tbuckley/cabot-search huggingface dataset:
Impact of SPARC expression level on outcome in patients with advanced pancreatic cancer <i>not</i> receiving nab-paclitaxel: A pooled analysis from prospective clinical and translational trials.
Authors: Steffen Ormanns, Michael Haas, Sibylle Baechmann, Anna Remold, Detlef Quietzsch, Michael R. Clemens, Martin Bentz, Konrad Schoppmeyer, Stephan Kruger, Thomas Kirchner, Volker Heinemann, Stefan Hubert Boeck
Journal: Journal of Clinical Oncology (2015)

e15264 Background: Previous evidence suggests that SPARC expression might have a prognostic role in patients with resectable pancreatic cancer (PC); in contrast, SPARC might not serve as a predictive tissue biomarker for the efficacy of nab-paclitaxel. Methods: For this pooled retrospective translational analysis tumor tissue from 134 patients (pts) with confirmed advanced pancreatic adenocarcinoma was collected from three terminated clinical trials and from a prospective single center biomarker study. None of the included pts was treated with nab-paclitaxel or with targeted agents. SPARC expression level was determined by immunohistochemistry using an anti-SPARC monoclonal antibody (clone ON-1, Invitrogen) classifying a moderate to strong expression in ≥ 25% of the peritumoral stroma as SPARChigh cases and all other cases as SPARClow (as reported by Illei PB et al, USCAP 2013). Translational biomarker data were correlated with overall survival (OS) by using Kaplan-Meier estimates and the log rank test. Results: Median age was 62 years, 73 of 134 pts had a KPS > 80%; 14 pts had locally advanced and 120 pts metastatic disease at chemotherapy initiation. 112/134 pts received gemcitabine-based 1st-line treatment and 22/134 pts fluoropyrimidine-based chemotherapy, respectively. Median OS in the entire study cohort was 7.6 months (95% CI 6.4-8.7) after initiation of palliative chemotherapy. Archival tissue origin was primary tumor (PT) in 64 cases (including 45 resected specimens) and metastasis (M) in 70 pts. Of 134 samples, 90 (67%) were classified as SPARChigh and 44 (33%) as SPARClow. Estimated median OS was 9.1 months for SPARChigh and 7.6 months for SPARClow pts, respectively (HR 0.83, 95% CI 0.56-1.21; p = 0.32). For the PT subgroup, 46/64 cases (72%) were SPARChigh and 18/64 cases (28%) SPARClow, with corresponding median OS estimates of 10.8 months and 8.3 months (HR 0.95, p = 0.86). In the M subgroup 44/70 cases (63%) were SPARChigh and 26/70 cases (37%) SPARClow, with median OS estimates of 7.8 months and 6.8 months (HR 0.77, p = 0.32). Conclusions:SPARC expression level does not serve as a prognostic biomarker in advanced PC.
Randomized trial of arginine deprivation with pegylated arginine deiminase in patients with malignant pleural mesothelioma.
Authors: Peter Wojciech Szlosarek, Jeremy Peter Steele, Luke Nolan, David Gilligan, Paul Taylor, James F. Spicer, Michael J. Lind, John S. Bomalaski, Dean Anthony Fennell, Allan Hackshaw
Journal: Journal of Clinical Oncology (2014)

7507 Background: Argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM) cells are sensitive to arginine deprivation. We examined the efficacy and safety of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20, Polaris Group, US) among patients with MPM. Methods: Patients with good performance status (0-1), non-resectable disease, ASS1-deficient MPM, and measurable disease by modified RECIST were randomized (2:1) in a multicenter phase II trial. They received best supportive care (BSC) or BSC plus ADI-PEG20 (i.m. injection 36.8mg/m2, weekly). Primary endpoint was progression-free survival (PFS); target hazard ratio (HR) 0.60. Other endpoints: overall survival (OS), tumor response rate (modified RECIST), and toxicity. We measured plasma [arginine], [citrulline] and [ADI-PEG20 antibody], ASS1 methylation status, and metabolic response by [18F]Fluorodeoxyglucose Positron Emission Tomography (FDG-PET). [ClinicalTrials.gov NCT01279967, funding Cancer Research UK]. Results: We screened 214 patients (March 2011-May 2013), and randomized 68 with ASS1-deficient MPM: 44 ADI-PEG20+BSC and 24 BSC alone. PFS HR was 0.53 (95% CI 0.31 to 0.90, p=0.02), median 98 vs. 59 days favouring ADI-PEG20+BSC. The OS HR was 0.81 but the curves crossed, so we used the restricted mean survival times: 390 vs. 317 days (difference +73 days favoring ADI-PEG20+BSC,p=0.20). The best response was stable disease: at 4 months 67% ADI-PEG20+BSC vs. 50% BSC alone. The main grade 3/4 toxicities associated with ADI-PEG20+BSC were: neutropenia (11%), thromobocytopenia (5%), fatigue (7%), anaphylactoid reactions (7%), skin rash (2%), and serum sickness (2%). Plasma arginine levels declined with ADI-PEG20+BSC only, and correlated with the following FDG-PET changes in 39 evaluable ADI-treated patients with aberrant MPM ASS1 methylation: 46% partial response, 31% stable disease, 15% progressive metabolic disease, and 8% mixed metabolic response. Conclusions: Arginine deprivation using ADI-PEG20 in patients with ASS1-deficient MPM almost doubled PFS and was generally safe. It should be examined further either alone or in combination with selected therapies. Clinical trial information: NCT01279967.
Prognostic value of pathologic complete response to preoperative chemotherapy in early-stage non small cell lung cancer: Combined analysis of two IFCT randomized trials.
Authors: Guillaume Mouillet, Elisabeth Monnet, Bernard Milleron, Marc Puyraveau, Elisabeth Quoix, Philippe David, Alain Ducolone, Oliver Molinier, Gerard Zalcman, Alain Depierre, Virginie Westeel
Journal: Journal of Clinical Oncology (2012)

7057 Background: Our study aimed to evaluate whether pathologic complete response (pCR) in early-stage non-small cell lung cancer (NSCLC) following neoadjuvant chemotherapy resulted in improved outcome and to determine predictive factors for pCR. Methods: Eligible patients with stage IB or II NSCLC were included in two consecutive Intergroupe Francophone de Cancérologie Thoracique (IFCT) phase III trials evaluating platinum-based neoadjuvant chemotherapy, with pCR defined by the absence of viable cancer cells in the resected surgical specimen. Results: Among the 492 patients analyzed, 41 (8.3%) achieved pCR. In the pCR group, 5-year overall survival (OS) was 80.0% compared to 55.8% in the non-pCR group (p=0.0007). In multivariate analyses, pCR was a favorable prognostic factor of OS (RR=0.34; 95% CI=0.18-0.64) in addition to squamous cell carcinoma (SCC), weight loss ≤5%, and stage IB disease. Five-year disease-free survival (DFS) was 80.1% in the pCR group compared to 44.8% in the non-pCR group (p&lt;0.0001). Two patients (4.9%) in the pCR group experienced disease recurrence compared to 193 patients (42.8%) in the non-pCR group. SCC subtype was the only independent predictor of pCR (OR=4.30; 95% CI=1.90-9.72). Conclusions: Our results showed that pCR after preoperative chemotherapy was a favorable prognostic factor in Stage IB-II NSCLC. Our study is the largest published series evaluating pCRs following preoperative chemotherapy. The only factor predictive of pCR was SCC. Identifying molecular predictive markers for pCR may help in distinguishing patients likely to benefit from neoadjuvant chemotherapy and in choosing the most adequate preoperative chemotherapy regimen.
Prospective correlative study of FDG-PET SUV and proteomic profile (VeriStrat) of non-small cell lung cancer patients treated with erlotinib.
Authors: Chiara Lazzari, Marcello Tiseo, Vanesa Gregorc, Fiorenza Latteri, Massimo Ippolito, Segio Balderi, Sebastiano Cosentino, Maura Scarlattei, Heinrich Roder, Julia Grigorieva, Joanna Roder, Roberto Bordonaro, Andrea Ardizzoni, Luca Gianni, Hector J. Soto Parra
Journal: Journal of Clinical Oncology (2012)

e18096 Background: Matrix Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry (MALDI TOF MS) was used to create and validate a plasma proteomic algorithm VeriStrat (VS), based on 8 m/z peaks, and able to select advanced NSCLC pts who may benefit from EGFR TKIs. The algorithm was associated with PFS and OS of patients treated with EGFR TKIs and not with chemotherapy. Standardized Uptake Value (SUV) is of prognostic value for survival in non-small cell lung cancer. Aim of the current study was to analyze the OS and TTP in advanced NSCLC pts treated with erlotinib (E) according to baseline VeriStrat classification and baseline SUVs of FDG-PET. Methods: Plasma samples were collected before the beginning of E from metastatic NSCLC patients. Acquired spectra were classified according to the VeriStrat algorithm. The FDG-PET was performed the day before the beginning of E. Results: Thirty eight NSCLC pts on E therapy with the following characteristics were analyzed: median age 62 years old, 63% were males, 53% had adenocarcinoma histology, response rate was 26%, median OS 10 mos and (TTP) 3.4 mos. Twenty-six (68%) were classified as VS Good, 12 (32%) as Poor. TTP and OS for VS Good and Poor were 4.1 vs 2.1 mos (HR 0.86, log-rank p=0.6) and 11.1 vs 4.1 mos (HR 0.45,log-rank p=0.02), respectively. Baseline SUV levels were associated with TTP (Wilcoxon test p=0.001) but not with OS (all pts progressed, 5 still alive). All Poor classified pts had SUV ≥ 7 and had the worst TTP and OS; VS Good classified patients had worse TTP and OS if their baseline SUV level was &gt; 7 than those who were VS Good and had SUV&lt;7(see Table: 3-curves comparison log-rank test p value for a trend). Conclusions: We confirmed that pts with VS Poor classification have significantly shorter OS than those classified as VS Good. Pts with VS Good profile and with low baseline SUV levels may benefit more from EGFR TKI than VS Good pts with high SUV.
A phase 1 dose-escalation study of the oral selective inhibitor of nuclear export (SINE) KPT-330 (selinexor) in patients (pts) with relapsed/refractory acute myeloid leukemia (AML).
Authors: Karen W. L. Yee, Michael Savona, Morten Sorensen, Peter Brown, William G. Blum, Daniel J. DeAngelo, Martin Gutierrez, Ramiro Garzon, Andre C. Schuh, Nashat Y. Gabrail, Martha Wadleigh, Jeffrey E. Lancet, Bijal D. Shah, Jesus G. Berdeja, Nina D. Wagner-Johnston, Ian Flinn, Tami Rashal, Michael Kauffman, Sharon Shacham, Richard M. Stone
Journal: Journal of Clinical Oncology (2014)

7032 Background: KPT-330 (Selinexor) is a slowly reversible XPO1 inhibitor that forces the nuclear retention and activation of >10 tumor suppressor proteins (TSP) including NPM1c, reduces cMYC and BCLx, and induces AML cell death while sparing normal hematopoietic cells. Methods: Oral KPT-330 was given at 8-10 doses per 28-day cycle. Elevation in leukocyte XPO1 mRNA following XPO1 inhibition was a pharmacodynamic (PDn) marker for KPT-330 activity. Pharmacokinetic (PK) analyses were performed. Appetite stimulants and anti-emetics were given as part of supportive care. Results: 48 pts (24 M / 24 F; median age 68 yrs; ECOG PS 0/1: 11/37; pts were heavily pretreated with median 3 prior regimens (range of 1-7). Pts received KPT-330 across 5 dose levels (16.8 - 55 mg/m2). There have been no DLTs. Cycle 1 grade 3/4 non-DLT adverse events (AEs) in >1 pt included: fatigue (8%), thrombocytopenia (8%), neutropenia (8%), and nausea (4%). The most common Cycle 1 grade 1/2 AEs were diarrhea (35%), anorexia (33%), nausea (29%), and fatigue (25%). Prolonged administration (>4 months) of KPT-330 was feasible and there were no drug-associated deaths. PK and PDn analyses showed dose-dependent increases in Cmax / AUC0-inf (T1/2 ~6 hrs) and increases in XPO1 mRNA. Higher doses of KPT-330 were associated with greater reductions in blast counts, which were also observed across different AML subtypes. 16 pts did not complete cycle 1 and were therefore not evaluable for response. Responses in 32 evaluable pts were: complete response (CR) with full hematological recovery: 4 pts (12%), marrow CR (CRm): 1 pt (3%), CR without hematological recovery: 1 pt (3%), duration of CR/CRi/CRm 6-13 weeks; Morphological leukemia free state: 1 pt (3%), Partial Response (PR) 2 pts (6%). Twelve (37%) of the remaining pts have experienced stable disease for > 30 days, and 11 (34%) have had progressive disease. Conclusions: KPT-330 treatment can be given over months and induce remissions in pts with heavily pretreated AML. A randomized study of KPT-330 vs available agents in chemotherapy-ineligible relapsed AML is being initiated. Clinical trial information: NCT01607892.
Exploring thoughts of suicide
Authors: Lindsey Sinclair, Richard Leach
Journal: BMJ (2017)

#### What you need to know

A 50 year old man describes feeling low in mood. He has recently lost his job and his wife has left him. During the consultation he mentions that life is not worth living any more. Dr Smith is worried about how to follow up on this comment; the patient is making poor eye contact.

Many doctors worry about how best to assess suicide risk in individuals who present to them with thoughts of self harm.

The topic of suicide is difficult to research and consequently much of the evidence is of low quality. In a recent qualitative study, general practitioners in the UK reported that they found it difficult to identify who was “really” suicidal, to effectively assess risk, and to manage patients at risk of suicide.1 Patients who repeatedly self harm can evoke powerful emotions in the healthcare provider, such as anger, fear, or a desire to save them.2

Clinicians should not fear asking about suicide; a review article failed to identify any studies in which asking about suicidal ideation increased the risk of a further attempt.3 This article suggest how to asses someone who has thoughts of ending their life, perform a risk assessment, and decide who might benefit from additional input from a specialist mental health team.

Suicide itself is a rare event. In 2014 there were 10.8 deaths by suicide per 100 000 of the population in the UK.4 Between 3.5% and 5% of people reported suicidal thoughts in the last year, but only 0.5%-0.7% of individuals made an attempt to end their life, according to UK …
Phase II trial of dose-dense temozolomide as initial treatment for progressive low-grade oligodendroglial tumors: A multicentric study of the Italian Association of Neuro-Oncology (AINO).
Authors: Roberta Ruda, Luca Bertero, Elisa Trevisan, Andrea Pace, Carmine Maria Carapella, Cristina Dealis, Manuela Caroli, Marina Faedi, Chiara Bomprezzi, Riccardo Soffietti
Journal: Journal of Clinical Oncology (2012)

2037 Background: Standard temozolomide has been shown to be active in progressive low grade gliomas after surgery, whereas few data are available on the impact of dose dense regimens. Thus, we developed a phase II single arm multicenter study to evaluate the efficacy and toxicity of a regimen of dose dense temozolomide in progressive low grade oligodendroglial tumors. Methods: The inclusion criteria of the study were as follows: 1)biopsy-proven supratentorial WHO grade II oligodendroglioma and oligoastrocytoma; 2)progressive disease, clinically (epileptic seizures)or radiologically; 3)measurable disease on MRI (at least 1 cm); 4)age ≥18 years; 5)Karnofsky Performance Status ≥70. Temozolomide was administered at 150mg/m2 1 week on/1 week off up to a maximum of 18 cycles or unacceptable toxicity. The primary end-point was response rate (RR) according to RANO criteria, whereas secondary end-points were clinical benefit in terms of reduction of epileptic seizures ≥50%, progression-free survival (PFS), quality of life and toxicity. Results: From January 2005 until December 2010 60 patients (median age 39 and median KPS 80) have been accrued and are now evaluable for response. Response rates on T2/FLAIR images were as follows: CR 0/60, PR 21/60 (35%), MR 14/60 (23%), SD 21/60 (35%) and PD 4/60 (7%). The clinical benefit was significant in 29/34 patients (85%). As for toxicity 5/60 (8%) patients stopped treatment for lymphopenia grade IV, whereas 11/31 patients (35%) were switched to the standard regimen of temozolomide. PET with methionine was added to MRI in 17 patients: in 10/17 (59%) a disappearance or a significant reduction of uptake was observed, being the reduction of seizures better correlated with the response on PET rather than that on MRI. 1p/19q codeletion was not associated with either the response or the clinical benefit, whereas the analysis of MGMT methylation and IDH1 mutations are ongoing. Thirty-nine (65%) patients are still free of tumor progression. Conclusions: Dose-dense TMZ seems to be active, especially in terms of clinical benefit, but the myelotoxicity could be a concern.
Addition of darbepoetin alfa to sequential high-dose VIP chemotherapy for patients with advanced metastatic germ cell cancer.
Authors: Joerg Thomas Hartmann, Bernd Metzner, Claudia Binder, Hans-Guenther Mergenthaler, Oliver Rick, Herbert G Sayer, Frank Mayer, Joerg Beyer, Anja Lorch, Wolfgang E. Berdel, Norbert Frickhofen, Carsten Bokemeyer, Jan Schleicher, Thomas C. Gauler
Journal: Journal of Clinical Oncology (2012)

e15026 Background: High-dose VIP chemotherapy plus ABSCT given as first line treatment might be a strategy in patient with advanced germ cell tumors (GCT) with poor prognosis. The objective of the trial was to investigate the addition of darbepoetin alfa to HD-VIP in order to reduce anemia/red blood cell (RBC) transfusions. Methods: This was a randomized, open-label multicenter phase 2 study conducted in 20 hospitals. Darbepoetin 2.25 mcg/kg weekly or 500 mcg Q3W s.c., started with high dose VIP (dose level 6) was applied in arm B (arm A: HD-VIP alone). The primary objective was freedom from blood transfusions (FFT). Secondary objectives included objective remission rate (ORR) after chemotherapy, 24 mos PFS and OS, median course of hemoglobin (Hb) levels during 3 HD-VIP cycles as well as drug safety. Results: Between 7/2003 and 11/2008 108 pts were allocated to the study, and 106 were included in the intention-to-treat (ITT) analysis. By March 2011 the median follow-up time after randomization was 20 mos. Localisation of primary was gonadal in 66%, retroperitoneal in 19% and mediastinal in 14%s. A favourable treatment outcome (CR/NED/PR m-) in conjunction with secondary surgery (n = 76 pts) was achieved in 58% of pts with no difference between arms A and B. Overall FFT occurred in 2 pts (4.2%) in arm A and 3 pts (5.6%) in arm B, and in 23%/15%/15% and 15%/17%/19% of pts during cycles 1-3, respectively. No differences in baseline Hb, severity of anemia, no of RBC transfusions and area under the curve of Hb levels during HD-VIP was observed. Pts assigned to darbepoetin had similar treatment toxicity compared to those assigned to HD-VIP alone. 24-mos OS in arm A was 86.3% compared to 67.8% (p=.064) in Arm B. 2-year RFS was 66.8% in arm A vs 55.5% in Arm B (p=0.45). Darbopoetin was generally well tolerated with 2 pts discontinuing treatment due to thrombosis. Since compliance to study protocol was generally poor (6 out of 55 pts never received study drug during HD-VIP) a per-protocol analysis is in preparation. Conclusions: Based on ITT analysis, the addition of darbepoetin alfa to the high dose regimen compared to HD-VIP alone does not appear to impact on FFT, ORR, and 2-year survival rate in poor prognosis GCT pts (NCT00204633).
The IMPACT of <sup>68</sup>GA-PSMA-PET in definitive radiotherapy planning for prostate cancer patients.
Authors: Cem Onal, Nese Torun, Berna Akkus Yildrim
Journal: Journal of Clinical Oncology (2017)

79 Background: The implementation of 68 Ga-PSMA-PET-imaging for staging and the impact on stage adaption during treatment radiotherapy (RT) planning is not well studied yet. The present work is to evaluate the integration of 68 Ga-PSMA-PET into standard RT planning and to determine the influence on staging and on changes in the initially planned treatment concept for definitive RT in prostate cancer patients. Methods: A total of 66 prostate cancer patients with PSMA-PET delivered before treatment were retrospectively analyzed. All patients had bone scintigraphy and magnetic resonance imaging (MRI) of abdomen (52 patients; 79%) or thoraco-abdominal computed tomography (CT) (14 patients; 21%). After PSMA-imaging, all information was reviewed and re-classification was performed with the additional information taken into account. Thereafter, patients were evaluated with the information obtained by PSMA-PET imaging led to a change in staging and subsequently resulted in a change of the RT concept and treatment fields. Results: Median age of patients was 66 years (range 46 – 84 years). Median pretreatment PSA level was 25.2 ng/mL (range 4.4 – 130.8 ng/mL). The initial stage was changed in 27 patients (41%); 8 patients (12%) under-staged, 11 patients (17%) over-staged and 8 patents (12%) had distant metastasis. RT fields changed in 9 patients (14%) and RT cancelled because of distant metastasis detected with PSMA-PET in 6 patients (9%). The mean pretreatment PSA values were significantly higher in over-staged patients or patient with distant metastasis compared to under-staged patients (55.0±38.8 ng/mL vs. 28.1±19.1 ng/mL; p = 0.02). Also upstaging was observed more frequently in patients with ≥ T3a disease compared to patients with &lt; T3 disease (15 patients [56%] vs. 4 patients [15%]; p = 0.04). However, Gleason score and primary tumor SUV had no significant impact on stage change and particularly on RT decision and treatment plan changes. Conclusions: The performance of a PSMA-PET frequently leads to changes in the stage, altering the RT treatment regimen especially in patients with extensive stage disease and higher pretreatment PSA values.
Survival after resection plus intra-operative radiofrequency ablation (IRFA) to treat colorectal liver metastases (CLM): Results of an international collaborative study.
Authors: Serge Evrard, Abou Diallo, Veronique Brouste, Caroline Lalet, Gregoire Desolneux, Simone Mathoulin-Pelissier, Peter Kissmeyer-Nielsen, Frank Mortensen, Graeme John Poston, Stefan Staettner, Ioannis Konstantinidis, Ronald P. DeMatteo, Michael Ian D'Angelica, Peter J. Allen, William R. Jarnagin, Yuman Fong
Journal: Journal of Clinical Oncology (2013)

3558 Background: Adding IRFA to parenchymal resection to treat CLM is gaining increasing acceptance in specialized HPB teams treating complex, bilobar disease. Objectives were to confirm the promising results of the prospective CLOCC and ARF2003 trials on a larger international scale. Methods: Four centers combined their clinical databases regarding IRFA for CLM. Demographics, treatments, CLM characteristics, complications (Clavien-Dindo), local recurrence, and survivals (liver progression-free, LPFS, relapse-free, RFS and overall, OS) were analyzed. Results: 280 patients (38% female, median age 61y) received resection plus IRFA over 2001-2011. 205 had synchronous CLM (73%) and 247 bilateral (88%). 227 patients received pre-operative chemotherapy (173 one line, 37 two lines, 10 three lines, 7 missing); 189 received post-operative chemotherapy (103 one line, 46 two lines, 40 three lines). Median number of tumors resected was 2 (range 1-19) and ablated 2 (1-12). Median size (mm) of largest CLM ablated per patient was 8.5(0.1-50). 96 patients experienced complications: 29 G1, 19 G2, 35 G3, 10 G4, and 3 deaths. 48 patients had local recurrence of ablated CLM. 155 patients developed new CLM, 165 extra-hepatic metastases, and 119 patients died during follow-up. One-year, 3-year and median (months) RFS, LPFS and OS were respectively: RFS 41%(95CI35-47), 14%(95CI9-19), 9m (95CI8-11); LPFS 53%(95CI47-59), 31%(95CI25-37), 15m (95CI11-19); OS 90%(95CI85-93), 58%(95CI51-65), 40m (95CI37-50). Median follow-up was 38m (95CI34-49). Conclusions: In this difficult-to-treat group, survival results were good and comparable with rates reported after resection only. IRFA complements resection, enabling to treat more patients, and offers the advantage of sparing healthy parenchyma.