tbuckley/cabot-search huggingface dataset:
Toxicities of tyrosine kinase inhibitors: Occurrence of hemoptysis and tracheo-oesophageal fistula in 150 patients with advanced thyroid cancer.
Authors: Livia Lamartina, Serena Ippolito, Amandine Berdelou, Abir Al Ghuzlan, Isabelle Borget, Sophie Leboulleux, Dana Hartl, Haitham Mirghani, Pierre Blanchard, Desiree Deandreis, Martin Schlumberger, Eric Baudin
Journal: Journal of Clinical Oncology (2014)

6077 Background: Anti-angiogenic Tyrosine Kinase Inhibitors (TKI) represent the main systemic treatment for patients with refractory advanced thyroid cancer (TC), but may induce severe adverse events. Methods: The objective is to determine the incidence and risk factors of hemoptysis (H) or tracheo-oesophageal fistula (TOF) in TC patients during TKI treatment. Subjects and methods: A retrospective analysis of all advanced TC patients treated with TKI between 2004 and 2013 at Gustave Roussy, was performed. 150 patients were enrolled (94 M; median age at initiation of the first TKI treatment: 60 yr), 85 (57%) with medullary TC and 65 (43%) with differentiated TC (28 papillary, 20 follicular and 17 poorly differentiated). Total thyroidectomy was performed in 133 (89%) patients, and neck and mediastinum external beam radiation therapy (ERBT) in 44 patients (median dose 60 Gy). Tracheal invasion (TI) was present at initiation of TKI treatment in 32 (21%) cases and was evidenced in 7 patients by CT scan, in 3 by fibroscopy, in 10 with both techniques, and in 12 as an intra-operative finding. No patient disclosed H before initiation of TKI treatment (H within one month is an exclusion criteria in all trials). Patients received from 1 to 4 lines of TKI treatments (median 1). Median follow-up after the initiation of the first TKI treatment was 24 months. Occurrence of mild (grade 1 or 2) or severe (grade 3 to 5) H or TOF according to CTCAE v 4 were collected. Risk factors for H/TOF were investigated. Results: Grade 1-2 H occurred in 10 patients (7%) all aged ≥45 yr and was associated with TI in 7 [p 0.0008], EBRT in 7 [p 0.007], and differentiated TC in 9 [p 0.002]. Grade 3-5 events occurred in 3 (2%) patients (TOF in 1 case and fatal H in 2 cases), all with known TI. One fatal H and the TOF were preceded by grade 1-2 H. No significant relationship with age, gender, EBRT, surgery, pathology or number of TKI lines was found for grade 3-5 events. The rate of grade 3-5 event was 9% in patients with TI [p 0.0008]. Conclusions: Grade 3-5 H/TOF occurred during TKI treatment in 9% and grade 1-2 in 22% of patientswith known TI even in the absence of H prior to TKI treatment. This should lead to a careful use of TKI in these patients.
Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of necuparanib combined with nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer: Phase 1 results.
Authors: Eileen Mary O'Reilly, Devalingam Mahalingam, James M. Roach, Birgit Corinna Schultes, Molly E. Rosano, Paul Justin Miller, Julie Wolf, Keith Flaherty, David P. Ryan
Journal: Journal of Clinical Oncology (2015)

4114 Background: Preclinical studies have shown necuparanib (necu)'s ability to bind growth factors, adhesion molecules, and chemokines to inhibit tumor progression, invasion, metastasis, and angiogenesis. Necu is being evaluated in a phase I/II trial with nab-paclitaxel (nabP) + gemcitabine (gem) in patients (pts) with metastatic pancreatic cancer (ClinicalTrials.gov NCT01621243). Part A is an open-label safety/pharmacokinetic (PK)/pharmacodynamic (PD) study to determine a Part B dose; Part B will evaluate efficacy, safety, and PK/PD relative to nabP + gem. Methods: In Part A, necu was given as daily escalating s.c. doses in combination with i.v. 125 mg/m2 nabP and 1000 mg/m2 gem (Days 1, 8, 15 of each 28-day cycle). The necu start dose was 0.5 mg/kg, with escalation via a modified 3+3 design until the maximum tolerated dose (MTD) was determined. The protocol was amended to include nabP after 2 necu + gem cohorts were completed. Results: As of January 15, 2015, 39 pts in 7 cohorts (0.5 and 1 mg/kg + gem; 1, 2, 4, 6, and 5 mg/kg + nabP + gem) received necu. Two dose-limiting toxicities (DLTs) occurred: increased AST/ALT at 0.5 mg/kg necu (N = 1) and cellulitis at injection site at 6 mg/kg (N = 1). Mild aPTT increases were observed at 4-6 mg/kg. There were no increases in known AEs of chemotherapy across doses. PK data (Cmax, AUC) increased linearly from 2 mg/kg. Release of heparin-binding proteins (e.g. HGF, a PD marker) from heparan sulfate stores increased with dose and plateaued at 4-5 mg/kg. Given the cellulitis and mild aPTT increases at 6 mg/kg, 5 mg/kg was considered MTD. 16 pts treated with necu + nabP + gem completed Cycle 1 and had ≥ 1 scan on treatment; 8 (50%) achieved RECIST partial response and 6 (38%) more achieved stable disease, for an overall disease control rate of 14/16 (88%). Of 15 CA19.9 evaluable pts, 15 (100%) had > 20%, 14 (93%) had > 50%, and 7 (47%) had > 90% decreases from baseline. Conclusions: The MTD was necu 5 mg/kg combined with nabP + gem. Acceptable tolerability and encouraging signals of activity were observed with the combination. These results supported the initiation of the randomized, double-blind, phase II trial. Clinical trial information: NCT01621243.
The effect of cerebellar tumor resection on pain perception in pediatric patients.
Authors: Katie E. Silva, Julia Rosner, Nicole A. Ullrich, Christine Chordas, Lino Becerra, Peter E. Manley, Eric A. Moulton
Journal: Journal of Clinical Oncology (2017)

126 Background: Acute cerebellar infarctions have been shown to lead to affective and cognitive deficits in pediatric patients. However, the consequences of cerebellar insult on pain processing are unknown. Recent evidence not only suggests that the cerebellum plays a role in affective processing, but it also demonstrates increased activity in this area when individuals experience experimental or clinical pain, particularly in the posterior cerebellum. The goal of this study is to evaluate the effect of cerebellar resection of low-grade astrocytomas in children on pain perception. Describing the impact of this treatment may be of particular importance in children, as it may alter sensory development into adulthood. Methods: Twelve pediatric patients treated with surgery only for non-malignant astrocytomas (mean age = 13.78 ± 5.64) and ten age-, gender-, race- and handedness-matched healthy controls (mean age = 14.52 ± 5.96) were evaluated using quantitative sensory testing and magnetic resonance imaging, comprising diffusion tensor imaging, resting state and event-related functional MRI scans. Five of these patients had tumors localized to the posterior cerebellar hemispheres. The psychophysical measures assessed included heat and cold detection thresholds (HDT, CDT), heat and cold pain thresholds (HPT, CPT), and cold pain tolerance using a cold pressor task. Results: Patients with lesions in the posterior cerebellum (n = 5) were shown to have a significantly lower tolerance to the cold pressor test than controls (n = 10). No significant differences were detected for the threshold measures. This suggests increased pain sensitivity in these patients to suprathreshold noxious stimuli compared to controls. Patients with lesions that did not include the posterior cerebellar hemispheres (n = 7) did not show significant differences with controls in terms of cold pain tolerance or thresholds. Conclusions: The differences in cold pain tolerance between patients and controls are presumed to result from damage to the posterior cerebellar hemispheres, potentially interfering with the modulation of pain pathways. Analysis of the preliminary imaging data is underway and recruitment is ongoing. Support: NIH/R21CA185870(EM)
The Role of PIAS SUMO E3-Ligases in Cancer
Authors: Andrea Rabellino, Cristina Andreani, Pier Paolo Scaglioni
Journal: Cancer Research (2017)

SUMOylation modifies the interactome, localization, activity, and lifespan of its target proteins. This process regulates several cellular machineries, including transcription, DNA damage repair, cell-cycle progression, and apoptosis. Accordingly, SUMOylation is critical in maintaining cellular homeostasis, and its deregulation leads to the corruption of a plethora of cellular processes that contribute to disease states. Among the proteins involved in SUMOylation, the protein inhibitor of activated STAT (PIAS) E3-ligases were initially described as transcriptional coregulators. Recent findings also indicate that they have a role in regulating protein stability and signaling transduction pathways. PIAS proteins interact with up to 60 cellular partners affecting several cellular processes, most notably immune regulation and DNA repair, but also cellular proliferation and survival. Here, we summarize the current knowledge about their role in tumorigenesis and cancer-related processes. Cancer Res; 77(7); 1542-7. ©2017 AACR.
Isolation and characterization of lung cancer sphere-forming cells as platforms for the development of new therapeutic strategies.
Authors: Silvia Calabuig-Fariñas, Alicia Martinez-Romero, Eloisa Jantus-Lewintre, Rut Lucas, Jose Miguel Pardo, Sandra Tejedor, Ana Blasco, Santiago Figueroa, Eva Escorihuela, Carlos Camps, Rosa Farras
Journal: Journal of Clinical Oncology (2015)

e22190 Background: Resistance to treatment is one of major causes influencing the high mortality of lung cancer. This feature seems to be dependent of a minority of cancer cells with special characteristics of self-renewal and differentiation, known as Cancer Stem Cells (CSCs).To date, specific markers for lung-CSCs have not been identified. The aim of our study was to isolate and characterize sphere-forming cells from lung cancer cell lines, and to use them as a platform to test drug efficacy on these cells. Methods: We performed flow cytometry immunophenotyping of lungspheres generated from lung cancer cell lines toanalyze the distribution of different subpopulations, based on the expression of Epcam, CD90, CD166, CD44, CD133 and E-cadherin. In vivo tumor formation assay in NOD/SCID mice were used to study lungspheres properties. The lungspheres were used to (i) evaluate the cytotoxic effect of anticancer drugs and (ii) to perform a high throughput screening with commercial chemical libraries Cell viability was evaluated using MTS assay. Results: Flow-cytometry analysis showed high heterogeneity in the expression of the stem-related surface markers in spheres obtained from lung cancer cell lines. Two main subpopulations were characterized (Epcam+ and CD90+). Only Epcam+/CD90− cells were able to generate tumorspheres. The potential of tumorspheres as tumor initiating cells (TIC) was explored by injecting different amounts and subpopulation of cells in NOD/SCID mice. The Epcam+/CD166- spheres showed the highest tumor induction frequency. Classical anticancer drugs (cisplatin, paclitaxel) showed mild or null cytotoxic effects on lungspheres. Remarkably, three compounds from a commercial drug library significantly reduced the number of viable tumorspheres. Conclusions: Our data suggest that Epcam+ lungspheres were able to generate tumors in immunosuppressed mice. In culture, these lungspheres showed resistance to classical anticancer drugs, strengthening its possible use as a platform for a simple, and cost- effective method to search for novel CSC-targeting drugs.
Association of age with utilization of radical cystectomy for high-grade nonmuscle invasive bladder cancer: Results from the National Cancer Database.
Authors: William P. Parker, Harras B. Zaid, Elizabeth B. Habermann, Igor Frank, Robert Houston Thompson, Matthew K. Tollefson, Jeffrey Karnes, Stephen A. Boorjian
Journal: Journal of Clinical Oncology (2017)

312 Background: Radical cystectomy (RC) is a preferred option for high−grade non−muscle invasive bladder cancer (HG NMIBC), particularly after failure of intravesical therapy. However, clinicians may be reluctant to offer surgery to older patients with NMIBC given concerns regarding morbidity. We therefore sought to evaluate the association of age with use of RC and clinicopathologic outcomes after RC for HG NMIBC. Methods: The National Cancer Data Base was queried to identify patients diagnosed with HG NMIBC between 2004−2013. Patients were stratified according to age at diagnosis: &lt;60, 61−70, 71−80, &gt;80 years. Multivariable logistic regression was performed to assess the associations of age group with utilization of RC and with pathologic upstaging (pT2−4 or pN+). Overall survival (OS) was evaluated using unadjusted and inverse propensity score weighted (IPTW) Kaplan−Meier methods and compared with the log-rank test. Results: RC was performed in 3,641 (5.7%) of 63,402 patients with HG NMIBC. Utilization of RC remained relatively constant over the study period (4.3%−6.8%; p=0.44). On multivariable analysis, increasing age was inversely associated with RC utilization, with the lowest utilization in those &gt;80 (2.1% rate; OR 0.24; p&lt;0.01). Similar associations of age with RC were observed at high volume centers (&gt; 15 cases/year), academic centers, and for patients with cT1 disease. Among patients who underwent RC, pathologic upstaging was identified in 1,445 (43.6%), and no significant association was noted with age. NMIBC pathologic tumor stage was associated with improved OS compared to progression to pT2−4 or N+ disease at RC for all age groups: median OS improvement not reached in those under 60; 32 months in those 61−70; 55 months in those 71−80; and 34 months in those over 80 (all p&lt;0.01). Similar improvements in survival were noted after IPTW. Conclusions: Older patients are significantly less likely to receive RC for HG NMIBC, despite a similar risk of upstaging and an improved survival when pathologic NMIBC is found at RC. These data support the use of RC for HG NMIBC in well selected patients across age strata.
A 10-year review of primary CNS lymphoma treatments and outcome: The Irish experience.
Authors: Scheryll Paula Alken, MinYuen Teo, Richard Martin Bambury, Mohd Syahizul Nuhairy Mohd Sharial, Anuradha Jayaram, Francesca Brett, Catherine Keohane, Michael Anthony Farrell, Maccon M. Keane, Derek Gerard Power, Eugene J. Moylan, William Grogan, Seamus O'Reilly, Oscar S. Breathnach
Journal: Journal of Clinical Oncology (2013)

e13020 Background: PCNSL is a rare variant of diffuse large B cell lymphoma. Optimum treatment strategies are yet to be defined. We report the Irish experience. Methods: We examined the Irish National Cancer Registry to assess the incidence of PCNSL. Patients diagnosed between 2001 and 2011 were cross referenced and identified from medical oncology, neuropathology and pharmacy database in the 3 cancer centres. Progression-free survival (PFS) and overall survival (OS) were estimated via Kaplan-Meier methods, and Cox proportional hazard model was used to identify risk factors. Results: 74 patients were treated in the 3 centres over the time period, representing 57% of all cases diagnosed in Ireland (ranging from 12.5% in 2001 to over 90% from 2008 onwards). 39 (52.7%) were male, with a median age of 60 years (range 17 – 78). 64% had an ECOG PS of 0 – 1 at presentation. Involvement of the deep structures occurred in 37.5% (n=24), with 29.7% (n = 19) having multifocal disease. 20.3% presented with hemiparesis with 18.6% presenting with symptoms suggestive of raised intracranial pressure. 80% were treated with the DeAngelis regimen and 14% with the Ferreri regimen. 35.7% received whole brain radiotherapy. The median PFS was 22.4 months, (95% CI, 14.2 – 32.1), and median OS was 33.3 months, (95% CI, 22.3 – 68.8). ECOG PS and presence of hemiparesis at diagnosis were independent poor prognostic factors for PFS but not for OS. Age, tumour site, multi-focality, chemotherapy regimen and delivery of radiotherapy did not significantly affect PFS or OS. Conclusions: Our data compares favourably with published series. Increased understanding of the molecular biology of PCNSL is urgently needed in order to define optimum therapies. PCNSL should be treated in specialist centres to facilitate increased casemix, enrolment in clinical trials and banking of tumor tissue.
A phase II study of S-1 in patients with hormone-refractory prostate cancer: The S-1 Cooperative Study Group (Prostate Cancer) study
Authors: H. Akaza, I. Ikemoto, M. Namiki, M. Usami, M. Kobayashi, H. Fujimoto, T. Tsukamoto, S. Naito
Journal: Journal of Clinical Oncology (2006)

14650 Background: S-1 is an oral fluoropyrimidine antitumor drug that combines three pharmacological agents: tegafur, a prodrug of 5-fluorouracil;gimeracil, an inhibitor of dihydropyrimidine dehydrogenase; and potassium oxonate, which reduces gastrointestinal toxicity. We evaluated the efficacy and safety of S-1 in patients with hormone-refractory prostate cancer. Methods: To be eligible patients (pts) had to have given informed consent, an age of &lt;80 years, elevations of serum prostate specific antigen (PSA) on three consecutive occasions despite effective hormonal therapy and antiandrogen withdrawal for at least 4 weeks, adequate organ function, a PS of 0–2, and a life expectancy of ≥3 months. S-1 was given orally at 40 mg/m 2 b.i.d. for 28 consecutive days followed by a 14-day rest period. This 42-day cycle was repeated until confirmation of disease progression. Results: 32 pts were enrolled at 15 institutions. Their median age was 73 years (55 to 79). The median number of courses administered was 2.5 (1 to 11). On the basis of the change in the PSA level, 3 pts had a complete response (CR, &lt;4 ng/ml), and 4 had a partial response (PR, ≥50% decrease), yielding a response rate of 21%. There was no change (NC) in 15 pts, and progressive disease (PD) in 10 pts. The median time to PSA progression was 71 days (95% CI: 44 to 161) overall, 234 days (152 to 435+) in the CR+PR group, and 157 days in the CR+PR+NC group. Grade 3 major toxicity comprised anorexia (3 pts) and anemia (2 pts). No toxicity-related deaths occurred. Conclusions: S-1 is active and well tolerated as a single agent in patients with hormone-refractory prostate cancer. Effectiveness and safety will be confirmed in subsequent large-scale phase II studies. No significant financial relationships to disclose.
Does the orphan nuclear receptor ERRγ link cholesterol synthesis to endocrine therapy resistance
Authors: Rebecca Riggins, Jennifer Lan, Alan Zwart, Robert Clarke
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

990 

Estrogen receptors alpha and beta (ERα, ERβ) play a central role in the etiology of breast cancer and drive our approach to therapeutic intervention. While these and many other nuclear receptors (NRs) are responsive to specific ligands, there are orphan NRs for which no ligand has yet been identified. The function of these receptors in breast cancer biology is often poorly understood. Estrogen-related receptor gamma (ERRγ) is one orphan NR with structural similarities to ERα and ERβ. In addition to its ability to transactivate classical and imperfect estrogen response elements (EREs), ERRγ is a potent activator of transcription from steroidogenic factor-1 (SF-1) response elements (SF-1REs). Many genes regulated by SF-1REs control key aspects of cholesterol and fatty acid synthesis, important not only for generation of the plasma membrane but also for the synthesis of steroid hormones. Consequently, upregulation of ERRγ may increase the cholesterol production capacity of breast cancer cells poised to proliferate in response to estrogen. This has the potential to promote the development of hormone-refractory breast cancer, and is also likely to attenuate the therapeutic effectiveness of antiestrogens designed to inhibit ER function. We have found that ERRγ is upregulated 4-fold (p=0.015) in LCCTam cells, a multi-antiestrogen resistant variant of the ER-positive SUM44 breast cancer cell line, a model of invasive lobular carcinoma. ERRγ overexpression is accompanied by a significant increase in basal and estrogen-stimulated ERE transcriptional activity, and siRNA-mediated knockdown of ERRγ in LCCTam cells completely restores sensitivity to both 4-hydroxytamoxifen and Fulvestrant (p=0.03). Furthermore, LCCTam cells produce greater levels of cholesterol than SUM44, and we have found that the expression of three genes with established connections to cholesterol and steroid hormone synthesis is significantly increased in LCCTam: HMG-CoA synthase 2 (HMGCS2, 9.6-fold), GATA binding protein 4 (GATA4, 4.4-fold), and sterol regulatory element binding transcription factor 1 (SREBF1, 1.8-fold). Together these data suggest that ERRγ may affect endocrine resistance in the LCCTam breast cancer model by regulating cholesterol production.
Sexual morbidity and unmet needs among members of a metastatic breast cancer registry.
Authors: Joanne S. Buzaglo, Melissa F Miller, Barbara L. Andersen, Margaret Longacre, Patricia A. Robinson
Journal: Journal of Clinical Oncology (2015)

9585 Background: An estimated 155,000 people are living with metastatic breast cancer (MBC) in the US. As the duration of survival increases, quality of life needs become more salient. Women treated for MBC often report adverse sexual effects, yet many surveys suggest that oncology providers rarely discuss sexual issues. Our objective was to study the impact of MBC on sexual morbidity. Methods: Since March 2013, we registered 909 people living with MBC to the Cancer Experience Registry: MBC, an online initiative designed to study the psychosocial impact of MBC. 599 registrants completed questions about sexual morbidity and a cancer-related distress screening tool, including a depression subscale. The sample was predominantly Caucasian (91%), well educated (69% had college degree), with a median age of 56 years. Median time since MBC diagnosis was 3 years. Results: Overall, 71% reported MBC negatively impacted their sexual life, and 50% reported sexual activity was a source of distress. Specifically, 80% reported they had no interest in sex, 76% reported vaginal dryness, 68% had pain during or after sex, 64% had difficulty having an orgasm, 71% felt anxious about having sex, and 64% did not enjoy sex. Having no interest in sex (p = 0.014), difficulty having an orgasm (p = 0.020), and feeling anxious about sex (p = 0.002) were significantly more common among those at risk for depression. Difficulty having an orgasm was more common among women concerned about body image (p = 0.001). More than half (59%) felt they could talk to a member of their health care team about sexual concerns, yet only 20% reported that a member of their health care team ever asked about sexuality. Only 17% sought treatment for sexual dysfunction, and 39% said they would never go to a mental health expert for sexual counseling even if it was free. Conclusions: MBC has a significant impact on sexual health. Patients report substantial sexual morbidity which is associated with symptoms of mood disorder. The direction of the association is unclear, and should be studied in prospective surveys. More efforts are needed in oncology settings to screen for sexual problems in people with MBC and make appropriate referrals for care. Research on effective treatment programs is also lacking.