tbuckley/cabot-search huggingface dataset:
The role of IL-23 in regulating metastatic prostate cancer through STAT-3/ROR-gamma signaling.
Authors: Nasser Ghaly Yousif, Salam Alhasani, H Slimani, Jim Doug, Bassim I Mohammad, Suzan Machil, Abdallah Ali Deb, Niky Romalid
Journal: Journal of Clinical Oncology (2014)

142 Background: Interleukin-23 (IL-23) plays an important role in expanding the Th17 cell population and induce signal transducer and activator of transcription 3 (STAT-3) to up-regulates the expression of Retinoic Acid Receptor-Related Orphan Receptor Gamma-T (ROR-gamma). STAT-3 regulates the expression of a variety of genes in response to cellular stimuli, and thus plays a key role in cell growth and apoptosis. Furthermore, recent studies identified a critical role for ROR-gamma in lineage specification of uncommitted CD4+ T helper cells into Th17 cells. The goal of this study is to evaluate prospectively the prognostic importance of circulating IL-23 in patients with metastatic prostate cancer through downstream signaling. Methods: The study involved 140 men diagnosed with stages I to IV prostate cancer and 120 healthy controls. IL-23 serum concentration measure by a quantitative enzyme immunoassay technique associated with clinical-pathological variables. Blocking IL-23 with anti-p19 Ab in mice inoculation with two types of metastatic prostate cancer cell lines (LNCaP and DU-145) to study the pathway of IL-23 in vivo by using western blot and real-time RT-PCR. Results: We found a statistically significant higher systemic IL-23 level in the metastatic group in comparison with non-metastatic group (19.32±5.35 pg/ml vs. 7.25±3.42 pg/ml, p&lt;0.05). Patients with shorter overall survival presented higher IL-23 levels, suggesting a negative prognostic correlation. Furthermore, systemic delivery of blocking Abs directed against IL-23 completely inhibited STAT3/ROR-gamma levels in mice. Conclusions: These results demonstrate that STAT3/ROR-gamma, is a downstream mediator for IL-23–induced prostate metastasis in murine mice. IL-23 may represent an attractive therapeutic target or a biomarker in metastatic prostate cancer by blocking downstream effects. However, further studies are needed in larger samples to better investigate the implications of IL-23 in prostate cancer.
Switching to anastrozole (ANA) vs continued tamoxifen (TAM) treatment of early breast cancer (EBC). Updated results of the Italian tamoxifen anastrozole (ITA) trial
Authors: F. M. Boccardo, A. Rubagotti, M. Puntoni, P. Guglielmini, M. Porpiglia, M. Mesiti, M. Rinaldini, G. Paladini, V. Distante, R. Franchi
Journal: Journal of Clinical Oncology (2005)

526 Background: We have previously shown that switching to ANA after 2–3 years of TAM is well tolerated and significantly improves event-free (EFS) and progression-free survival (PFS) of postmenopausal ebc (Breast Cancer Res Treat 82, 2003). Here we report on an additional analysis at a median follow-up time of 52 mos (1–80 mos). Methods: This was an open phase III trial comparing 5 years of TAM vs 2–3 years of TAM followed by 3–2 years of ANA (total duration of treatment: 5 years). PFS was the primary end point. EFS, OS and safety were secondary end points. Results: 448 node positive, ER positive patients were enrolled. At the time of the present analysis 87 events had occurred and 26 deaths. The first site of recurrence was the ipsilateral breast or the thoracic wall or the loco-regional nodes in 16 patients. Distant metastasis were the first site of recurrence in 47 patients; 19 patients developed second primaries (including 5 controlateral breast cancers). The Hazard Ratios of patients switched to ANA for EFS, PFS, local (l) PFS and distant (d)PFS are summarized in the table (Hazards of previous analysis are reported for comparison).17 women continued on TAM died as compared to 9 of those switched to ANA (HR: 0.52; 95% CI 0.23–1.17; p=0.1). The percentages of women developing at least one AE were 40% and 46% in the two groups respectively (p=0.2). However there were 6 endometrial cancers in the TAM group compared to 1 in the ANA group. Conclusions:Safety and clinical benefits of switching to ANA following 2 or 3 years of TAM are confirmed by this updated analysis. No significant financial relationships to disclose.
Effectiveness of massage therapy (MT) as a treatment strategy and preventive modality for chemotherapy-induced peripheral neuropathy (CIPN) symptoms.
Authors: Alvaro G. Menendez, Regina Cobb, Alejandro Ramon Carvajal, Kathi Healey, Diane D'Ambra, N. Joseph Espat
Journal: Journal of Clinical Oncology (2016)

193 Background: CIPN has a known negative impact on quality of life (QoL) and can be a dose-limiting side effect of cytotoxic drugs with no generally agreed upon therapeutic intervention. In this study MT was assessed as a primary and secondary preventive modality of CIPN symptoms under the hypothesis that it can be used as an effective prophylactic and therapeutic option. Methods: A single arm 10-week prospective study (n = 62) with pre/post intervention assessment using a validated survey instrument adapted from “Peripheral neuropathy associated with novel therapies […]”. (Clin J Onc Nur. 2008; (12)3:9-12) Results: 97% (60/62) had at least 2 CIPN-related symptoms. (Table 1) After a single MT session, at least 50% of pts (range 52-100%) reported improvement in all CIPN-related symptom categories. These observations were maintained until 2nd MT session except for vestibulocochlear related symptoms. Initially, 25/60 were on analgesics. Of these, 14 (56%) had no progression of symptoms after 1st MT session. 13/25 presented for 2nd session. 5/13 (38%) reported no progression, 4/13 (31%) reported complete resolution of symptoms and 4/13 (31%) had progression. Conclusions: With the exception of vestibulocochlear symptoms associated with CIPN, study participants reported 50% or greater improvement, which was maintained after 1st MT session. The data suggests that pts on analgesics may also benefit from MT as at least 66% (17/25) reported lack of progression or resolution of symptoms after MT intervention. Consideration for an MT-inclusive treatment strategy is supported by this study. [Table: see text]
Prognostic value of lymphovascular invasion in squamous cell carcinoma of the urinary bladder.
Authors: Simone Lucia Vernez, Kyle Spradling, Jacob B Morgan, Yair Lotan, Ahmed Shokeir, Hassan Abol-Enein, Ahmed Mosbah, Mohamed Ghoneim, Ramy F Youseff
Journal: Journal of Clinical Oncology (2016)

454 Background: The prognostic value of lymphovascular invasion (LVI) has been well studied in urothelial carcinoma of the bladder (UCB) but not in squamous cell carcinoma (SCC). Herein, we evaluate the association of LVI with oncologic outcomes of SCC following radical cystectomy (RC). Methods: We retrospectively evaluated 1280 patients who underwent RC and pelvic lymph node dissection (LND) for invasive bladder cancer between 1997– 2003 at a single institution in Mansoura, Egypt. Only patients with pure SCC pathology were included. Prognostic significance of LVI was evaluated for patients with SCC. Results: Our cohort included 360 patients with SCC. Median patient age and follow-up were 55 years (20 – 87) and 44 months (0 – 108), respectively. LVI was present in 47 (13.1%) and lymph node metastasis (LN+) was present in 66 (18.3%). In Kaplan-Meier analyses, 5-year disease free survival rates for LVI-/LN- and LVI+/LN- patients were 80.2±3% and 38.9±12% (p &lt; 0.001), respectively; 5-year cancer specific survival rates were 88.2±2% and 50.4±13% (p &lt; 0.001), respectively. Moreover, cancer specific mortality was highest in LVI+/LN- patients (HR = 3.657; 95% CI: 1.614 – 8.284; p = 0.002). Multivariate Cox-regression analyses showed that LVI+ status was independently associated with disease recurrence (HR = 2.827; 95% CI: 1.451 – 5.509; p = 0.002 and cancer specific mortality in patients with SCC (HR = 3.657; 95% CI: 1.614 – 8.284; p = 0.002). Conclusions: Lymphovascular invasion is a strong independent predictor of oncological outcomes after RC for SCC of the urinary bladder. The incorporation of LVI status into classic prognostic models for SCC of the bladder may lead to improved identification of high-risk patients.
A phase I/II study of biweekly XELIRI plus bevacizumab for patients with metastatic colorectal cancer as second-line chemotherapy (BIXER study): Reports of phase I part and interim analysis of phase II part.
Authors: Mitsukuni Suenaga, Satoshi Matsusaka, Eiji Shinozaki, Nobuyuki Mizunuma, Kiyohiko Hatake, Toshiharu Yamaguchi
Journal: Journal of Clinical Oncology (2012)

643 Background: Capecitabine is an oral fluoropyrimidine prodrug, which is converted to fluorouracil (5-FU) predominantly in the tumor cells. In Japan, capecitabine is mainly used in combination with oxaliplatin (XELOX) in treatment for metastatic colorectal cancer (mCRC) since its approval in 2009. The results of capecitabine plus Irinotecan (CPT) (XELIRI) with or without bevacizumab (BV) in EU or US patients were previously reported, but not in Japanese. Thus, we conducted this study to assess the safety and efficacy of XELIRI plus BV in Japanese patients with mCRC. Methods: Patients with prior chemotherapy including oxaliplatin and BV for mCRC, wild or hetero type of UGT1A1 *6*28 were eligible for this study. This was a phase I study composed of two steps, and dose limiting toxicity (DLT) was assessed during the first treatment cycle. Treatment comprised capecitabine 1,000 mg/m 2 twice daily from the evening of day 1 to the morning of day 8, intravenous CPT 180 mg/m 2 on day 1, and BV 5mg/kg on day 1 every two weeks. To evaluate the initial safety, 3-6 patients received XELIRI+BV (CPT 150mg/m 2 ) in step 1, and 6 patients received XELIRI+BV (CPT 180mg/m 2 ) in step 2. If DLT occurred in 1 patient in step1, 3 patients would be newly added to step 1, and if in none of 3 or 1-2 of 6 patients, the step 2 would be started. If DLT occurred in less than or equal to 2 of 6 patients in step 2, phase II study would be proceeded, and if In more than 2 of 6 patients, phase II would be conducted at the recommended dose of step 1. Results: In step 1 and 2 of phase I, initial safety of 9 patients was confirmed without occurrence of DLT. Adverse events observed in step 1 and 2 were: neutropenia in 2 and 1; anorexia in 1 and 1; diarrhea in 1 and 1; stomatitis in 1 and 1; alanine or aspartate aminotransferase increased in 1 and 3, respectively. There was no grade 3 or greater adverse events. Conclusions: In mCRC patients with wild or hetero of UGT1A1*6*28 genotype, safety of biweekly XELIRI+BV was confirmed and recommended dose of CPT-11 was determined as 180mg/m 2 . Interim analysis of safety of phase II part will be reported at the meeting.
The impact of Barrett’s esophagus on overall survival of colon cancer patients.
Authors: M. Mozayen, M. Omaira, M. Kanaan, K. Katato
Journal: Journal of Clinical Oncology (2011)

e14143 Background: The association of Barrett’s esophagus (BE) and colon cancer (CC) is still conflicting. Barrett’s esophagus as a prognostic factor has not been well studied in colon cancer patients. We aim to evaluate the effect of Barrett’s esophagus on overall survival of colon cancer patients. Methods: A retrospective observational study was conducted from 1995 to 2005 using data from Mclaren Reginal Medical Center in Flint, Michigan, on patients who were diagnosed with BE and then developed CC. All patients with BE were treated with Proton pump inhibitor. Patient’s characteristics including age at diagnosis, gender, race, and stage of colon cancer were recorded. The five-year overall survival was considered the primary outcome. Patients who developed esophageal cancer were excluded. Results: A total of 6,600 patients were identified with a diagnosis of BE. Only thirty-nine patients developed colon cancer. Female: male ratio 1:1.4. African American percentage was 5%. Patients were classified according to the pathologic stage of colon cancer as stage I, II, III, IV (27%, 24%, 43%, 6%) respectively. The 5-year stage-specific survivals were calculated and compared to the SEER data (Table). Conclusions: The presence of Barrett’s esophagus in colon cancer patients may have a negative effect on stage-specific overall survival. Colon cancer preceded by Barrett’s esophagus seems to be more aggressive disease compared to the colon cancer not preceded by BE. This could be due to the biology and genetic defects of the tumor. Further studies are needed to clarify this effect and association. The stage-specific 5-year survival of patients with Barrett’s esophagus and colon cancer compared with SEER database. Stage BE and CC SEER data (1991-2000) I 60% 93% II 33% 72-85% III 31% 44-83% IV 0% 8%
Serum parathyroid hormone and calcium changes in metastatic castration resistant prostate cancer patients receiving enzalutamide in post-docetaxel setting.
Authors: Angela Gernone, Maria Nicla Pappagallo, Francesco Silvestris
Journal: Journal of Clinical Oncology (2016)

349 Background: Among novel hormonal therapeutic targets for post docetaxel mCRPC, Enzalutamide is an oral androgen-receptor blocker disrupting the androgen-receptor nuclear translocation that significantly increases the OS. In this study we evaluated the potential association of both PTH and Ca levels change in pts with mCRPC after the first Enzalutamide administration. Methods: Between 01 and 05/2015, 20 mCRPC pts relapsed after 2-3 prior lines of therapy (docetaxel, cabazitaxel, abiraterone) have been treated with Enzalutamide that was orally administered at 160 mg/day as continuous dosing. Patient characteristics included: median age 67 years (range 50-84), median baseline PSA 120 ng/ml (range 6-1200), median ECOG P S: 1 (range 0-2), Gleason score ≥ 7. In addition 80% of pts had ≥ 2 metastatic sites. Pretreatment baseline and follow up data including measurement of serum Ca and PTH levels (6.5-36.8 pg/ml), ALP, PSA and QoL parameters were evaluated through all lines of therapy. Pts with bone metastasis received zoledronic acid or denosumab with Ca and vitamin D supplementation. Results: In 18/20 pts with bone disease progression we recorded increased PTH levels and, contrarily, decreased Ca levels after 1 month of Enzalutamide despite vit. D and Ca supplementation. PTH levels remained unchanged after 3 months. In 2/20 pts without bone disease progression PTH ranged normal. All pts reported PSA response ≥ 50%, with improved QoL and are still on treatment since Enzalutamide is well tolerated. We did not find PTH change in bone mCRPC pts treated with prior therapy. Conclusions: Our study showed that increase in PTH levels and reduction in Ca levels and increase in PTH levels after 1 month of Enzalutamide treatment is associated with a dramatic reduction of PSA level. These data support a relationship between PTH and Ca changes in pts treated with Enzalutamide and, thus, their changes level may be adopted in clinical practice as surrogate to reflect the drug activity. No studies have evaluated the variations in serum PTH levels following Enzalutamide treatment and whether these early changes relate to the clinical outcome.
Neoadjuvant anastrozole or tamoxifen for premenopausal breast cancer: Ki67 expression data from the STAGE study.
Authors: T. Kinoshita, N. Masuda, Y. Sagara, H. Iwata, S. Nakamura, Y. Yanagita, R. Nishimura, H. Iwase, S. Kamigaki, H. Takei, H. Tsuda, S. Noguchi
Journal: Journal of Clinical Oncology (2011)

501^ Background: The study of tamoxifen or arimidex, combined with goserelin acetate, to compare efficacy and safety (STAGE) study recently reported a greater best overall tumor response rate (BORR) for anastrozole 1 mg/day plus goserelin 3.6 mg/month (A+G) versus tamoxifen 20 mg/day plus goserelin 3.6 mg/month (T+G) during 24 weeks of pre-operative breast cancer treatment. We report the preplanned exploratory analysis of Ki67 expression. Methods: STAGE is the first phase III, randomized, double-blind, parallel-group, multicenter study which enrolled premenopausal Japanese women with estrogen receptor-positive (ER+), HER2-, operable breast cancer. Tumor response was measured by caliper and MRI or CT. Ki67 indices (%), ER and progesterone receptor (PgR) Allred scores were determined from samples obtained at baseline (Day 0) and surgery (Wk 24). Ki67 ratio from baseline to Wk 24 was calculated; the estimate of reduction ratio between groups was compared by ANCOVA. A post hoc analysis explored any correlations between Ki67 index and tumor response or ER/PgR status. Results: In total, 197 pts were randomized to A+G or T+G. Reduction in Ki67 index from baseline to Wk 24 was significantly greater with A+G (n=96; 21.9% to 2.9%) than T+G (n=96; 21.6% to 8.0%; estimate of reduction ratio [A+G/T+G], 0.35; 95% CI, 0.24, 0.51; p<0.001). BORR (MRI/CT) was significantly higher with A+G in those pts with a baseline Ki67 index of ≥20% vs <20% (73.2% vs 52.5%; p=0.036). BORR results with T+G were: Ki67 ≥20%, 44.8%; <20%, 29.0% (p=0.118). BORR was higher with A+G vs T+G both in pts with Ki67 ≥20% (p=0.002) and <20% (p=0.035). There was no apparent relationship between baseline ER Allred score and Ki67 reduction or BORR in either treatment group. Mean Ki67 decrease was numerically greater in PgR rich pts (Allred score ≥7; A+G −88.8%; T+G −67.6%) than in pts with Allred score <7 (A+G −74.1%; T+G −32.8%). Conclusions: Reduction in Ki67 index was greater with A+G compared with T+G as neoadjuvant treatment for premenopausal pts with breast cancer. BORR was higher with A+G vs T+G both in pts with Ki67 index ≥20% and pts with Ki67 index <20%.
Variations in care for operable breast cancer and outcomes between rural and metropolitan centers in Australia
Authors: P. S. Craft, J. Buckingham, J. E. Dahlstrom, K. Beckmann, Y. Zhang, R. Stuart-Harris, G. Jacob, D. Roder, N. Tait
Journal: Journal of Clinical Oncology (2009)

e11517 Background: The causes of variation in breast cancer survival remain uncertain. Care provided to women with breast cancer may vary in relation to both the care setting and characteristics of the clinicians. Methods: To compare the outcomes of management of breast cancer treated in rural and metropolitan centers, a prospective audit of breast cancer in a region of Australia was undertaken. Over a nine-year observation period 2102 women with invasive breast cancer underwent potentially curative surgery. Treatments received, including systemic adjuvant therapy, were compared to contemporary guideline-based indicators. Breast cancer specific mortality was analyzed using Cox proportional hazards models. Results: Overall agreement of received treatment with the indicators was high. Women treated within rural centers were, however, much less likely to receive post operative radiotherapy after breast conserving surgery (86.4% vs. 97.0%; p&lt;0.001). The overall recurrence rate, including distant metastases, for all women was 11.6%. Local or regional recurrence was more frequent in rural centers compared with metropolitan centers (4.1% versus 2.1%; p=0.05). Breast cancer mortality was increased in women with large tumors, high grade disease, and positive axillary lymph nodes. Non-compliance with treatment guidelines was associated with a trend towards increased breast cancer mortality (HR=1.55; p=0.056). After adjustment for these factors and patient age, undergoing surgery in rural centers was associated with increased breast cancer mortality (HR=1.84; p&lt;0.001). Although women treated in rural centers were older, their cancer stage and tumour characteristics were similar to those of women treated in metropolitan centers. Non-cancer related mortality was elevated in women treated in rural centers compared with women travelling to a city for surgery (HR=2.08; p=0.005). Conclusions: Increased non-cancer related mortality in rural treated women suggests increased medical co-morbidity in this group, which may have influenced treatment choices and outcomes. Low rates of adjuvant radiotherapy were noted for women treated in rural centers. In addition, clinically significant differences in outcome, including breast cancer mortality, were observed. No significant financial relationships to disclose.
Impact and mechanistic role of MicroRNA-1291 on pancreatic tumorigenesis.
Authors: Mei-Juan Tu, Yu-Zhuo Pan, Jing-Xin Qiu, Edward Jae-hoon Kim, Aiming Yu
Journal: Journal of Clinical Oncology (2016)

243 Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death. Better understanding of pancreatic cancer biology and identification of new targets are highly warranted. MicroRNAs (miRs or miRNAs) play a critical role in the control of tumor progression via crosstalk with cancer signaling pathways. Our recent studies showed that miR-1291 improved chemosensitivity through targeting of efflux transporter ABCC1. This current study investigated the mechanistic role of miR-1291 in the suppression of pancreatic tumorigenesis. Methods: PANC-1 and AsPC-1 cell lines were stably transfected with miR-1291. Cell cycle status and apoptosis of stable miR-1291-expressing cells were tested against control cells using flow cytometry. Cells were injected subcutaneously into nude mice and tumorigenesis was measured in vivo. Proteomic studies were performed by two-dimensional difference gel electrophoresis, matrix-assisted laser desorption/ionization time of flight mass spectrometry analysis. Computationally predicted miR-1291 targets were assessed by luciferase reporter assay and Western blot. Primary PDAC and control samples were tested for miR-1291 and target gene expression levels. Results: Our data showed that stable miR-1291-expressing PANC-1 and AsPC-1 cells both showed a significantly lower rate of proliferation than the control cells, which was associated with a cell cycle arrest and enhanced apoptosis. Furthermore, miR-1291 suppressed the tumorigenesis of PANC-1 cells in mouse models in vivo. Proteomic studies revealed the protein level of several cancer-related genes were downregulated by miR-1291, including a pancreatic tumor promoting protein AGR2 which was reduced ~10-fold. Through computational and experimental studies we further identified that FOXA2, a transcription factor governing AGR2 expression, was a direct target of miR-1291. In addition, we found a significant down-regulation of miR-1291 in a set of PDAC patient tumor samples overexpressing AGR2. Conclusions: These results indicate that miR-1291 suppresses pancreatic tumorigenesis via targeting of FOXA2-AGR regulatory pathway providing new insight supporting development of miR-1291-based therapy for PDAC.