tbuckley/cabot-search huggingface dataset:
Clinical observation of nab-paclitaxel plus S-1 as first-line chemotherapy for advanced gastric cancer.
Authors: Yi Hu, Danyang Sun
Journal: Journal of Clinical Oncology (2017)

e15554 Background: Gastric cancer is the third leading cause of death in the world with poor prognosis. Until recently, no standard treatment was available for patients with advanced gastric cancer in the first-line setting. Nab-paclitaxel and S-1 were both proved to have antitumor activity in many solid tumors including gastric cancer. We aimed to evaluate the efficacy and tolerance of nab-paclitaxel in combination with S-1. Methods: Patients with unresectable or recurrent gastric cancer received combination therapy of nab-paclitaxel plus S-1 every 3 weeks as one cycle. Nab-paclitaxel was administered at total dose of 260mg/ m 2 on day 1 and 5 or on day 1 and 8. S-1 was given orally twice a day for 14 days, the doses were assigned according to body surface area. S-1 alone was administered as maintenance therapy after 6 to 8 cycles of combination therapy until disease progression. Results: Among the 33 patients enrolled, 28 patients (84.8%) had KPS 90, one third of patients were recurrent after gastrectomy. They received an average of 5.7 cycles of combination treatment. The median PFS was 6.6 months (95%CI, 5.557-7.716 months). The overall response rate was 51.5%, with one CR, 16 PR, 16 SD, and no PD. The median overall survival time was not obtained at the time of analysis. In safety profile, the highest incidence rate of grade 3 and grade 4 adverse events was neutropenia (12.1%). Conclusions: The combination of nab-paclitaxel plus S-1 was well tolerated and presented antitumor efficacy which may be a new therapeutic option for patients with advanced gastric cancer.
Characterisation and treatment of patients with castration-resistant metastatic prostate cancer (mCRPC) developing neuroendocrine clonal divergence (NCD): A case series.
Authors: Thomas Bauernhofer, Jelena Belic, Martin Pichler, Angelika Bezan, Ellen Heitzer, Jochen Bernd Geigl, Herbert Stoger, Michael Speicher, Maria Anna Smolle
Journal: Journal of Clinical Oncology (2017)

e16520 Background: The introduction of Abiraterone (Abi) and Enzalutamide (Enza) into treatment of mCRPC has led to a survival benefit. However, in a subset of patients treated with Enza/Abi, rapidly progressive disease with atpical metastatic spread develops. According to Eric Small et al. (ASCO 2015 Abstract 5003), 39% of metastases in mCRPC-patients treated with Enza/Abi have small cell neuroendocrine or mixed type histologies. Based on these findings we aimed at characterising NCD in a case series of 8 patients using 1) clinical, laboratory, radiological parameters, 2) molecular features generated by liquid biopsy and 3) to present outcome variables after treatment of these patients with combination chemotherapy carboplatin/etoposide (CE). Methods: Clinical, radiological, laboratory parameters, whole-genome sequencing of cfDNA (PlasmaSeq) and ctDNA taken at different time points during treatment were ascertained from 8 mCRPC-patients with NCD. Results: All patients presented with rapid tumour progression and atpical metastatic spread (3x liver, 3x lungs, 1x skin, 1x adrenal glands) during treatment with Enza/Abi. Laboratory findings revealed marked increase in CRP, AP and LDH levels and elevation of NSE ( &gt; 5x times upper normal limit), whilst PSA levels were low or declining. All patients received Carboplatin AUC5 day 1 and Etoposid 100 mg/m3 day 1-3 q3w. In 7 out of 8 patients, initially high levels of CRP, LDH, AP and NSE decreased under CE therapy. Very good partial response on radiological examination was observed after 3-6 cycles of CE in these patients. One patient had progressive disease. Copy number profiles of ctDNA taken peri-interventionally revealed loss of androgen receptor and a clonal shift in comparison to profiles taken during endocrine treatment phase. Conclusions: Rapid clinical and radiologic progression, atypical metastases and sharp rise in LDH, CRP, AP and NSE levels combined with low PSA are indicative of NCD. For these patients, CE-based chemotherapy is a promising treatment option. In order to identify clonal shift from adenocarcinoma to neuroendocrine cancer, genetic profiling using ctDNA may be of use.
Preclinical effect of selinexor (KPT-330), a selective inhibitor of nuclear export, in pediatric rhabdoid tumors.
Authors: Lianna Jean Marks, Daniel Diolaiti, Prabhjot Singh Mundi, Ervin Gaviria, Allison Rainey, Filemon Dela Cruz, Andrea Califano, Andrew Kung
Journal: Journal of Clinical Oncology (2018)

10552 Background: Malignant rhabdoid tumors (MRTs) are rare, aggressive pediatric solid tumors characterized by a 22q11 chromosome rearrangement that inactivates the SMARCB1 gene. Outcomes remain poor despite multimodality treatment. MRTs are among the most genomically stable cancers and lack therapeutically targetable genetic mutations. We used the Virtual Inference of Protein-activity by Enriched Regulon analysis (VIPER) algorithm to computationally infer protein activity from MRT whole transcriptomic data available in the TARGET database to identify candidate non-genetically encoded vulnerabilities. This approach identified markedly aberrant activation of the nuclear export protein Exportin-1 (XPO1) in MRTs compared to other tumor types. We hypothesized that MRTs may be dependent on high XPO1 activity and this dependence can be co-opted as a novel non-oncogene directed therapeutic approach using the XPO1 inhibitor selinexor. Methods: A panel of 6 MRT and 3 atypical teratoid/rhabdoid tumor (ATRT) cell lines were used for in vitro studies. Two patient-derived xenograft (PDX) mouse models of MRT were treated with selinexor to determine anti-tumor effects. Results: All MRT cell lines demonstrated marked baseline activation of XPO1. The median IC50 following 72 hour selinexor treatment was 200 nM (IQR 175-435 nM) for MRT, 460 nM (IQR 400 nM-1.4 μM) for ATRT and 1.1 μM (IQR 580 nM-1.4 μM) for 5 non-MRT cell lines. There was a correlation between inferred XPO1 activity and IC50 with cell lines with the highest inferred activity being the most sensitive to selinexor. Treatment with selinexor in vitro led to cell cycle arrest and induction of apoptosis in MRT cell lines. Post-perturbation RNAseq of selinexor treated cell lines with VIPER dynamic protein activity inference demonstrated decreased activity of XPO1, SWI/SNF complex proteins, kinetochore regulators and cell cycle regulators. In vivo treatment of two MRT PDXs with oral selinexor for 15 days significantly inhibited tumor growth in both models (p < 0.0001 and p = 0.0002). Conclusions: Selinexor demonstrates efficacy in preclinical models of MRT. These results supports further investigation of selinexor in a phase II study in children with MRT.
Long-term survival of adults with B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) after treatment with blinatumomab and subsequent allogeneic hematopoietic stem cell transplantation (HSCT).
Authors: Max Topp, Anthony Selwyn Stein, Gerhard Zugmaier, Hervé Dombret, Monika Brueggemann, Massimiliano Bonifacio, Xiaoyu Dong, Hagop M. Kantarjian, Ralf C. Bargou, Nicola Gökbuget
Journal: Journal of Clinical Oncology (2018)

7044 Background: In BCP-ALL, blinatumomab has demonstrated efficacy in two phase 2 trials: MT 103 -203 (Gökbuget et al, Blood 2017) in minimal residual disease (MRD) and MT 102 – 211 in relapsed/refractory (R/R) disease (Topp et al Lancet Oncology 2104). We describe the long-term outcomes after blinatumomab followed by HSCT. Methods: Survival after blinatumomab and HSCT in continuous complete remission (CCR) was evaluated. In the MRD trial, 116 patients between Nov 2010 and Feb 2014 were treated with blinatumomab; in the R/R trial, 189 patients between Jan 2012 and Oct 2013 were treated. Follow up in both trials continued through 2017. Results: Most patients with HSCT in CCR in the MRD trial were >35 yrs of age whereas those in the R/R trial were younger (Table). After follow up of at least 3 yrs in the MRD trial of patients ≤35 yrs, 16/26 (62%) were alive with HSCT vs 2/9 (22%) for non-HSCT; in patients >35 yrs, 19/48 (40%) and 13/27 (48%) were alive with HSCT and for non-HSCT, respectively. Median overall survival (OS) from HSCT was not reached in patients ≤35 yrs in either trial (Table). Conclusions: These results suggest that in transplant-eligible patients in CCR, HSCT following blinatumomab is a potential option. Clinical trial information: NCT01466179, NCT01207388.Patients with on-study HSCT in CCR. MT 103 -203 N=74b n (%) MT 103 -211 N=34 n (%) Characteristics Age, n (%), yrs ≤35 26 (35) 19 (56) >35 to 55 29 (39) 9 (26) >55 19 (26) 6 (18) Median (range) 43 (18, 67) 31 (18, 65) Donor Related, n (%) 19 (26)a 8 (23) Unrelated, n (%) 53 (72) 23 (68) Matched, n (%) 20 (27) 9 (26) Unmatched 23 (31) 10 (29) Unknown, n (%) 6 (8) 3 (9) Cord 4 (5) 1 (3) Unknown, n (%) 2 (3) 3 (9) Conditioning regimen Myeloablative 32 (43) 15 (44) Reduced intensity/nonmyeloablative 35 (47) 12 (35) Unknown 7 (20) 7 (21) 100-day mortality after HST, n (%)c 5 (7) 4 (12) Outcomes Median OS from HSCT, months Age ≤35 yrs NE NE Age >35 yrs 25.7 15.9 Median RFS from HSCT, months Age ≤35 yrs NE 16.4 Age >35 yrs 15.5 15.9 NE, not estimable. a 1 haploidentical. b 74 patients received on-study HSCT in CR; Ph+ and patients not in CR at treatment start excluded. c No VOD-related deaths. Study Sponsored by Amgen.
Prevalence and complications associated with off-label use of lenalidomide in older patients with myelodysplastic syndromes (MDS).
Authors: Andrew Mark Brunner, Shicheng Weng, Angel M. Cronin, Amir Tahmasb Fathi, Richard M. Stone, Timothy A. Graubert, David P. Steensma, Gregory A. Abel
Journal: Journal of Clinical Oncology (2017)

7054 Background: Lenalidomide (LEN) is approved for patients with lower-risk MDS with del5q who are transfusion-dependent (TD). We aimed to assess the prevalence and complications associated with LEN use in non-TD older patients with MDS. Methods: Using the SEER-Medicare database we identified Medicare enrollees diagnosed with MDS from 2007-2011. Medicare part D claims were analyzed for evidence of LEN use. CPT, HCPCS, and ICD-9 codes were used to characterize TD MDS (claims for ≥ 2 RBC transfusions within 8 weeks prior to LEN), complications, and baseline risk per SEER-Medicare MDS Risk Score (SMMRS; Uno, Leuk Res 2014). Incident complications during LEN were noted if there were no prior claims for the same within a 1-yr look-back window. Results: Among 469 patients initiating LEN (median age 78 years), 77% received it first-line, and 23% after a hypomethylating agent. Among all, 19% had del5q, 37% had non-del5q MDS, and 44% no histology specified (MDS NOS). SMMRS risk was evenly distributed between low (36%), intermediate (30%), and high (34%). Only 42% of patients were TD at the time of first LEN prescription, and 26% had not been transfused within six months prior to LEN. Non-TD patients receiving LEN were more likely to have lower-risk disease (p = .004), and less likely to have pre-treatment thrombocytopenia (p = .005) or neutropenia (p = .003); they did not differ significantly in age (p = .85), documentation of del5q (p = .51), comorbidity (p = .65) or treatment center volume (p = .80). Median days on LEN for the non-TD was 121. Incident complications post-LEN among the non-TD are shown. Conclusions:These data suggest there is widespread off-label use of LEN in older patients with MDS, as many receive the drug who are not TD. Moreover, off-label exposure to LEN in these patients is associated with a sizable risk of incident complications, which is difficult to justify given they are already living free of transfusion dependence. [Table: see text]
TCT-11 Assessment of the adenosine-dependent hyperemic response during the subacute phase of a myocardial infarction: insights for FFR-guided coronary revascularization in non-infarcted-related arteries
Authors: Hernan Mejia-Renteria, Joo Myung Lee, Nina van der Hoeven, Guus de Waard, Nieves Gonzalo, Pilar Jimenez-Quevedo, Luis Nombela-Franco, Ivan Nuñez-Gil, Pablo Salinas, Maria Del Trigo, None Tania Rodriguez Gabella, Niels van Royen, Paul Knaapen, Bon-Kwon Koo, Carlos Macaya, Antonio Fernandez-Ortiz, Javier Escaned
Journal: Journal of the American College of Cardiology (2018)
Adjuvant radiation therapy to induce a transitory adaptive up-regulation of programmed death ligand 1 (PD-L1) on circulating epithelial tumor cells (CETCs) to affect the anti-tumor immune response in primary breast cancer patients.
Authors: Dorothea Schott, Monika Pizon, Katharina Pachmann, Ulrich A. Pachmann, Matthias Maeurer
Journal: Journal of Clinical Oncology (2017)

11558 Background: Radiation therapy (RT) is an integral part of the treatment of breast carcinoma but unfortunately many patients experience local recurrence. During the inflammatory response that accompanies radiation tumor cells may develop multiple resistance mechanisms for example the up-regulation of PD-L1 on tumor cells which leads to immune evasion. Since CETCs arise from the tumor it is conceivable that under evolutionary pressure they might share some of the immune escape mechanism inherent to tumor cells. In this study we demonstrate that RT leads to a transitory adaptive up-regulation of PD-L1 expression on CETCs. Methods: CETCs and the expression of PD-L1 and Ki-67 were analyzed from 25 patients with primary non-metastatic breast cancer using the maintrac method. The fraction of PD-L1 and Ki-67 positive CETCs were assessed at baseline, 3 and 6 weeks after start of RT and 6 weeks after end of therapy. Additionally, copy number status of PD-L1 was determined using FISH. Results: Fractionated-dose RT leads to a significant increase in PD-L1 expression on CETCs with the highest expression level midterm of irradiation as compared to baseline (49% vs. 74%, p &lt; 0.01). 6 weeks after end of RT the number of PD-L1 positive CETCs returned to baseline value. The up-regulation of PD-L1 was dose dependent. Patients who received higher total dose had significantly more PD-L1 positive CETCs as compared to patients treated with lower total dose midterm of RT (64% vs. 43, p &lt; 0.05). Before start of therapy there was a correlation between the fraction of PD-L1 and Ki-67 positive CETCs (r = 0.6, p &lt; 0.01). PD-L1 copy number gains were significantly associated with PD-L1 expression (r = 0.6, P &lt; 0.05). Conclusions: RTleads to an up-regulation of PD-L1 expression on CETCs, which could be a possible mechanism of acquired radioresistance. Combining immunomodulatory agents with radiation might have the potential to overcome this resistance and could improve clinical outcome in breast cancer.
Lengthy Progression-Free Survival and Intracranial Activity of Cabozantinib in Patients with Crizotinib and Ceritinib-Resistant ROS1-Positive Non–Small Cell Lung Cancer
Authors: Thomas Yang Sun, Xiaomin Niu, Amit Chakraborty, Joel W. Neal, Heather A. Wakelee
Journal: Journal of Thoracic Oncology (2018)
Patients with myeloproliferative neoplasms (MPN) who later develop <i>ph</i>+ chronic myelogenous leukemia (CML): A case series.
Authors: Shahina Patel, Seo-Hyun Kim, Jamile M. Shammo, Jerald P. Radich, Howard R. Terebelo
Journal: Journal of Clinical Oncology (2017)

e18563 Background: Myeloproliferative Neoplasms are divided by the presence or absence of the Philadelphia Chromosome. Ph- MPN, typically possess driver mutations of JAK-2, MPL and CALR. CALR is involved with apoptosis and cell proliferation . MPL leads to TPO receptor stimulation and mutations are reported as a known cause of AA. JAK-2 mutations render hematopoietic stem cells more sensitive to growth. Though the true incidence is unknown, there are infrequent reports of pts with ET who later develop CML. CALR, MPL and JAK-2 mutations may have some further role in determining whether these are two separate events or clonally derived. We report three pts with MPN who later developed CML. Methods: Chart Review Results: Pt 1 had ET, diagnosed 21 yrs earlier treated with hydroxyurea. He then developed a rising WBC and platelets which necessitated a marrow which detected Ph+ CML. He was CALR positive. NGS was negative for nondriver mutations. Platelets initially declined from 3 million to 975K with TKI and he achieved a MMR. However, the inability to control his thrombocytosis required the addition of ruxolitinib. Pt 2 was diagnosed with ET and was treated with P 32 . Nine yrs later CML was diagnosed and TKI administration achieved a MMR. Subsequently, a profound anemia evaluation diagnosed PNH requiring eculizumab without benefit and repeat marrow with NGS revealed a MPLmutation and post-ET myelofibrosis. Pt 3 presented with a JAK-2 positive mutation and Polycythemia Vera. After four yrs of hydroxyurea extreme leukocytosis led to a marrow revealing a diagnosis of Ph+ CML. Dasatinib achieved a prompt MMR. NGS revealed KIT D618 V , coinciding with a diagnosis of systemic mastoytosis (SM). Conclusions: The rare observation of patients with both ET and CML have been reported by others with some recent implications of CALR as a common clone with double-mutant properties of CML. Our patients had a lead time of 21, 9, and 4 yrs, all having different mutations. Pts with MPN who develop unexplained leuko or thrombocytosis should be evaluated for CML.We plan to retrieve archival tissue to perform serial genetic analyses. Further work is required to determine whether these events are stochastic or represents clonal evolution.
Management of platinum-sensitive recurrent ovarian cancer (PSROC) in the era of biologics: Can ASCO’s net health benefits (NHB) inform our decisions?
Authors: Jonathan Foote, Laura Jean Havrilesky, Elizabeth Lin Jewell, Charlotte Gamble, Jessie Ehrisman, Gloria Broadwater, Robert L. Coleman, David E. Cohn, Angeles Alvarez Secord
Journal: Journal of Clinical Oncology (2017)

5544 Background: The ASCO value framework allows assessment of novel cancer therapies based on NHB. We assessed novel biologic therapies in the management of PSROC. Methods: ASCO’s revised value framework NHBs were constructed for key therapies based on randomized clinical trials for PSROC. BRCA-germline and HRD status were included. Additionally, patient-centered NHB calculations were weighted based on results from a prospective patient preferences study (n=54) and compared to ASCO-based NHB. Results: ASCO-centered NHB calculations were: platinum + taxane-based chemotherapy (ICON4) = 35; carboplatin + liposomal doxorubicin (CALYPSO) = 22; platinum-based chemotherapy + bevacizumab (OCEANS = 35; GOG 213 = 26). NHB scores based on germline-BRCA alterations were maintenance niraparib (NOVA) = 50 and maintenance olaparib (Study 19) = 62; wild-type BRCA, maintenance niraparib = 36 and maintenance olaparib = 33; and HRD-positive status, maintenance niraparib = 42. Patients valued clinical benefit as the most important component of NHB. Patients valued OS as the most important component of clinical benefit, followed by response rate (RR), then PFS. Patient-weighted NHB were significantly lower than ASCO-weighted scores (mean NHB 37.8 versus 23.5; p=0.009) due to decreased preference for PFS compared to other clinical benefit measures (Table). Conclusions: NHB scores for treatment of PSROC were highest in women with germline-BRCA and HRD tumor alterations who were treated with maintenance PARPi. Our data suggest that a patient-centered NHBs can be used to inform treatment decisions. [Table: see text]
P05.04 Intramedullary spinal cord tumours - a single centre ten year analysis
Authors: O Richards, E Goacher, C Derham
Journal: Neuro-Oncology (2018)

Intramedullary spinal cord tumours are relatively rare tumours of the central nervous system. Surgical outcomes are affected by many variables, including pre-operative neurological function, tumour histology and extent of resection. Emphasis remains on surgical treatment due to the limited adjunctive therapeutic options and poor drug penetration. 49 patients were identified from a surgical database. Variables collected included pre-and post-operative Frankel Grade and Modified McCormick Scale assessments, tumour histology, extent of resection and length of follow up. Chi-Squared, Kaplan-Mier Survival and Mann-Whitney U-Tests were completed. Ependymoma, Haemangioblastoma and Pilocytic Astrocytoma were the commonest tumour histologies. In total 21 different histological tumours were identified in the series. There was a statistically significant relationship between identification of the tumour plane and extent of resection (p<0.01), along with the extent of resection and recurrence (p<0.01). Compared to the other histological subtypes, ependymoma’s demonstrated a significantly greater extent of resection (p=0.02). There was a significant relationship between the grade of tumour and progression free survival (p<0.01). We did not find a significant relationship between pre- and post-operative neurological function and survival. Tumour plane and the extent of tumour resection are significant determinants of progression free survival. Ependymoma, whilst being the commonest histology in our series were also the most resectable. Whilst complete resection reduces the rate of recurrence, tumour grade is the most important predictor of outcome.
Patterns of canonical and non-canonical TGFβ signaling in inflammatory breast cancer cells on cancer cell motility.
Authors: Charlotte Rypens, Melike Marsan, Patrick Neven, Peter B Vermeulen, Filip Lardon, Marc Peeters, Luc Dirix, Jean Vandebroek, Steven J Van Laere
Journal: Journal of Clinical Oncology (2016)

e23008 Background: Inflammatory breast cancer (IBC) is rare and aggressive type of breast cancer, characterized by its rapid invasion and spread. Recent evidence suggests that TGFβ signaling may be an important driver of the disease. Here, we describe data from patient samples and preclinical models that corroborate this hypothesis. Methods: The xCELLigence system was used to profile a series of subtype-matched IBC and non-IBC (nIBC) cell lines for the cell motility inducing capacity of 11 chemokines. Significant results were confirmed using wound healing assays (WHA). RNAseq was performed on the same cell lines after TGFβ1 treatment at either 1 hr, 4 hrs or 14 hrs. Using immunohistochemistry (IHC), a series of 79 IBC and 133 nIBC patient samples was evaluated for nuclear SMAD2 and -3 protein expression. In a subseries of these samples, protein and gene expression data were integrated and significantly correlated gene sets were translated into signal transduction networks. Expression2Kinases was used to identify key components of TGFβ signaling in IBC. Results: Whereas TGFβ induced cell motility in all nIBC cells, we noted an 18-fold reduction of cell motility in IBC cells. These results were confirmed using WHA. RNAseq revealed a SMAD3-dependent, transcriptional program in nIBC cells, while in IBC cells, target genes of MYC were found to be overexpressed. IHC demonstrated an attenuated SMAD3 nuclear staining, combined with an increased SMAD2 nuclear staining. When integrating protein and gene expression data, we revealed that absence of SMAD3 activity in samples from patients with IBC correlates with elevated transcriptional activity of MYC and that increased nuclear SMAD2 expression was linked to activation of the classical TGFβ signaling pathway. Conclusions: We show that IBC cells do not induce cell motility in response to TGFβ stimulation. This observation can be explained by impaired non-canonical TGFβ signaling in IBC, which is essential for SMAD3-driven epithelial to mesenchymal transition (EMT). SMAD2 on the other hand is a proven driver of EMT-independent modes of cell motility. Our results strengthen the vision that EMT is not required for IBC cell invasion.