tbuckley/cabot-search huggingface dataset:
The effect of androgen deprivation therapy on prostate cancer-specific mortality in high-risk prostate cancer: Patients treated with low dose-rate brachytherapy without supplementary external beam radiotherapy.
Authors: Jay P. Ciezki, Chandana A. Reddy, Michael A. Weller, Rahul D. Tendulkar, Kevin L. Stephans, James Ulchaker, Kenneth Angermeier, Steven C. Campbell, Andrew J. Stephenson, Eric A. Klein
Journal: Journal of Clinical Oncology (2017)

e550 Background: Androgen deprivation therapy (ADT) is a mainstay accompaniment of external beam radiotherapy (EBRT) for treating high-risk prostate cancer (HPCaP). Both low dose-rate brachytherapy (LDR) as the sole method of radiotherapy and the need for ADT in conjunction with it are relatively unexplored with HRCaP. We present an inception cohort study of HRCaP patients treated with LDR alone with or without ADT. Methods: The study includes 515 patients with HRCaP according to NCCN guidelines. They were treated with I-125 LDR alone to a dose of 144 Gy with lateral, superior, and inferior margins of at least 5 mm (medin D90 = 149.39 Gy). The association of prostate cancer-specific mortality (PCSM) with pre-treatment variables was assessed with Fine and Gray regression with non-PCSM mortality treated as a competing event. PCSM rates were calculated using the cumulative incidence method. Results: The median age is 70 years. The median f/u is 48.9 months. Fifty-four percent were Gleason 7, 28% were Gleason 8, and 11% were Gleason 9. Fifty-three percent received ADT for a median duration of 6 months (range = 1-32 months). At 5 years, the PCSM rate was 1.2 % for LDR and 4.2% for LDR + ADT, and at 10 years, the PCSM rate for LDR was 3.3% and 4.2% for LDR + ADT (p = 0.34). Table 1 shows the association of pre-treatment factors with PCSM. Conclusions: ADT does not affect PCSM for HRCaP patients. Further studies should be done to explore if ADT is necessary with LDR for HRCaP. [Table: see text]
Isolated limb perfusion for soft-tissue sarcoma and regional melanoma.
Authors: Olfa Derbel, Eve-Marie Neidhardt, Adeline Stoltz, Pierre Meeus, Aurelien Dupre, Patrick Combemale, Isabelle Ray-Coquard, Philippe Alexandre Cassier, Arnaud de la Fouchardière, Dominique Ranchere-Vince, Jean-Yves Blay
Journal: Journal of Clinical Oncology (2013)

10579 Background: Isolated limb perfusion (ILP) represents a treatment option for locally advanced melanoma and sarcoma confined to a limb. The advantage of this approach is to deliver high-dose regional chemotherapy without serious systemic effects. However, the ILP technique involves a complex and invasive operative procedure, requiring accurate monitoring to avoid major local toxicity. Methods: From November 2004 to December 2011, 58 patients underwent IPL for unresectable soft tissu sarcoma (STS= 34) and advanced in-transit melanoma (n=24). IPLs were performed at mild hyperthermic conditions with 1-2 mg of TNF and 40-80 mg of melphalan (M) for arm and leg perfusions, respectively. The response rate, disease free intervals, overall survival, toxicity and limb salvage rate were evaluated. Results: Median age was 68 years (range: 29-91 years), with 58% of women. For sarcoma patients, median tumor size was 60 mm, 16 patients (47%) had a high grade STS. Twenty-one patients (61%) received IPL before definitive surgery. Eight patients finally underwent amputation, giving a long-term limb salvage of 77%. The overall response rate was 73.5% (Complete response rate 14.7%, partial response rate 58.8 %). For melanoma patients, 9 (38%) had an AJCC stage III disease, the median thickness of the primary tumor was 3.5 mm. A complete response was obtained in 21% of patients while 54% exhibited a partial response. The local and metastatic recurrence rates were similar between sarcoma and melanoma patients (41% and 33% respectively). All but one of the patients with non-operated sarcoma presented a local or metastatic relapse.There was no mortality and no systemic toxicity. Regional toxicity (Wieberdink scale) was: grade I (no reaction) 53 %, II (erythema, oedema) 34%, III (blistering) 8% and IV 3%. The median local relapse-free survival was 40 months in sarcoma group (26.6 months for non operated patients) and 10 months in melanoma one. The overall 3-years survival rate was 44% for sarcoma and 25% for melanoma patients. Conclusions: ILP induces a high tumour response rate, leads to a high limb salvage rate but is associated with an important recurrence rate. It provides a limb salvage alternative to amputation when local control is necessary.
Early stage ovarian cancer clinical behavior according to FIGO 2014 Staging changes with a focus on IC subtype: data from prospective GEICO registry.
Authors: Ignacio Romero, Cristina Maria Churruca, Andrés Redondo, Ana Santaballa, Elisa Calvo, Belen Ojeda, Jose Maria Del Campo, Nuria Laínez, Elena García-Martínez, Margarita Romeo, Isabel Bover, Cesar Mendiola, Cristina Caballero, Jeronimo Martinez, Ana Herrero, Ana Beatriz Sánchez, Ana De Juan, Susana Hernando Polo, Jose Antonio Lopez-Guerrero, Andres Poveda
Journal: Journal of Clinical Oncology (2015)

5554 Background: Early stage ovarian cancer (ESOC) represents 10-15% of all Ovarian Cancer (OC) cases and most frequent ESOC substage (IC) has undergone major changes in FIGO 2014 staging. Methods: A centralized prospective registry of ESOC (I-IIb) patients treated at GEICO (Spanish Group of Ovarian Cancer Research) centers was initiated on January 1998 and updated up to November 2014. We aim at prospectivley explore both the robustness of FIGO in ESOC and the role of ascites in terms of prognosis. We analyze FIGO 2014 stage IA-IB (1), IC1+IC2 (2), IC3 citology positive in washing (3) or in ascites (4) and IIA-B (5). Results: A total of 1,178 cases with a median age of 53 yrs. (16-97 yrs) have been included. Histology distribution according to Kurman (Int J Gynecol Pathol 2008) showed type I 65.5% and type II 34.5%, grade 1 23.6%, grade 2 21.4% and grade 3 45%. Distribution of ESOC stages, frequency and Relapse Free Survival (RFS) and Disease Specific Survival (DSS) are summarized in table 1; subclassification in IC stage was unavailable in 80 cases. With a median follow-up of 77 months [0-285 mo], 16.7% relapsed after a median of 27 months [2-221 mo] and 9.1% died after a median of 42 months [4-181 mo]. RFS at 5 and 10 years were 84%, 80% and and DSS 93.5% and 87.2% respectively. RFS was inversely associated with stage (p<0.001) (table 1). The presence of positive citology in ascites had worse outcome than in washings. Up to 81% received adjuvant chemotherapy. Conclusions: In this large prospective cohort of ESOC, FIGO 2014 staging system for ESOC is prognostic. We propose to further explore the bad prognosis of positive citology in ascites. Group FIGO 2014 N % RFS 5-yrs (%) RFS 10-yrs (%) DSS 5-yrs (%) DSS 10 yrs (%) 1 IA-IB 428 36.3 96 94 98 97 2 IC1+IC2 398 33.7 93 88 97 96 3 IC3 positive citology in washing 68 5.7 80 74 88 83 4 IC3 positive citology in ascites 33 2.8% 72 72 86 75 5 IIA-IIB 171 14.5 69 63 87 80
A novel approach to extend chemotherapy efficacy: SBRT for oligometastatic progression.
Authors: Rana Fawzi Hawamdeh, Justin W. Wray, Nalini Hasija, Alan B. Grosbach, Judith L. Lightsey, Karen Colleen Daily, Thomas J. George, Carmen Joseph Allegra, Paul Okunieff, Robert Zlotecki, Long H. Dang
Journal: Journal of Clinical Oncology (2015)

e14569 Background: Stereotactic body radiation therapy ( SBRT) has been used for oligometastatic disease management with local control rates in excess of 90%. Oligoprogression is the term applied to limited disease progression, with overall disease control. Standard care would be changing systemic therapy. A novel approach is to attempt to locally control the progressing lesions and continue the same systemic therapy. For patients on a Tyrosine kinase inhibitor (TKI), progressing lesions were found to accumulate new mutations that cause resistance to the TKI. Hence, treatment with non-overlapping mechanism of resistance such as radiation may be offered. This approach was reported in a retrospective study of patients with anaplastic lymphoma kinase (ALK) positive metastatic non-small-cell lung cancer treated with crizotinib, who received SBRT to oligoprogressive disease. This prolonged the duration of therapy with crizotinib as well as overall survival. We hypothesize that progressing lesions in patients undergoing systemic polychemotherapy would also accumulate genetic changes responsible for resistance. In our retrospective series, patients whose metastatic disease was controlled by chemotherapy, a limited number (five or fewer) of progressing lesions were treated with SBRT with intent to increase time from systemic therapy initiation to disease progression Methods: Patients eligible for treatment had metastatic disease treated with polychemotherapy with 5 or fewer progressing lesions amenable to SBRT. Multiple courses of SBRT were administered. Disease progression was based on the Response Evaluation Criteria in Solid Tumors (RECIST) . We report Five patients: 2 with metastatic colon cancer, 2 with metastatic rectal cancer, and 1 with metastatic pancreatic carcinoma. Imaging was done prior to SBRT and every 3 months. Results: Four of the five patients achieved disease control for more than 6 months with SBRT while continuing the same polychemotherapy regimen. The patient who failed to respond had progressive disease at 3 months. Conclusions: SBRT is an option for overall systemic control of oligoprogressive disease. Randomized controlled trials are needed to validate this approach
Phase 2 trial of GS-9973, a selective syk inhibitor, and idelalisib (idela) in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL).
Authors: Paul M. Barr, Gene Brian Saylors, Stephen Edward Forbes Spurgeon, Bruce D. Cheson, Daniel Reif Greenwald, Susan Mary O'Brien, Andre K. D. Liem, Rosemary McIntyre, Esteban Abella-Dominicis, Michael J. Hawkins, Anita Reddy, Julie Di Paolo, Meihua Wu, Flordeliza Melchor-Khan, Feng Jin, Jonathan W. Friedberg
Journal: Journal of Clinical Oncology (2014)

7059 Background: GS-9973 is an orally bioavailable, small-molecule, selective inhibitor of Spleen Tyrosine Kinase (Syk). The Kd of GS-9973 for Syk was 7.6 nM with no other kinase < 100 nM. Methods: This Phase 2 trial enrolled subjects (subj) with relapsed/refractory CLL (1 cohort) or NHL (4 cohorts). Subj underwent intra-subj dose escalation from GS-9973 400 mg and Idela 100 mg (400/100) BID up to a maximum of 800/150 BID. Plasma drug levels were obtained concurrently with plasma chemo/cytokine levels and phospho flow analysis of circulating leukemic cells. Results: This study initiated in July 2013. When enrollment was suspended, 66 subj with CLL (36) or NHL (30) had been enrolled. Median age was 68 (range 28 - 92), 53% were male. The median number of prior treatment regimens was 3 (range 1-9). Of the subj with investigator response assessments, 14 (70%) and 10 (50%) of 20 CLL subj had a decrease of > 50% and > 75% respectively in their measurable lymph node disease; 7 (35%) of 20 NHL subj achieved a decrease of > 50%. (iNHL 6/14; DLBCL 1/4; MCL 0/2). The study was terminated early due to the development of severe, steroid responsive, pneumonitis in 9 subj that occurred despite dose reduction in 4 after a median of 83 (raange 50-105) days on study. Reversible Grade 3 or 4 ALT elevations occurred in 10 (15%) subj. Treatment emergent adverse events occurring in ≥ 15% of subj were fatigue, nausea, pyrexia, rash, diarreha, headache, constipation and cough and were typically low grade. 5 subj died while on study: 2 from disease progression, 1 from pneumonitis, 1 from pneumonia, 1 from sepsis. Conclusions: Despite promising activity in CLL, the combination of GS-9973 and Idela resulted in an unexpectedly high rate of pneumonitis and resulted in stopping dosing of the combination These data need to be considered when designing future investigations combining inhibitors of B cell receptor signaling. Additional studies are needed to understand the underlying mechanism of pneumonitis seen with dual Syk and PI3k inhibition Clinical trial information: NCT01796470.
A first-in-human study of AMG 780, an angiopoietin-1 and -2 (ANG1/2) inhibitor, in patients (pts) with advanced solid tumors.
Authors: Afshin Dowlati, Gordana Vlahovic, Ronald B. Natale, Erik Rasmussen, Indrajeet Singh, Yuying C. Hwang, John Rossi, Michael B. Bass, Gregory R. Friberg, Cheryl Ann Pickett-Gies
Journal: Journal of Clinical Oncology (2014)

2542 Background: AMG 780 is a fully human monoclonal antibody binding Ang1/2, thereby inhibiting their interaction with Tie2. This first-in-human study evaluated AMG 780 in advanced solid tumors. Methods: Pts (≥ 18 yrs) received open-label AMG 780 IV Q2W until pts progressed, developed intolerable toxicities, or withdrew consent. Doses (0.1, 0.3, 0.6, 1.2, 2.5, 5, 10, 20, 30 mg/kg) were escalated in a 3 + 3 design. Primary endpoints were dose-limiting toxicities (DLTs), treatment-emergent adverse events (AEs), and pharmacokinetics (PK). Secondary endpoints included tumor response per RECIST and tumor vascularity (Ktrans, IAUC) measured with DCE-MRI. The profile of circulating angiogenic factors was an exploratory endpoint. Results: 44 pts were enrolled (n = 3 – 9 per cohort; 25 males; mean age [SD] = 61 [9] yrs). Three DLTs occurred (0.6 mg/kg, gr 3 thrombocytopenia; 10 mg/kg, gr 3 proteinuria; 30 mg/kg, gr 3 pericardial effusion; all n = 1). The most frequent AEs were hypoalbuminemia (n = 16; gr ≥ 3, n = 1), peripheral edema (n = 13; gr ≥ 3, n = 0), fatigue (n = 12; gr ≥ 3, n = 1), and decreased appetite (n = 12; gr ≥ 3, n = 0). The most common gr ≥ 3 AEs were blood alkaline phosphotase increase (n = 4) and hyponatremia (n = 3). No treatment-related deaths occurred. At 30 mg/kg, a maximally tolerated dose was not identified. PK was nearly dose-linear. Mean terminal half-life was 8 – 12 days. Steady state was reached after three doses. Of 31 evaluable pts, six pts had stable disease (SD); one pt had SD lasting > 6 months. Twenty pts had progressive disease. Of 16 pts with DCE-MRI data, Ktrans for 6 pts and IAUC for 5 pts decreased > 20% at week 5 postdose relative to baseline. No Ktransor IAUC responses occurred prior to reaching the 0.6 mg/kg cohort. Levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) and placental growth factor (PLGF) levels increased and soluble kinase insert domain receptor (sKDR) decreased with higher AMG 780 doses. Circulating angiogenic factors did not correlate with tumor response. Conclusions: Results suggest that AMG 780 IV Q2W is tolerable up to 30 mg/kg. Based on safety and PK, additional trials of AMG 780 at 20 – 30 mg/kg monotherapy or combined with targeted agents or chemotherapy are warranted. Clinical trial information: NCT01137552.
Association of expression of aquaporin 5 (AQP5) with prognosis in hormone-responsive early breast cancer patients.
Authors: Soo Jung Lee, Yee Soo Chae, Yoo Jin Lee, Jong Gwang Kim, Ho Yong Park, Byung Woog Kang, Ji Yun Jeong, Ji-young Park, Tae-Hwan Kwon, Hyun Jun Jung
Journal: Journal of Clinical Oncology (2013)

e11594 Background: Our previous study showed the association of AQP5 up-regulation with cancer proliferation and migration in hormone-responsive breast cancer cell lines (MCF-7) and with unfavorable prognosis in a small number of patients with breast cancer. Accordingly, we analyzed the prognostic impact of AQP5 expression in a number of patients with early breast cancer (EBC). Methods: We enrolled 447 patients who underwent operation for EBC between June 2003 and August 2008 and performed immunohistochemical (IHC) stain for AQP5 expression in tissue microarray (TMA) collected from tumor tissue. Two pathologists independently scored staining intensity (IS, 0 through3) and percentage of positive tumor cells (PC, 0 through 4) and categorized as negative (0 through 2), weak (3 through 5), and strong (6 or more) according to the sum. Results: The median age of patients was 49 years (range 23-82). 80 (17.9%) patients underwent breast conserving surgery and adjuvant chemotherapy was given to 406 (90.8%) patients. Among enrolled subjects, 298 (66.7%) were hormone-responsive, 64 (14.3%) for HER2 overexpressed, and 79 (17.7%) for triple negative EBC by ER, PgR, and HER2 expression. AQP5 expression (staining score &gt;2) was observed in 267 (59.7%) patients including 123 (27.5%) overexpression (stating score &gt;5). In univariate analysis, AQP5 overexpression was associated with survival in patients with hormone-responsive and HER2 overexpressed EBC. Moreover, multivariate survival analysis revealed that AQP5 overexpression was an independent prognostic marker for survival in patients EBC, which was prominent in patients with ER/PgR-positive tumor type. However, no difference in AQP5 expression was observed based on patient and tumor characteristics. Conclusions: Consistent with our previous study with breast cancer cell lines, AQP5 expression in tumor tissue can be considered as a prognostic marker in patients with EBC after curative operation.
Use of [-2]proPSA and prostate health index (phi) to improve the diagnostic accuracy of prostate cancer compared to t-PSA and %f-PSA in young men (≤ 65 years old).
Authors: Martin Boegemann, Sebastien Vincendeau, Carsten Stephan, Alain Houlgatte, Laura-Maria Krabbe, Axel Semjonow, Jean-Sebastien Blanchet
Journal: Journal of Clinical Oncology (2013)

5074 Background: Although prostate-specific antigen (tPSA) screening reduced prostate cancer (PCa) mortality recent recommendations do not endorse PSA-screening due to overdiagnosis and overtreatment and the resulting harm afflicted to patients. Screening studies showed the maximum benefit in young men &lt; 65 years of age. tPSA and percent free PSA (%fPSA) lack specifity in the diagnosis of PCa. [-2]proPSA and the prostate health index (phi) improved this diagnostic specifity. Markers to diagnose clinicaly relevant cancers in young men are needed. Methods: The clinical performance of [-2]proPSA and phi was evaluated in a multicenter study. A total of 1362 patients scheduled for initial or repeated prostate biopsy (668 with, 694 without PCa, each ≥ 10 core biopsies) were recruited in 4 different sites based on PSA level 1.6 – 8.0 ng/mL WHO-calibrated (2-10 ng/mL classically calibrated). Serum samples taken prior to digital rectal examination (DRE) were measured for the concentration of tPSA, fPSA and [-2]proPSA with Beckman Coulter immunoassays on Access 2 or DxI800 instruments. Phi was calculated as [-2]proPSA/fPSA*√tPSA. Results: In univariate analysis [-2]proPSA/fPSA (%[-2]proPSA) and phi were the best predictors of PCa detection in patients at initial biopsy (AUC: 0,72 and 0,73) and repeated biopsy (AUC: 0,74 and 0,74). Analysis of the data for men ≤ 65 years of age (n=593) showed that %[-2]proPSA and phi significantly improved PCa dectection (AUC: 0,72 and 0,73) as compared with tPSA (AUC: 0,54) or %fPSA (AUC: 0,62). In the detection of significant PCa (based on PRIAS criteria) %[-2]proPSA and phi demonstrated the best performance in the whole cohort and in young men (≤ 65) years as well (AUC 0,68 and 0,73). Conclusions: This multicenter study showed that [-2]proPSA and phi have a superior clinical performance in detecting PCa in the PSA range of 2-10 ng/mL compared with tPSA and %fPSA at initial and repeated biopsies. This superiority is maintained for the detection of PCa in young men (≤ 65 years of age).
Targeting PTBP1 as a therapeutic strategy to reverse lineage-specific splicing of ANXA7 and ensuing EGFR activation in glioblastoma.
Authors: Markus Bredel, Roberto Ferrarese, Nanda K. Thudi, Vinesh K.T. Puliyappadamba, Eva Bug, Hoa Trummell, Joshua Anderson, Christopher Douglas Willey, Eddy Shih-Hsin Yang, William Beck, James A. Bonner, Maria Carro
Journal: Journal of Clinical Oncology (2015)

2075 Background: Tissue-specific splicing involves evolutionarily conserved, alternative exons many of which have functional features that influence cell signalling. The membrane-binding tumor suppressor ANXA7 belongs to a family of proteins involved in endosomal organization and function. ANXA7 contains an alternative cassette exon that shows high prevalence in neurons, but its functional consequence is not well understood. PTBP1 is a ribonucleoprotein that is normally repressed during neuronal development. Methods: We used integrated molecular genetic and cell biology analyses, animal modeling, and clinical patient profiles to characterize the role of splicing of ANXA7 during glioblastomagenesis. We examined the cellular and kinomic effects of a new class of PTBP1 modulators and their effects on ANXA7 splicing. Results: Lineage-specific splicing of the cassette exon in ANXA7 diminished endosomal targeting of the EGFR oncoprotein and enhanced glioblastoma (GBM) progression. ANXA7 splicing was mediated by PTBP1, which was highly expressed in GBMs due to loss of brain-enriched microRNA miR-124 and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that GBM cells inherit the trait from a potential tumor-initiating ancestor. PTBP1 overexpression portended a poor clinical outcome in patients with GBM. Targeting PTBP1 with an FDA-approved compound, identified by a cell-based high-throughput assay that reports on the splicing activity of PTB, reduced PTBP1 levels and reversed ANXA7 splicing and ensuing EGFR activation. It revealed a significant inhibitory effect on GBM cell viability that was enhanced by the addition of radiation. Drug derivatives exerted even more potent effects on cell proliferation alone and when combined with radiation. Conclusions: PTBP1 mediates lineage-specific splicing of ANXA7 and eliminates its tumor suppressor function, thereby promoting GBM progression. Pharmacologic targeting of PTPB1 reverses the splicing event and exhibits anti-proliferative effects that are augmented by concurrent radiation, offering a potential new avenue for future therapeutic modulation in glioblastoma.