tbuckley/cabot-search huggingface dataset:
Evaluation of prognostic role of inflammatory index in glioblastoma multiforme patients undergoing to concomitant radio-chemotherapy.
Authors: Valentina Fausti, Flavia Foca, Nada Riva, Alberto Bongiovanni, Lorena Gurrieri, Giandomenico Di Menna, Sebastiano Calpona, Silvia Angela De Bonis, Laura Mercatali, Chiara Spadazzi, Alessandro De Vita, Chiara Liverani, Giacomo Miserocchi, Claudia Cocchi, Monia Dall'Agata, Luigino Tosatto, Antonino Romeo, Dino Amadori, Giovanni Martinelli, Toni Ibrahim
Journal: Journal of Clinical Oncology (2019)

e13549 Background: Hematologic markers of inflammation have been shown to be prognostic in different malignancies. Also in glioblastoma multiforme (GBM) a prognostic role has been demonstrated. The purpose of this study is to evaluate retrospectively the prognostic role of these markers in patients receiving a concomitant radio-chemotherapy after surgery. Methods: Sixty-five GBM patients have been treated with concomitant radio-chemotherapy after surgery at our institute from 2008 to 2017. Information on blood counts were carried out the day before starting therapy and after the day before the last cycle of chemotherapy. Neutrophil/lymphocyte ratio (NLR) and Platelet/lymphocyte ratio (PLR) were computed as the ratio of the absolute neutrophil count and absolute platelet count by the absolute lymphocyte count respectively. Systemic Inflammatory Index (SII) was calculated as platelet count × neutrophil count/lymphocyte count. The optimal cut-point was obtained using X-tile software version 3.6.1. Results: NLR and PLR baseline value didn’t show a statistic a statistically significant prognostic role in PFS or OS. Patients with baseline SII &lt; 480 showed both better PFS and OS (OS: 22.1 VS 11.8 mo p-values 0.0516; PFS: 10.6 VS 5.7 mo p-values 0.0351). Patients aged &lt; 60 years showed better PFS and OS. (PFS 10.3 VS 5.5 p-values 0.0501; OS: 20.6 VS 11.2 mo p-values 0.0124). Statistical significance for SII and age was maintained for both PFS and OS in multivariate analysis as shown in Table 1. Baseline values of NLR PLR and SII have also been correlated with the best response and ORR without showing statistical significance. Conclusions: This restorative study confirms the prognostic value of inflammatory indices in patients with GBM. Correlation analysis with the methylation status of MGMT is ongoing.[Table: see text][Table: see text]
The role of macrophage production of transforming growth factor-ß in epithelial ovarian cancer progression.
Authors: Brandon Roane, Michael J. Birrer, Whitney Goldsberry, Rebecca Christian Arend
Journal: Journal of Clinical Oncology (2019)

e17100 Background: Increased Transforming Growth Factor- ß (TGF-ß) signaling is associated with poorer prognosis in advanced stage epithelial ovarian carcinoma (EOC). Macrophages are known to produce high amounts of TGF-ß which plays a significant role in immune suppression in the tumor microenvironment Methods: A syngeneic mouse model was created using ID8 cell lines with p53 knocked out. These cells were injected intraperitoneally to establish tumor challenge. One mouse model was treated with TGF-ß monoclonal antibody at the time of tumor inoculation. A second model utilized a mouse line that was engineered to eliminate production of TGF-ß from macrophages specifically. Tumors were harvested and weighed after 42 days of tumor challenge. Flow cytometry was used to analyze differences in CD8 T-cell and T regulatory cell populations. Results: Tumor weights were significantly reduced in mice treated with anti-TGF-ß monoclonal antibody (p = 0.02). Average tumor weights were 125mg vs 101mg comparing non-treated to treated mice. Also, ascites volume was measured using syringe aspiration from peritoneal cavity at the time of sacrifice. Mean ascites volume was 4.7mL vs 2.9 mL (p = 0.004) in untreated mice versus mice treated with monoclonal antibody. In mice with macrophages specific deletion of TGF-ß production, tumors were unable to be established in these mice and omental weights were comparable to tumor naive mice with a mean weight of 34mg compared to 115 mg in wild type mice. In both mouse models there was a significant difference in CD8 : Tregs ratio in omental tumor microenvironment. Conclusions: Increased amounts of TGF-ß contribute to increased tumor invasion and migration, while loss of TGF-ß results in both a decrease in tumor burden and a decrease in suppressors of T cell activity. Inhibition of TGF-ß, demonstrated with a monoclonal antibody can effectively reduce TGF-β signaling. The macrophages within the omental tumor microenvironment are a source of large amounts of TGF-ß and when lost result in an inability to establish tumors in intraperitoneal tumors.
A phase I study of veliparib incorporated into front-line platinum based cheotherpy and bevacizumab in epithelial ovarian cancer (NCT00989651): A GOG/nrg trial.
Authors: Deborah Kay Armstrong, Kathleen N. Moore, Austin Miller, Katherine M. Bell-McGuinn, Russell J. Schilder, Paula M. Fracasso, Joan L. Walker, Linda R. Duska, Cara Amanda Mathews, Alice P. Chen, David M. O'Malley, Heidi J. Gray, Roisin Eilish O'Cearbhaill, Saketh R Guntupalli, Andrea R. Hagemann, Carol Aghajanian
Journal: Journal of Clinical Oncology (2019)

5523 Background: Veliparib, a poly-(ADP-ribose)-polymerase inhibitor, increases anti-tumor activity when combined with platinum chemotherapy and has monotherapy activity in BRCA deficient tumors. This study was done to determine the recommended phase II dose (RP2D) of veliparib in combination with front line treatment for epithelial ovarian cancer (EOC). Methods: Eligible patients had newly diagnosed, stage II-IV EOC. Six regimens were evaluated, 3 variations of chemo delivery with either continuous (D1-21) or intermittent (days-2-5) veliparib BID. Chemo included 1: IV q3week carboplatin (C) (AUC 6) and paclitaxel(T) (175mg/m2); 2, IV q3week C (AUC 6) and weekly T(80mg/m2); and 3, IV T (135mg/m2, day 1), IP cisplatin (75mg/m2, day 1 or 2) and IP T (60mg/m2, day 8). Bevacizumab 15mg/kg started cycle 2 and continued as monotherapy cycles 7-22. A 3+3 dose escalation design evaluated dose-limiting toxicities (DLTs) in cycles 1 and 2. Once &lt; 2/6 patients experienced a DLT, that dose level was expanded to evaluate feasibility over 4 cycles. Results: The study accrued 424 treated patients. For regimen 1, continuous (Reg1c) the maximum tolerated dose (MTD) was 250mg veliparib BID but the feasible dose was found to be 150mg BID. For regimen 1, intermittent (Reg1i) the MTD and feasible dose were 400 and 250mg BID respectively. For Reg2c the MTD and feasible dose were the same at 150mg BID. For Reg2i the MTD and feasible dose were 250 and 150mg BID respectively. For Reg3c the MTD and feasible dose are both 150mg BID and for Reg3i, the MTD was 400mg BID and the feasible dose felt to be 300mg BID. Median PFS by residual disease and BRCA status is: (Positive residual disease) 14.6, 19.1 and 16.9 months for BRCA+, BRCAwt and BRCA ukn respectively. For no gross residual disease the PFS is NR, 34.2 and 24.5 months respectively. Conclusions: Given the difficulty with toxicity not defined as a DLT, the RP2D for all regimens is veliparib 150mg BID. This data informed the dose that moved into the phase III trial GOG 3005/Velia: NCT02470585. Velia also incorporated maintenance veliparib instead of maintenance bevacizumab among all high grade serous patients (BRCA+ and wt). These results will determine utilization of veliparib in this space. Clinical trial information: NCT00989651.
Effect of neoadjuvant treatment on locally advanced rectal mucinous adenocarcinoma or signet-ring cell carcinoma: A post-hoc analysis from 3 prospective studies.
Authors: Jianwei Zhang, Yanhong Deng, Yue Cai, Huabin Hu, Zehua Wu, Jiayu Ling
Journal: Journal of Clinical Oncology (2019)

3608 Background: Mucinous adenocarcinoma and signet-ring cell carcinoma were uncommon in locally advanced rectal cancer. And it has been reported that both mucinous adenocarcinoma and signet-ring cell carcinoma showed poor response to standard neoadjuvant chemoradiotherapy. Here, we tried to compare the efficacy of different neoadjuvant treatment regimen on locally advanced rectal mucinous adenocarcinoma or signet-ring cell carcinoma (M/S). Methods: We enrolled patients with locally advanced rectal cancer from 3 prospective clinical trials (NCT01211210, NCT02217020 and NCT02887313), including FOWARC study (N = 309), mFOLFOXIRI neoadjuvant chemotherapy trial (N = 103) and the total neoadjuvant treatment with FOLFOX and radiotherapy (N = 129). Among the 541 patients, 41 (7.6%) patients were M/S and 500 were non-M/S. Totally, 7 M/S patients and 84 non-M/S patients received 5FU concurrent with radiotherapy (Group A), 20 M/S patients and 208 non-M/S underwent FOLFOX concurrent with radiation or total neoadjuvant treatment (Group B), 11 M/S patients and 92 non-M/S patients underwent mFOLFOXIRI neoadjuvant chemotherapy alone (Group C). Other 3 M/S patients and 116 non-M/S patients received FOLFOX neoadjuvant chemotherapy alone (Group D). Results: Among M/S patients, only 4 (9.7%) achieved pathologic complete response (pCR), and 6 (14.6%) patients had tumor downstaging to ypstage 0-I. In group A, the pCR rate was 14.3% and 11.9% (p = 0.85), and the tumor downstaging rate was 14.3% and 36.9% (p = 0.22) in M/S and non-M/S patients, respectively. In group B, the pCR rate was 15.0% and 34.6% (p = 0.07), and the tumor downstaging rate was 25.0% and 60.1% (p = 0.002) in M/S and non-M/S patients, respectively. However, in group C and group D with chemotherapy alone as neoadjuvant treatment, no M/S patients showed pCR or tumor downstaging; while in non-M/S patients higher tumor downstaging rate was observed. Conclusions: M/S showed resistance to neoadjuvant chemotherapy along regimens. Even with chemoradiotherapy, M/S patients showed poorer response than that of non/M/S patients. Further study was warranted to explore the new regimen for M/S patients. [Table: see text]
Randomized phase 3 study of maintenance therapy with S-1 plus best supportive care (BSC) versus BSC alone after induction therapy with carboplatin plus S-1 for advanced or relapsed squamous cell lung carcinoma (WJOG7512L).
Authors: Kaoru Tanaka, Satoshi Morita, Masahiko Ando, Takuma Yokoyama, Atsushi Nakamura, Hiroshige Yoshioka, Takashi Ishiguro, Satoru Miura, Ryo Toyozawa, Tetsuya Oguri, Haruko Daga, Ryo Ko, Akihiro Bessho, Motoko Tachihara, Yasuo Iwamoto, Katsuya Hirano, Yoichi Nakanishi, Kazuhiko Nakagawa, Nobuyuki Yamamoto, Isamu Okamoto
Journal: Journal of Clinical Oncology (2019)

e20531 Background: Our previous phase 3 study established carboplatin plus the oral fluorinated pyrimidine formulation S-1 as a standard option for first-line treatment of advanced non–small cell lung cancer (NSCLC) (J Clin Oncol 2010; 28:5240). The importance of maintenance therapy for patients with advanced squamous NSCLC has been unknown, however. Methods: WJOG7512L was designed as a randomized phase 3 study to evaluate whether maintenance therapy with S-1 improves clinical outcome after induction therapy with carboplatin plus S-1 in such patients. Before randomization, patients received carboplatin (AUC of 5 on day 1 every 3 weeks) plus S-1 (40 mg/m 2 twice per day on days 1 to 14 every 3 weeks) as induction therapy. Those who did not progress after four cycles of induction therapy were randomized to receive either S-1 plus best supportive care (BSC) or BSC alone. The primary objective was to confirm the superiority of S-1 plus BSC with regard to progression-free survival. Results: Of the 365 patients enrolled, 347 participated in the induction phase and 131 of these individuals were randomized to receive S-1 plus BSC ( n = 67) or BSC alone ( n = 64). Baseline demographics and clinical characteristics of the subjects, including the response to induction therapy, were well balanced. Patients receiving S-1 plus BSC showed a significantly reduced risk of disease progression compared with those receiving BSC alone (hazard ratio [HR], 0.548; 95% confidence interval [CI], 0.374–0.802; P = 0.0019). Median overall survival from randomization did not differ significantly between the two arms: 17.8 months for BSC alone and 16.7 months for S-1 plus BSC (HR, 0.890; 95% CI, 0.583–1.357). Time to deterioration in quality of life also showed no significant difference ( P = 0.8754 for FACT-TOI, P = 0.9016 for FACT-LCS). The incidence of adverse events during maintenance therapy was low, with neutropenia, anemia, and thrombocytopenia of grade 3 or 4 each occurring in ~1% to 4% of patients. Conclusions: Maintenance with S-1 plus BSC is an effective and well-tolerated treatment option for patients with advanced squamous NSCLC. Clinical trial information: UMIN000010396.
Abstract 11795: Effect of Targeted Insulin Adherence Interventions for Glycemic Control With Predictive Analytics: The TARGIT-Diabetes Randomized Clinical Trial
Authors: Julie Lauffenburger, Jennifer Lewey, Saira Jan, Sagar Makanji, Christina Ferro, Alexis Krumme, Jessica Lee, Roya Ghazinouri, Niteesh Choudhry
Journal: Circulation (2018)

Introduction: Despite numerous new therapies, the management of cardiometabolic diseases remains suboptimal, in part because of poor adherence. Most adherence improvement interventions are only mod...
Histological growth pattern as a potential prognostic factor in patients operated for breast cancer liver metastases.
Authors: Ali Bohlok, Lara Botzenhart, Valerio Lucidi, Jean Christophe Noel, Pieter Demetter, Denis Larsimont, Vincent Donckier, Peter B. Vermeulen
Journal: Journal of Clinical Oncology (2019)

e12576 Background: Indications for surgery in patients with breast cancer liver metastases (BCLM) remain ill-defined. Recently, the histological growth pattern (HGP), such as desmoplastic (dHGP), associated with angiogenesis and inflammation, or replacement (rHGP), associated with vessel co-option and in the absence of immune infiltrate, has been demonstrated as a significant prognostic factor in patients operated for colorectal liver metastases. In BCLM, the distribution and the prognostic value of HGP are poorly documented. We aimed to characterize HGP in a series of patients undergoing liver resection for BCLM and correlate these patterns with postoperative outcomes. Methods: A consecutive series of 58 patients undergoing liver resection for BCLM was reviewed. Clinicopathologic parameters of these patients were analyzed. HGPs were assessed in archival H&amp;E stained tissue sections, according to international consensus guidelines. The proportions of rHGP and dHGP were determined in each metastasis. In case of multiple metastases, mean HGP was calculated for each patient. Patients were categorized as pure (100% rHGP or dHGP) or dominant phenotype ( &gt; 50% rHGP or dHGP, on the entire tumor/normal liver interface). All these factors were correlated with overall and disease-free survivals (OS and DFS). Results: After a mean follow-up of 81 months, 5-years OS and DFS in global population were 49.7% and 22.7%, respectively. No clinicopathologic preoperative factor was found to be predictive for OS or DFS. HGPs were analyzed in a first set of 21 patients. All patients showed some rHGP component. Of these, 11 were pure rHGP (52.4%), 4 dominant-rHGP (19%) and 6 dominant-dHGP (28.6%). Five-years postoperative OS and DFS were of 19.4 and 18.2% in pure rHGP, as compared with 64.8 and 33.3% in patients with some dHGP component (p = 0.089). Conclusions: rHGP appears as the main phenotype of BCLM. First analyzes suggest that surgery for BCLM with pure rHGP is associated with a worse oncological outcome as compared to BCLM with a dHGP component.
Recent Developments of Supramolecular Metal-based Structures for Applications in Cancer Therapy and Imaging
Authors: Alexander Pöthig, Angela Casini
Journal: Theranostics (2019)

The biomedical application of discrete supramolecular metal-based structures, including supramolecular coordination complexes (SCCs), is still an emergent field of study.However, pioneering studies over the last 10 years demonstrated the potential of these supramolecular compounds as novel anticancer drugs, endowed with different mechanisms of action compared to classical small-molecules, often related to their peculiar molecular recognition properties.In addition, the robustness and modular composition of supramolecular metal-based structures allows for an incorporation of different functionalities in the same system to enable imaging in cells via different modalities, but also active tumor targeting and stimuli-responsiveness.Although most of the studies reported so far exploit these systems for therapy, supramolecular metal-based structures may also constitute ideal scaffolds to develop multimodal theranostic agents.Of note, the host-guest chemistry of 3D self-assembled supramolecular structures -within the metallacages family -can also be exploited to design novel drug delivery systems for anticancer chemotherapeutics.In this review, we aim at summarizing the pivotal concepts in this fascinating research area, starting with the main design principles and illustrating representative examples while providing a critical discussion of the state-of-the-art.A section is also included on supramolecular organometallic complexes (SOCs) whereby the (organic) linker is forming the organometallic bond to the metal node, whose biological applications are still to be explored.Certainly, the myriad of possible supramolecular metal-based structures and their almost limitless modularity and tunability suggests that the biomedical applications of such complex chemical entities will continue along this already promising path.
Prognostic impact of paraneoplastic syndromes in patients with small cell lung cancer, real-world data.
Authors: Gabrielle Picard Leblanc, Normand Blais, Mustapha Tehfe, Bertrand Routy, Marie Florescu
Journal: Journal of Clinical Oncology (2019)

e20082 Background: Small cell lung cancer (SCLC) remains an aggressive cancer, with a reported mOS of 15-20 mo when localized (L-SCLC) and 9-11 mo when extensive (E-SCLC). Paraneoplastic syndromes (PNS) are a debilitating condition either related to the embryogenic stem cell origin or to auto-immune antibodies produced against the tumor. These mechanisms may be even more relevant with the use of immunotherapy for first-line treatment of E-SCLC. Methods: We retrospectively reviewed our clinical database of patients diagnosed with SCLC between 2006 and 2017 at CHUM University Center. The primary outcome was to compare OS of patients with and without PNS in L-SCLC and E-SCLC. No patients received immunotherapy. Results: We identified 426 unselected SCLC patients, 39% L-SCLC and 61% E-SCLC. 84 patients (20%) were diagnosed with a PNS: 66 (15%) SIADH, 8 (2%) paraneoplastic Cushing syndromes, 2 (1%) humoral hypercalcemia and 8 (2%) paraneoplastic neurologic syndromes. 25% of patients with PNS vs 14% without PNS had a PS 3-4 and would not have been eligible to a clinical trial. 65% of patients with PNS received chemotherapy vs 63% without PNS. Neurologic PNS were all diagnosed in patients with L-SCLC. PNS affecting the central nervous system (4 limbic encephalitis and 1 cerebellar degeneration) were associated with a poorer prognosis than L-SCLC without PNS (mOS 3,5 mo vs 16,7 mo (p = 0,003)). The 2 patients with Lambert-Eaton myasthenic syndrome had a long survival (29 and 82 mo), but persistence of the neurologic symptoms. 86% of patients with paraneoplastic Cushing syndrome were diagnosed with an E-SCLC and had a worse prognosis than E-SCLC without PNS (mOS 1,1 mo vs 4,63 mo (p = 0,022)). SIADH had a significative poor impact on OS in patients with L-SCLC (mOS 10,1 mo vs 16,7 mo (p = 0,016)), but no impact in survival for patients with E-SCLC (mOS 3,63 mo vs 4,63 mo (p = 0,735)). Conclusions: PNS either in patients with L-SCLC or E-SCLC worsen the overall prognosis, except for Lambert-Eaton myasthenic syndrome. A more systematic detection of these syndromes is suggested before starting immunotherapy as first-line standard treatment for E-SCLC. Furthermore, this real-world unselected clinical cohort shows our E-SCLC patients have a worse prognosis than the clinical trial experience.
Colorectal cancer molecular subtypes by immunohistochemistry in a patient cohort from Nigeria.
Authors: F Biade Abdulkareem, Galina Khramtsova, Babatunde Adedokun, Olorunda Rotimi, Kunle Abudu, Kabir Badmos, Abiola Falilat Ibraheem, Andrey Khramtsov, Lise Sveen, Ian Hurley, Hattori Masaya, Dezheng Huo, Olufunmilayo I. Olopade
Journal: Journal of Clinical Oncology (2019)

e15145 Background: Colorectal cancer (CRC) classificationusesclinico-pathological characteristics. However, patients with similar histologic features and tumor stages have different clinical outcomes and drug responses. Studies of CRCmolecular heterogeneity have used genome-wide gene-expression data to classifypatients into four consensus molecular subtypes (CMS), but the complexity of analysis has limited its use in practice. Methods: With IRB approval, tissue microarray (TMA) blocks were constructed, IHC was performed and semi-quantitative scores completed. For the MMR proteins, MLH1 (Pierce), MSH2 (LifeTechnologies), MSH6 (Novex), PMS2 (Pierce) antibodies were used. Three markers were selected from transcriptomic analysis for IHC: CDX2 (LifeTechnologies), HTR2B (LifeTechnologies), and ZEB1 (eBioscience). Ki-67 (DAKO) proliferation rate was used as anequivalent marker for β-catenin activation.The CMS1 subtype was first separated using MSI/MSS status. A panel of CDX2, HTR2B, and ZEB1was then used to distinguish between CMS4 and CMS2/CMS3 subtypes, while Ki-67 was used to separate CMS2 from CMS3 subtype. Results: Of the total evaluable 75 CRC cases(mean age 44.8 years (SD = 16.1), 38% were &lt;40 years old, and 60% were males. Of tumors with data on tumor grade (n=66), 62% were well differentiated. 59 patients (79%) had MSS, and the remaining16(21%) had MSI (i.e. CMS1). 22 (29%) patients with increased ZEB1 and lower CDX2 expression were classified as CMS4. 37 (49%) displayed increased CDX2 and lower ZEB1 expression and were classified as CMS2 (n=24) or CMS3 (n=13). HTR2B was universally expressed, but a higher median HTR2B score of 3 was observed in CMS4 cases compared to 1 for other subtypes (p=0.0001). The CMS4 subtype was significantly more likely to occur among young patients (p&lt;0.001): in patients &lt; 40 years, 70% of patients were CMS4 subtype, while in patients &gt; 40, 7% were CMS4 subtype. Of the left-sided cancers, only 5% were CMS1 subtype, while CMS1 composed 75% of right-sided cancers (p&lt;0.001). Conclusions: Using TMAs and a panel of antibodies, we show an association of a poorer prognostic subtype (CMS4) with younger age at diagnosis. IHC-based classification and screening could be a cost effective prognostic and predictive tool for Nigerian reference laboratories.