tbuckley/cabot-search huggingface dataset:
Extracellular matrix (ECM) circulating peptide biomarkers as potential predictors of survival in patients (pts) with untreated metastatic pancreatic ductal adenocarcinoma (mPDA) receiving pegvorhyaluronidase alfa (PEGPH20), nab-paclitaxel (A), and gemcitabine (G).
Authors: Song Wang, Nicholas Willumsen, Cecilie Bager, Morten A Karsdal, Dimitrios Chondros, Darin Taverna
Journal: Journal of Clinical Oncology (2018)

12030 Background: Hyaluronan (HA) and collagens are major constituents of the ECM. HA accumulation in the tumor microenvironment may result in elevated interstitial fluid pressure, vascular compression, and reduced drug delivery and immune cell access. PEGPH20 degrades HA, increasing tumoral access for therapeutics and immune cells. Liquid biopsies reflecting ECM remodeling may provide a non-invasive approach to identify pts most likely to benefit from PEGPH20 therapy. Methods: Peptide markers of ECM remodeling (C3M, PRO-C3, PRO-C6, and VCANM) were measured using baseline plasma samples from Stage 1 (n=94) and Stage 2 (n=95) of HALO-109-202 (NCT01453153), a Phase 2, open-label, randomized study of PEGPH20 + A + G (PAG) vs AG in previously untreated pts with Stage IV PDAC. Univariate and ratio analyses were conducted to correlate biomarker levels with survival outcomes (PFS, OS). Results: The ratio of C3M (MMP degradation fragment of type-III collagen) vs PRO-C3 (N-terminal pro-peptide of type-III collagen) predicted for PFS benefit in PEGPH20-treated pts in Stage 1. The predictive value of this ratio for PFS and OS of PEGPH20-treated pts was further validated in Stage 2. Conclusions: This supports development of a liquid biopsy-based companion diagnostic for selecting pts that may benefit from PEGPH20. Biomarker levels and survival outcome. Measurement cut-off PFS Median (mths) Log-rank, P HR (95% CI) AG PAG Stage 1 (Discovery cohort) C3M/PRO-C3 ratio (0.550, 50th percentile) Ratio-high pts (≥0.550) 5.3 8.0 0.026 0.40 (0.17–0.92) Ratio-low pts (<0.550) 5.2 3.0 0.810 1.09 (0.55–2.18) Measurement cut-off PFS OS Median (mths) Log-rank, P HR(95% CI) Median (mths) Log-rank, P HR(95% CI) AG PAG AG PAG Stage 2 (Validation Cohort) C3M/PRO-C3 ratio (0.550, stage-1 cut-off) Ratio-high pts (≥0.550) 3.4 8.8 0.039 0.46 (0.21–0.99) 8.5 13.8 0.006 0.35 (0.16–0.77) Ratio-low pts (<0.550) 5.8 5.3 0.560 1.30 (0.54–3.16) 9.0 7.9 0.523 0.80 (0.41–1.57)
P01.167 Impact of retreatment or chemoterapy on survival in patients affected by recurrent glioblastoma: analysis from a single institution.
Authors: C Mazzarella, S Chiesa, s Bracci, T Zinicola, F Beghella Bartoli, S Luzi, G Sabatino, C Anile, A Olivi, V Valentini, M Balducci
Journal: Neuro-Oncology (2018)

There is no standard treatment available for recurrent high-grade gliomas. Despite some evidence of improvement in progression-free survival, no significant increase in overall survivor (OS) has been demonstrated with any particular approach. The porpose of this retrospective analysis was to evaluate the impact on OS with different salvage therapies, including no treatment, systemic therapy, or retreatment plus systemic therapy in patients affected by recurrence of Glioblastoma (GBM) to generate new hypotheses for future trial. Patients (pts) affected by GBM’s recurrence and treated with Stupp’s schedula, were included in this retrospective analyses. Those who died less a month after progression or with a poor performance status were excluded. Patients were divided into 3 groups: reirradiation plus chemotherapy (group A) chemotherapy alone (group B) no treatment (group C). Overall Survival was calculated using the Kaplan-Meier method and compared between three groups. We retrospectively evaluated files relative to 217 patients with recurrence treated according to Stupp’s schedula for GBM from January 2009 to May 2016. Among them, 153 patients were evaluable for this analysis; 64 patients were excluded because they died less than one month after progression or for a poor performance status. Sixty-nine out of 153 patients (45%) belonged to Group C, 63 (41%) to group B, and 21 (14%) to group A. Median follow-up was 48 months in all patients. Median survival time from diagnosis was 18 months for the entire cohort: 14 months for patients of Group C, 28 months for group B, and 30 months for those of group A. Type of treatment at recurrence time proved to significantly impact on OS (p=0.0001). Patients who received no salvage treatment had poorer survival than those who received chemotherapy alone or in combination with radiotherapy. Reirradiation plus chemotherapy seems to favor highest survival. Further investigations are needed to define the optimal choice of therapy, and in particular the role of reirradiation patients with recurrent GBM.
Influence of mRNA expression of <i><i>fibroblast growth factor 2</i> (<i>FGF2</i>)</i> in colorectal cancer (CRC) cell lines and in patients with metastatic colorectal cancer (mCRC) treated with FUFIRI or mIrOx (FIRE1).
Authors: Arndt Stahler, Sebastian Stintzing, Manuela Urbischek, Dominik Paul Modest, Ludwig Fischer von Weikersthal, Joerg Kumbrink, Volker Heinemann, Thomas Kirchner, Andreas Jung
Journal: Journal of Clinical Oncology (2016)

3570 Background: Our aim was to evaluate fibroblast growth factor 2 (FGF2) expression in CRC cell lines exposed to 5-Fluorouracil (5-FU) and validate results with clinical data from mCRC patients receiving first-line treatment. Methods: 5-FU IC50 was determined in the CRC cell lines DLD1, LoVo, and HCT-15 applying MTT assays. mRNA expression of FGF2 was measured by RT-qPCR using HPRT as reference gene. Threshold values were determined by minimum p-value method. FGF2 expression was knocked down using sh (short hairpin) RNA in vitro with eGFP as control. In vitroresults were validated by data of the randomized FIRE1 trial (5-FU/LV/irinotecan [FUFIRI] vs. irinotecan/oxaliplatin [mIrOx] using Nanostring. 187 patients were included in this analysis. Results: Decreasing sensitivity of DLD1 [IC50 : 8.8 µM, 95% CI: 6.0 – 13.1 µM], LoVo [IC50 : 10.0 µM, 95% CI: 8.6 – 11.5 µM] and HCT-15 [IC50 : 15.4 µM, 95% CI: 13.3 – 17.9 µM] for 5-FU was associated with relative FGF2 expression levels [DLD1: 1.0; LoVo: 154.0; HCT-15: 92.4]. Knocking down FGF2 expression [rel. expression DLD1: sheGFP : 1.00, shFGF2 : 0.02, p = 0.009; LoVo: sheGFP : 1.00, shFGF2 : 0.19, p = 0.032] correlated with a significant decrease of IC50 for DLD1 [100 to 32% (95% CI: 29.9 – 34.8 %), p < 0.001] and LoVo [100 to 64% (95% CI: 55.2% - 74.1%), p = 0.001]. In FIRE1, high (n = 89) vs. low (n = 98) FGF2 expression was not correlated significantly with PFS [8.0 vs. 8.2 months, HR: 0.87, 95% CI: 0.65 – 1.17, p = 0.370], but with OS [17.9 vs. 23.5 months, HR: 0.70, 95% CI: 0.51 – 0.96, p = 0.025]. Higher FGF2 expression was significantly associated with worse objective response rate [PR and CR (n = 84) vs. SD and PD (n = 21); 24.85 vs. 31.89, p = 0.049]. Effects in FIRE1 were noticed in patients treated with FUFIRI as well as mIrOx. Conclusions: FGF2 expression might reflect chemosensitivity in CRC cell lines as a knockdown of FGF2 led to a decrease of IC50 for 5-FU in vitro. In FIRE1, high FGF2 expression was associated with lower response rate and overall survival significantly. Interfering the FGF2 system might be a modulator for acquired chemoresistance.
Regional lymph nodes involved by prostate cancer harbor immune suppressor cells that impair the function of tumor-reactive T cells.
Authors: Haidong Dong, Jeffrey Karnes
Journal: Journal of Clinical Oncology (2016)

e16551 Background: The role regional tumor draining lymph nodes (TDLN) plays in local immunity to prostate cancer (PCa) remains unknown. We hypothesized that TDLN harbor immune suppressor cells that impair function of tumor-reactive T cells. Treatments of regional PCa lymph node metastasis could benefit from secondary immune responses in order to restore an anti-tumor response. Methods: Men undergoing a salvage pelvic node resection, n = 12, for hormone naïve PCa recurrence were prospectively identified, and consented. Peripheral blood (PB) was collected pre-/post-resection and fresh nodal tissue (largest tumor extent; TDLN) was harvested at resection and compared. The frequency of tumor-reactive CD8 T cells (CD 11a & PD-1) was measured by flow cytometry and Ki-67 proliferation was also assessed. Myeloid derived suppressor cells (MDSC) {CD 11b & CD 33} and CD4+ Treg cells were also measured. MDSC were subgrouped into CD14+ monocytic and CD14- granulocytic. B7-H1 (PD-L1) and B7-DC (PD-L2) expression was also analyzed on the MDSC populations. Results: Tumor reactive CD 8 T cells accumulated in TDLN yet had decreased proliferation via Ki67 expression. CD 4+ Treg cells were not readily populated in then TDLN. Both CD 14+ and CD14- MDSC accumulated in the TDLN but only CD14+ in the PB and there was a relative increase of the granulocytic MDSC population (CD14-) in the TDLN. Additionally, these MDSC demonstrated a higher expression level of B7-H1 and B7-DC Conclusions: TDLN accumulate granulocytic MDSC which likely suppress tumor-reactive CD8 T cells and exhibit a high expression of immune checkpoint molecules in PCa nodal metastasis. With this pilot study, the data suggest that the interaction of PCa and TDLN results in a relative immunosuppressive state which has potential therapeutic implications.
Metastatic soft tissue sarcomas (STS) in elderly patients: 18 years of monoinstitutional experience.
Authors: Alessandro Comandone, Antonella Boglione, Elena Giubellino, Paola Bergnolo, Simona chiadò Cutin, Orietta Dal Canton, Ferdinando Garetto, Davide Ottaviani, Raimondo Piana, Paolo Pochettino, Veronica Prati
Journal: Journal of Clinical Oncology (2017)

e22528 Background: Elderly people represent more than 50% of STS patients, but few data are available in this population and old patients in clinical studies are underrepresented or not included. Aim of this retrospective, monoinstitutional study is to describe the activity and feasibility of first and second line chemotherapy in elderly patients with metastatic STS. Methods: Patients older than 65, with metastatic STS of the scalp, trunk, girdles and extremities, treated and followed from February 1998 to December 2015 in an Italian referral Center for diagnosis and care of STS were included. Median Overall survival (OS) was the principal end point calculated from the start of chemotherapy to the last date of follow up or death. Response rate and toxicities related to type of administered chemotherapy were the secondary end points. Results: 134 patients (79 M, 55F) were considered, (65-70 y) 63%, (71- 75y) 25%, ( &gt; 76 y)11% . STS histologies: mixoid and round cell liposarcomas (34%), leiomyosarcomas (25%), pleomorphic undifferentiated sarcomas (13%), Angiosarcoma (10%), Mixofibrosarcoma (6%), MPNST (4%), synovial sarcoma (2%), other histologies (6%). All the patients received at least one course chemotherapy (1-12). Mono CT was the preferred administered schedule (92%of cases). Median OS was 7.3 months; at the time of this analysis only 14 patients were alive (10%). In the first line therapy we recorded 1 CR, 14 PR and 43 SD. In second line therapy no CR, 4 PR, 23 SD. PR were recorded mainly in 65-70y old patients. Bad PS, low score in Comprehensive Geriatric Assesment (CGA), vulnerability, comorbidities, number of metastasis, were negative prognostic factors. No toxic death were recorded. 12% of the pts were recovered for febrile neutropenia, thrombocitopenia and mucositis . Conclusions: Our study confirms that elderly patients with metastatic STS is a difficult population to be treated. Only patients less aged, good PS, good GCA and 0-1 comorbidities can be treated with full dose of drug, generally with mono CT. Chemotherapy in elderly pts doesn’t produce a significant improvement in Median Survival and benefit observed support the routine use of citotoxic treatment in selected good performance status population.
Preliminary result of phase 1/2 study of ramucirumab plus nivolumab in patients with previously treated advanced gastric adenocarcinoma (NivoRam study).
Authors: Daisuke Takahari, Hirokazu Shoji, Hiroki Hara, Taito Esaki, Nozomu Machida, Kengo Nagashima, Kazunori Aoki, Kazufumi Honda, Takahiro Miyamoto, Narikazu Boku, Ken Kato
Journal: Journal of Clinical Oncology (2018)

4047 Background: Nivolumab (Nivo) has a significant survival benefit in salvage line of advanced gastric cancer (AGC) patients (pts) in ATTRACTION-2 trial. Based on synergistic anti-tumor effect induced by simultaneous blockade of PD-1 and VEGFR-2 in preclinical data, phase I/II study was conducted to investigate the safety and efficacy of Nivo plus ramucirumab (Ram) in the 2nd line chemotherapy for AGC. Methods: AGC pts with measurable lesions, ECOG PS 0-1, disease progression on 1st line chemotherapy containing platinum were eligible. Pts received Nivo (3mg/kg, Q2W) in combination with Ram (8mg/kg, Q2W) until unacceptable toxicity or disease progression. After feasibility was evaluated in six patients (phase I part), additional 40 patients were enrolled in a phase II part with the primary endpoint of a 6-months progression-free survival rate. Secondary endpoints included overall response rate, disease control rate, overall survival, and safety. PD-L1 tumor expression was assessed by immunohistochemistry (28-8 pharmDx assay) with a cut-off value for PD-L1 positivity set at 1% in tumor cells. Results: From 17-Jan-2017 to 31-Dec-2017, 46 AGC pts were enrolled. Patient characteristics were: median age 66 years, male 64%, ECOG PS1 40%, prior gastrectomy 35%, PD-L1 positive rate 44%. There were no dose limiting toxicities observed in phase I part. With median protocol treatment duration of 2.1 months, 40(87%) pts experienced any treatment-related AE (TRAE). Six (13%) pts had grade 3-4 TRAEs: hypertension (4%), hemorrhage (2%), colitis (2%), autoimmune pancreatitis (2%), liver dysfunction (2%), cholangitis (2%), hematoma (2%), and proteinuria (2%). There were no treatment-related deaths. Partial response was obtained in 10 (22%) pts with disease control rate (DCR) of 59%. With median follow-up time of 8.2 months, 20(44%) pts remain on treatment. Conclusions: Combination of Nivo and Ram showed no new safety signals and demonstrated promising antitumor activity in previously treated AGC. Clinical trial information: NCT02999295.
Using patient reported outcomes (PROs) to hear the patient: Are we listening?
Authors: Colleen A Cuthbert, Devon J Boyne, Brenda R Hemmelgarn, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2018)

e22134 Background: PROs may improve patient centered care by identifying the type and amount of care required. We aimed to examine PROs in a large Canadian province to identify symptoms and needs, and their subsequent management. Methods: A population-based cross-sectional study using administrative data. PROs collected at diagnosis between December 2016 to October 2017 included symptoms, supportive care needs from the Canadian Problem Checklist, demographic and tumor characteristics, and patient management (reported by the clinician). Patients were categorized into six cancer types: breast (Br), lung (L), prostate (Pr), colorectal (CRC), hematological (H), and other (Ot). Multiple linear regression was used to examine predictors of needs. Results: We evaluated 1295 patients. Median age 66 (range19-97) years and 51% men. There were 179 (14%) Br, 394 (30%) L, 83 (6%) Pr, 122 (9%) CRC, 182 (14%) H and 335 (25%) Ot cancers. Pain, tiredness, anxiety and low appetite were the most prevalent moderate to severe symptoms. 66% of patients had at least one need. The most frequent emotional needs were fear and worries. Finances were the highest practical need while strength, sleep, mobility and weight loss were the most common physical need. Information needs were about illness or treatment (Table). Predictors of having higher needs included Br cancer (p.024), higher emotional or physical symptom burden (p < .001), and attending an urban cancer center (p < .001). Health care providers most often provided information (62%), emotional support (43%) and prescriptions (14%) to address PROs, while referrals rates to multidisciplinary providers were low (Table). Conclusions: Many patients reported at least one need and had some moderate to severe symptoms. PROs were addressed mostly with information and emotional support. More understanding of barriers to referral may enhance integration of PROs into routine clinical practice. Need % Referral % Referred Fears and Worries 32 Psychology 2 Finances 13 Social Work 11 Strength 20 Physiotherapy 4 Sleep 20 No service Mobility 20 Physiotherapy 4 Weight loss 22 Dietician 7 Information 27 Information 62 Symptom % score ≤ 4 Pain 40 Pain Clinic 0.8 Tiredness 64 Fatigue Clinic 0.3 Appetite 43 Dietician 7 Anxiety 44 Psychology 2
Ten years of ASCO/ESMO global curriculum for training in medical oncology implementation at Instituto Oncologico Nacional in Panama City, Panama.
Authors: Omar Orlando Castillo Fernandez, Roberto Ivan Lopez, Juan Carlos Alcedo, Jorge Lasso De La Vega, Maria Lim, Anibal Villa-Real
Journal: Journal of Clinical Oncology (2018)

11010 Background: Cancer is a leading cause of death in Panama. In 2007 the Instituto Oncologico Nacional endorsed the ASCO/ESMO global curriculum core (GCC) for training in Medical Oncology with a view to address the lack of cancer specialists in the country. The aim of this study is to evaluate the benefit of GCC to our institution. Methods: We assess the benefit in three ways: Human resources benefit (the number of medical oncologist before and after the GCC implementation, numbers of fellows, number of fellows visiting from others countries/ programs), Academic benefit ( papers published and posters presentations in International Oncology meetings) and Inter-institutional benefit (number of academic center outside Panama receiving our fellows for observership and clinical rotations). Results: The proportion of medical oncologist in the institution has increased in 300% (from 4 to 14). Over this decade 15 fellows have been admitted (12 from Panama, 3 from Dominican Republic. 10 graduated and 5 currently in training). We have hosted clinical rotation visits from others medical oncology regional programs: 3 from Dominican Republic, 1 from Peru, 1 from El Salvador, 1 pathologist from Colombia, 1 surgical oncology form Nicaragua and 1 interventional radiologist from Costa Rica. Eight papers have been published in collaboration with mentors from others institutions and 18 posters were presented in International Oncology Meetings (1 ASCO Annual Meeting , 4 ESMO Congress, 4 ENETS Conference, 2 SABCS, 2 IASLC WCLC, 2 ESMO-WCGC, 4 LALCA-IASLC). Our fellows have undergone clinical rotations in academic centers in United States (Memorial Sloan Kettering Cancer Center, Cleveland Clinic, Massachusetts General Hospital Cancer Center) and Europe (Vall d´Hebron University Hospital, Instituto Valenciano de Oncologia and Instituto Oncologico Rosell). Conclusions: To integrate ASCO/ESMO GCC to local training programs offers assistance and academic benefits to institutions in developing countries. Closer relations with mentors and academic centers in developed countries is key to inspire and motivate fellows and trainers.
Efficacy of CDK 4/6 inhibitors in ER positive metastatic breast cancer: Systematic review and meta-analysis of randomized clinical trials.
Authors: Alessandra Gennari, Chiara Saggia, Valentina Rossi, Francesca D’Avanzo, Paolo Bruzzi
Journal: Journal of Clinical Oncology (2018)

e13040 Background: The introduction of cyclin-dependent kinase (CDK) 4/6 inhibitors led to a significant paradigm shift in the management of Estrogen Receptor (ER) positive metastatic breast cancer (MBC). The purpose of this analysis was to evaluate the effect of CDK 4/6 inhibitors (palbociclib, ribociclib, abemaciclib) in ER positive MBC patients across trials in terms of progression free (PFS) and OS. Methods: We searched literature databases to identify randomized controlled trials that compared endocrine therapy (ET) with ET plus CDK4/6 inhibitors in ER positive MBC. The main outcome measures for this analysis were OS and PFS. Log hazard ratios (HRs) for OS and PFS were pooled across the studies by inverse variance weighting. Primary analyses were done with a fixed effects model, since no heterogeneity was found among studies. Results: We found seven randomised clinical trials including 3854 patients. Of these, 4 included only first line therapy and 3 allowed prior treatments for MBC. Overall, the addition of CDK4/6 inhibitors to ET was associated with a significant improvement in PFS (HR = 0.54, 95% CI, 0.49 to 0.59; P < 0.001), without any remarkable heterogeneity (I2 = 0). In trials of first line therapy, the HR was 0.56 (95% CI, 0.49 to 0.63, P < 0.001); in trials including pretreated MBC the HR was 0.52 (95% CI 0.46 to 0.60, P < 0.001). OS was reported only in 2 out of 7 trials in first line therapy (833 patients), showing an improvement of borderline statistical significance (HR 0.77; 95% CI, 0.57 to 1.03; P 0.008). There were no differences in effects on PFS among subgroups defined by age, metastatic site and Disease Free Interval (DFI). Conclusions: The addition of CDK 4/6 inhibitors to ET in ER positive MBC is consistently associated with a 50% reduction in the rate of progression both in first and subsequent lines of treatment and this effect appears to be independent of age, site of metastasis and DFI. Overall survival data are available only for 2 studies, indicating that the PFS advantage translates into a clinically meaningful survival advantage.
Zürich Statement on Future Actions on Per- and Polyfluoroalkyl Substances (PFASs)
Authors: Amélie Ritscher, Zhanyun Wang, Martin Scheringer, Justin M. Boucher, Lutz Ahrens, Urs Berger, Sylvain Bintein, Stephanie K. Bopp, Daniel Borg, Andreas M. Buser, Ian Cousins, Jamie DeWitt, Tony Fletcher, Christopher Green, Dorte Herzke, Christopher Higgins, Jun Huang, Hayley Hung, Thomas Knepper, Christopher S. Lau, Eeva Leinala, Andrew B. Lindstrom, Jinxia Liu, Mark Miller, Koichi Ohno, Noora Perkola, Yali Shi, Line Småstuen Haug, Xenia Trier, Sara Valsecchi, Katinka van der Jagt, Lena Vierke
Journal: Environmental Health Perspectives (2018)

Summary: Per- and polyfluoroalkyl substances (PFASs) are man-made chemicals that contain at least one perfluoroalkyl moiety, –CnF2n–. To date, over 4,000 unique PFASs have been used in technical applications and consumer products, and some of them have been detected globally in human and wildlife biomonitoring studies. Because of their extraordinary persistence, human and environmental exposure to PFASs will be a long-term source of concern. Some PFASs such as perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) have been investigated extensively and thus regulated, but for many other PFASs, knowledge about their current uses and hazards is still very limited or missing entirely. To address this problem and prepare an action plan for the assessment and management of PFASs in the coming years, a group of more than 50 international scientists and regulators held a two-day workshop in November, 2017. The group identified both the respective needs of and common goals shared by the scientific and the policy communities, made recommendations for cooperative actions, and outlined how the science–policy interface regarding PFASs can be strengthened using new approaches for assessing and managing highly persistent chemicals such as PFASs. https://doi.org/10.1289/EHP4158