls. BC survivors with cardiac AD had reduced exercise capacity compared to those without AD (Table). Among controls, cardiac AD was not associated with decreased exercise capacity. Among BC survivors (age-adjusted hazard ratio 1.90 (95% CI 0.78-4.62) and controls (age-adjusted hazard ratio 4.09 (95% CI 0.49-34.18), cardiac AD was not associated with increased all-cause mortality. Conclusions: Among patients referred for ETT, BC survivors have an increased prevalence of cardiac AD relative to controls. Cardiac AD is associated with decreased exercise capacity, but not increased all-cause mortality, in BC survivors. Available strategies to modulate cardiac AD may improve functional capacity in BC survivors. Table: Impact of markers of cardiac AD on exercise capacity. [Table: see text]
P04.22 Data-driven prioritization and evaluation of novel therapeutic targets in glioblastoma
Authors: C G Brahm, A M E Walenkamp, M E van Linde, U K Abdul, B A Westerman, H M W Verheul, R S N Fehrmann
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM), the most common primary brain tumor in adults, universally recurs with dismal prognosis. Therefore, there is a need for new and more effective treatment strategies. Here, we aim to discover new therapeutic targets in GBM by bioinformatic prioritization of druggable genes and identification of advanced clinical drugs targeting these genes. Publicly available, RNA expression data of patient-derived GBM samples and normal brain tissue were collected from the Gene Expression Omnibus and The Cancer Genome Atlas. Subsequently, we applied functional genomic mRNA (FGmRNA) profiling to correct gene expression profiles for physiological and experimental factors in individual tumors. Next, FGmRNA-profiles of healthy brain tissue and glioblastoma were used to perform a class comparison analysis. Significantly upregulated genes in GBM were prioritized based on: 1) known interactions with antineoplastic agents, 2) the current status of clinical evaluation of these agents in patients and 3) biological pathways associated with GBM carcinogenesis. Lastly, responses to the drugs targeting these prioritized genes were analyzed in a panel of commercial (U87, U251 and T98G), and patient-derived (GBM8) GBM cultures using colorimetric and luminescent cell viability assays. After applying FGmRNA-profiling to 46 normal brain tissue samples and 1279 patient-derived GBM samples, class comparison identified 712 significant candidate genes. Of these candidate genes, 27 genes are targets of antineoplastic drugs. 17 out of these 27 targetable genes, including EGFR and VEGFA, have already been clinically evaluated in GBM with limited efficacy. Out of the 10 remaining targetable genes, RRM2, XIAP and MAPK9 were selected. In vitro, gallium nitrate, targeting RRM2, showed a heterogeneous response in all cell lines at high exposure. Five inhibitors of XIAP showed no response at rational concentrations. However, exposure to 0.1 μM RGB-286638, targeting MAPK9 and multiple CDKs, resulted in complete inhibition of tumor cell growth in all cell lines. Based on data-driven prioritization, we identified RRM2, MAPK9 and XIAP as potential novel therapeutic targets in glioblastoma. In particular, in vitro inhibition of MAPK9 with RGB-286638 shows promising results in vitro and warrants further in vivo evaluation.
Abstract 17304: Sudden Cardiac Death After Acute Heart Failure Hospitalization: Insights From ASCEND-HF
Authors: Sean Pokorney, Sana M Al-Khatib, Jie-Lena Sun, Phillip Schulte, Christopher M O'Connor, John R Teerlink, Paul W Armstrong, Jusitn A Ezekowitz, Randall C Starling, Adriaan A Voors, Eric C Velazquez, Adrian F Hernandez, Robert J Mentz
Journal: Circulation (2015)

Introduction: Despite concerns about sudden cardiac death (SCD) early after acute heart failure (AHF) hospitalization, the incidence of SCD and the factors and associated with its occurrence have not been well defined. We evaluated the incidence and predictors of SCD early after AHF hospitalization. Hypothesis: AHF is associated with SCD. Methods: ASCEND-HF included patients with AHF with any ejection fraction (EF). Clinical events including SCD, resuscitated SCD (RSCD), and sustained ventricular tachycardia/ventricular fibrillation (VT/VF) were adjudicated through 30 days. Patients could have more than one event. These three events were combined to form a new composite endpoint, and baseline characteristics associated with this composite were determined by logistic regression and stepwise selection. RSCD and VT/VF were used as time dependent variables in a Cox model to evaluate the association with 180-day all-cause mortality. Results: Among 7,011 patients with available date on SCD, RSCD, or VT/VF, median age was 67 years (IQR 56-76), median EF was 30% (IQR 20-37%), 9% had a history of VT, and 16% had an ICD. The 30-day event rates were 1.8% (n=121) for the composite, 0.6% for SCD (n=43), 0.4% for RSCD (n=24), and 0.9% for VT/VF (n=64). In the multivariable model, chronic obstructive pulmonary disease, history of VT, male sex, higher admission heart rate, and longer baseline QRS duration were associated with SCD, RSCD, or VT/VF (Table). The composite was independently associated with higher 180-day mortality (adjusted HR 6.6, 95% CI 4.8-9.1, p&lt;0.0001). Conclusions: Patients admitted for AHF had relatively high rates of SCD, RSCD, or VT/VF within 30 days of follow-up, and RSCD or VT/VF were associated with higher 180-day mortality. Further studies are needed to evaluate ways to predict and therapies to prevent and treat tachyarrhythmias early after AHF hospitalization, including in those patients who may be eligible for an ICD after medical therapy has been optimized.
Outcomes of patients treated with paclitaxel, ifosfamide and cisplatin (TIP) for relapsed germ cell tumour (GCT).
Authors: Mariam Jafri, Helen Clarke, Paul Hutton, Michael H. Cullen, Emilio Porfiri
Journal: Journal of Clinical Oncology (2016)

e16044 Background: Management of metastatic GCT which have relapsed after initial platinum based regimes is challenging. Data showing the efficacy of the TIP regime was published in 2005. We describe our 15 year experience with TIP. Methods: Patients who received ≥ 1 cycle of TIP for relapsed GCT between 1/1/2000 and 1/9/ 2015 were identified. Data was collated on: stage, site, histology, tumour markers, initial treatment, radiological response, relapse free interval, response to TIP, progression free survival (PFS), overall survival (OS), post TIP treatment. Results: Over 2000 patients were treated during this time, 56 patients received TIP. 4 patients were excluded: 1 patient had a previous paediatric sacrococcygeal tumour, 2 patients recieved TIP at another centre, 1 patient had a primary CNS GCT. 52 patients were analysed, their median age was 29 (range 19-55). 49% had a non-seminomatous GCT, 21% had a seminoma, 13% had a mixed GCT, 13% had marker only disease at diagnosis. 91% received 1st line chemotherapy for metastatic disease, 7.5% received adjuvant chemotherapy, data was unavailable for 1 patient. 36% had poor prognosis disease, 11% had intermediate prognosis disease, 38% had good prognosis disease, insufficient data was available for 15%. TIP was commenced a median 5.5 months (range 1-129) after completing initial chemotherapy. 24 patients relapsed ≤ 3 months, 26 patients ≥ 3 months, data was not available in the remainder. 25 patients were alive at the time of analysis, the median OS of the cohort was 24 months. PFS was 9 months (95% 6.1-11.9). Presence of poor prognostic factors as described by Beyer et al, was associated with decreased OS (p = 0.03). Response to TIP was associated with improved survival (p = < 0.005); 76% with complete response, 48% with partial response and 0% with progression were alive 24 months post TIP. In those who relapsed post TIP; 9 received HDCT, 11 had surgical excision, 14 had radiotherapy, 8 had palliative chemotherapy, 7 received supportive care. Conclusions: In our cohort TIP was associated with response rates and OS equivalent to those in published trials. Progression post TIP was associated with poor outcomes demonstrating the need for better treatment options in these patients.
Bleomycin-induced pulmonary toxicity: A retrospective review of incidence and risk factors.
Authors: Pritam Tayshetye, Parikshit Padhi, Rohit Rao, Tatyana Yurievna Sklyar, Abhishek Chilkulwar, Rickey Miller, Amy Tang, Shifeng Mao
Journal: Journal of Clinical Oncology (2018)

e16532 Background: Bleomycin has an established role in treatment of Hodgkin's lymphoma (HL) and testicular germ cell tumors (tGCT). Bleomycin-induced pulmonary toxicity (BPT) remains a dose-limiting toxicity. Risk factors such as age and G-CSF use have been implicated. We performed a retrospective review to analyze the incidence, association of risk factors, bleomycin dose and pulmonary function tests (PFTs) with BPT. Methods: Records of bleomycin-treated patients from July 2008 to September 2016 were analyzed. Patients diagnosed with BPT as per the treating physician were identified. Risk factors (age, smoking history, preexisting lung disease, renal function, radiation, oxygen use, G-CSF use, pulmonary-toxic drugs), primary cancer, bleomycin units administered, PFT results (DLCO, TLC) were compared between patients with and without BPT. Results: 121 bleomycin-treated patients were identified. 83 patients were analyzable; 27 with tGCT and 56 with HL. BPT was diagnosed in 14 (17%) patients, who had a significantly greater DLCO-decline (25.7% vs 5.4%, p < 0.001). The optimal DLCO-decline was 10.98%, yielding sensitivity 0.92 and specificity 0.79. There was no difference between the total bleomycin units administered between the BPT and non-BPT patients. More tGCT patients (n = 10) developed BPT compared to HL patients (n = 4). The tGCT patients received significantly more bleomycin compared to HL patients (232 vs 186 units, p = 0.015). Median time-to-onset of BPT was 57 (range: 21-140) days collectively (45 days for tGCT and 105 days for HL). There was no significant association between different risk factors, including age or G-CSF use, and BPT. Conclusions: Bleomycin exposure results in 1:6 odds of developing BPT. DLCO-decline with a threshold of 11% is a sensitive parameter for diagnosing BPT. The tGCT patients have a higher risk and develop BPT sooner compared to HL patients, perhaps due to higher dose-exposure and schedule. There is no association between the risk factors such as age or G-CSF use and development of BPT in our study.
Safety, PK/PD, and anti-tumor activity of RO6874281, an engineered variant of interleukin-2 (IL-2v) targeted to tumor-associated fibroblasts via binding to fibroblast activation protein (FAP).
Authors: Morten Mau Soerensen, Willeke Ros, Maria E. Rodriguez-Ruiz, Debbie Robbrecht, Kristoffer Staal Rohrberg, Juan Martin-Liberal, Ulrik Niels Lassen, Ignacio Melero Bermejo, Martijn P. Lolkema, Josep Tabernero, Christophe Boetsch, Hanna Piper-Lepoutre, Inja Waldhauer, Jehad Charo, Stefan Evers, Volker Teichgräber, Jan H. M. Schellens
Journal: Journal of Clinical Oncology (2018)

e15155 Background: High-dose (HD) IL-2 is approved for patients with melanoma and renal cell carcinoma but is associated with significant toxicity, given only in an inpatient setting. RO6874281 is a novel, monomeric, bispecific IL-2v immunocytokine that completely lacks binding to IL-2Rα, retains IL-2Rβγ binding, and shows pM binding affinity to FAP on tumor-associated fibroblasts. While the IL-2v domain activates IL-2R expressing immune effector CD8 T and NK cells independent of FAP-binding, targeting via FAP results in retention of IL-2v within tumors in order to selectively promote immune responses within the tumor microenvironment. Methods: Study BP29842 investigated safety, PK/PD and anti-tumor activity of RO6874281. Multiple ascending doses ranging from 5mg to 35mg were given weekly i.v. in an outpatient setting to 35 patients with metastatic solid tumors. Results: Most frequent adverse events ( > 30%) were pyrexia, infusion related reactions, fatigue/asthenia, nausea, diarrhea, decreased appetite and elevated aspartate and/or alanine transaminase. The majority of events were mild or moderate (Grade 1/2). The maximum tolerated dose was declared at 20mg, using one-step intra-patient escalation (15mg followed by 20mg). Preliminary PK analysis indicated a non-linear elimination profile typical of target mediated drug disposition. Single safe doses of RO6874281 yielded > 6 fold higher exposures than those achieved with a full cycle of conventional HD IL-2. As expected from abolished IL-2Rα binding, RO6874281 rapidly expands effector T and NK cells but not Tregs, both in peripheral blood and tumors. Objective long-lasting ( > 6 months) responses were observed in one patient each with head and neck cancer, penile squamous cell carcinoma and checkpoint inhibitor resistant malignant melanoma across the tested dose range. Conclusions: RO6874281 is the first targeted IL-2 variant with acceptable outpatient safety to display monotherapy activity including in tumor types not previously reported to respond to IL-2. Ph1b/Ph2 studies in combination with atezolizumab and other agents are currently underway. Clinical trial information: NCT02627274.