tbuckley/cabot-search huggingface dataset:
Impact of magnetic resonance imaging (MRI) in the local staging, risk group classification, and treatment of patients with prostate cancer with combination of high dose rate (HDR) brachytherapy and external beam radiotherapy (EBRT).
Authors: Alfonso Gomez-Iturriaga, Francisco Casquero, Claudia Carvajal, Arantxa Urresola, Begona Canteli, Ana Ezquerro, Eduardo Hortelano, Inigo San Miguel, Jon Cacicedo, Roberto Llarena, Lorea Martinez-Indart, Jose Maria Espinosa, Pablo Minguez, Pedro Bilbao
Journal: Journal of Clinical Oncology (2013)

202 Background: To assess the impact of magnetic resonance imaging (MRI) staging for patients undergoing High Dose Rate (HDR) brachytherapy with external beam radiotherapy (EBRT). Methods: Fifty consecutive patients with intermediate risk and high risk prostate cancer underwent staging MRI. The MRI findings were used to guide stage-appropriate treatment recommendations, and to assist in the preplanning and optimization of the brachytherapy isodose distributions. Results: Median age of the patients was 71 years (range 58-78), median pre-treatment PSA was 10.15 ng/ml (3.3-66), median prostate volume was 35cc (14-58). Eighty-four percent of the patients were Gleason ≥ 7. Fifty-two percent had ≥ 50 of cores involved. Fifty four percent of patient’s PSA was ≥ 10 ng/ml. Pre-MRI staging was T1 in 70% of the patients, T2 in 30 %. Of the 50 patients staged by MRI, 70% were upstaged from the digital rectal examination-based clinical stage; 46% of cT1- T2 patients were upstaged to cT3. This upstaging changed the risk group in 56% of the patients while using the NCCN classification and in 24% when the D’Amico classification was used. The treatment reccomendation was modified in 26% and 20% of the patients using the NCCN and the D’Amico classification respectively. Conclusions: Staging MRI impacts in the assessment of the local staging, leading to changes in risk group classification and treatment decision in intermediate and high risk patients undergoing HDR brachytherapy and EBRT.
Paradoxical cross-talk between the Stat3 and MAPK pathways in CCL25-CCR9 mediated pancreatic cancer growth and proliferation.
Authors: Maithao N. Le, Xiaoming Shen, Wendy Lee, Marjun Philip Duldulao, Julio Garcia-Aguilar, Joseph Kim
Journal: Journal of Clinical Oncology (2012)

231 Background: Chemokine receptors have been shown to regulate the progression of several malignancies. Signal transducer and activator of transcription 3 (Stat3) may contribute to the invasive phenotype of several human cancers, but its upstream signals have not been well characterized. Our objective was to investigate the relationship between the CCL25-CCR9 axis and Stat3 signaling in pancreatic cancer cells. Methods: We exposed two established human pancreatic cancer cell lines PANC-1 and MIAPaCa-2 to the cytokine CCL25 (800 ug/uL for 20 min) and measured the activation of Stat3 (phosho-Stat3) by Western blot assay. Stattic, a small molecule Stat3 inhibitor, was used (20uM) to antagonize Stat3 signaling. We also measured activation level of extracellular signal-regulated kinase (phospho-ERK) following CCL25 exposure and used UO126 (10uM), a small molecule MEK inhibitor, to antagonize the MAPK pathway. Changes in cell proliferation were measured by CellTiter Glo Fluorescence assay. Results: Constitutive phosphorylation of Stat3 was observed in both pancreatic cancer cell lines. Exposure of MIAPaCa-2 to CCL25 further increased phospho-Stat3 levels on Western blot assay. We also observed a concomitant increase in phospho-ERK levels with exposure to CCL25 in both cell lines. Exposure of pancreatic cancer cells to CCL25 significantly increased cell proliferation. To determine the mechanism of CCR9-mediated cell proliferation, we used stattic and UO126 to specifically inhibit Stat3 and MEK activation, respectively. Interestingly, pre-treatment with stattic prior to CCL25 exposure resulted in a paradoxical enhancement of phospho-ERK levels. Conversely, inhibition of the MAPK pathway with UO126 led to a paradoxical enhancement of phospho-Stat3 levels. Conclusions: Our results demonstrate that CCL25 activates Stat3 and MAPK pathways to contribute to pancreatic cancer proliferation. We also show potential cross-talk between Stat3 and MAPK pathways, wherein antagonism of one pathway resulted in paradoxical activation of the other pathway. Our findings suggest that therapeutic targeting of downstream pathways may require a multi-drug approach.
Levels of oxidative stress and telomeres in Lynch syndrome-associated malignancies.
Authors: Grainne O'Kane, Sarah A. McGarrigle, Nadia Rehill, Michael P. Farrell, Jacintha O'Sullivan, Cian Muldoon, Padraic M. Mac Mathuna, Desmond N. Carney, David James Gallagher
Journal: Journal of Clinical Oncology (2016)

582 Background: Lynch Syndrome (LS) is caused by germline mutations in mismatch repair genes (MMR) genes which are critical in maintaining cellular integrity. Failure of the MMR pathway in LS culminates in the hypermutable phenotype of Microsatellite Instability. LS confers an increased risk of malignancy of which colorectal cancer (CRC) is most common. Carriers exhibit significant phenotypic variation in the age of onset of malignancy which cannot be predicted. Telomere length attrition is considered an early step in carcinogenesis and may be accelerated by oxidative stress. We investigated an association between relative telomere length (RTL) and levels of DNA oxidative damage in LS affected carriers (AC), unaffected carriers (UAC) and in patients with MMR- proficient colorectal cancer (MPC). Methods: Peripheral blood mononuclear cells were isolated from patients within each group. DNA was extracted and RTL measured by quantitative polymerase chain reaction (PCR). Real-Time PCR was used to quantitate expression levels of TERT, TERC and DKC1 (telomerase components) from RNA. Serum levels of 8-hydroxydeguanosine (8-OHdG) were measured from patients using the ELISA technique. Pearson’s correlation was used to compare mean RTL, telomerase levels and 8-OHdG between groups. Results: RTL and telomerase components were measured in 27 AC (median age 50yrs) 27 UAC (median age 40yrs) and 27 MPC (median age 66yrs). Corresponding RTLs were 0.89, 0.91 and 1.69 respectively. AC had significantly shorter RTL compared to UAC (p = 0.03) and MPC (p &lt; 0.0001). There we no differences in the mean expression of TERT, TERC or DKC between groups. Younger age of tumour onset was associated with shorter telomere length in both AC (p = 0.0006) and MPC (p &lt; 0.0001). 8-OHdG levels have been measured in 17 AC, 19 UAC and 14 MPC. The mean levels of AC and UAC were not statistically different. However the mean MPC level was significantly less than UAC (p = 0.03) and AC (p &lt; 0.0001). Conclusions: Shortened telomere length is an important step in carcinogenesis. Affected LS patients have shorter telomeres and evidence of higher levels of DNA oxidative stress than patients with MMR-proficient CRC.
Determining optimal first-line chemotherapy for good and intermediate prognosis testicular germ cell tumors using decision analysis.
Authors: Sky Breeden Vanderburg, A. Lindsay Frazier, Jane Kim
Journal: Journal of Clinical Oncology (2014)

209 Background: Since 80-90% of testicular germ cell tumors (GCTs) are cured after first line therapy alone, minimizing toxicity should be an important consideration in the initial treatment decision between cisplatin and carboplatin. Cisplatin has been shown to be superior in 5-year disease-free survival, but cisplatin use confers a higher risk of key long-term toxicities. This study aims to quantify this trade-off between disease-free survival and toxicities using decision analysis. Methods: We developed a mathematical decision-analytic model that simulates competing strategies of initial treatment with cisplatin or carboplatin in terms of treatment response, long-term toxicity, and mortality associated with first, second, and third line therapies for patients with good and intermediate prognosis testicular GCTs and a median age of 20 years at diagnosis. Treatment toxicities included ototoxicity, neurotoxicity, and nephrotoxicity. Monthly probabilities were weighted means derived from a systematic review of total follow-up data reported in seminal clinical trials. The model projected life expectancies for each strategy. Sensitivity analysis was conducted to examine the impact of uncertain inputs and assumptions. Results: The life expectancies at diagnosis for cisplatin and carboplatin strategies were 436.1 months (36.3 years) and 663.2 months (55.3 years) respectively. Sensitivity analyses revealed life expectancy figures largely dependent on the risk of nephrotoxicity occurrence from first line therapy and death from nephrotoxicity. Unless these base monthly probabilities were reduced by 87% and 99% respectively, carboplatin consistently yielded higher life expectancy than cisplatin. Conclusions: Under the current model, first line carboplatin therapy yields longer life expectancy than cisplatin, but this difference is highly sensitive to variables concerning nephrotoxicity. These preliminary results suggest that first line carboplatin therapy could yield higher life expectancy, though this result may be mediated by inclusion of other factors in future analyses, including updated estimates of mortality from nephrotoxicity or other toxicities.
Objective sleep duration (SD) and overall survival (OS) in patients (pts) with metastatic colorectal cancer (MCC).
Authors: David Spiegel, Francis Levi, Georg A. Bjarnason, Ayhan Ulusakarya, Oxana Palesh, Pasquale F. Innominato
Journal: Journal of Clinical Oncology (2016)

511 Background: Sleep is often altered in patients with cancer, with clinical repercussions. Short sleep duration (SD) has been associated with increased risk of earlier death in the general population. The prognostic relevance of SD in cancer pts is unknown. We explored the effect of short ( &lt; 7 hours) SD on the clinical outcomes of pts with MCC before chemotherapy. Methods: Participants were 236 pts with MCC: M/F ratio: 1.66; median age: 60.4 years; range: 21-78; WHO Performance Status (PS) = 0/1/2: 60/34/6%; synchronous metastases: 63%; 2 or more metastatic sites: 55%; prior chemotherapy for metastatic disease: 35%. Pts wore an actigraph for 72 hours before receiving the initial course of an oxaliplatin-based chemotherapy; objective night-time SD was estimated from actigraphy recordings using the Cole-Kripke algorithm. SD was considered short if &lt; 7 hours, based on previous studies. Multivariate Cox proportional Hazard models were built to assess the prognostic value of short SD on OS and progression-free survival (PFS); Binary logistic regression was used to assess the predictive value of short SD for an objective response (OR) or grade 3-4 Toxicity (Tox). Results: Median night SD was 7.4 hours (range: 1.5-10.5). Short SD was observed in 105 (44.5%) pts. Median OS and 3-year survival rate were 14.6 months (mo) [95% C.I.: 11.8-17.4 mo] and 16% [9-23], respectively, in patients with short SD as compared to 16.4 mo [13.0-19.8] and 27% [20-36%] in those with longer SD (p = 0.04). There was no significant difference in PFS (p = 0.25), OR (p = 0.1) or Tox (p = 0.43) rates according to SD. The negative prognostic value of short SD on OS remained significant even after adjustment for age, sex, body mass index, PS, number of metastatic sites, prior chemotherapy and stage at diagnosis (multivariate hazard ratio: 1.45 [1.08-1.93]; p = 0.013). Conclusions: We observed that sleep duration of less than 7 hours before chemotherapy was associated with a significantly shorter survival, independently from other prognostic factors, in pts with MCC. Sufficiently long restorative sleep should be promoted in cancer pts. More research is needed to understand the relationship and mechanisms behind shorter sleep duration and prognosis.
Open-label phase II study evaluating the efficacy of concurrent administration of radium Ra 223 dichloride (Ra-223) and abiraterone acetate (AA) in men with castration-resistant prostate cancer (CRPC) patients with symptomatic bone metastases.
Authors: Neal D. Shore
Journal: Journal of Clinical Oncology (2016)

177 Background: Abiraterone Acetate (AA), a CYP17 inhibitor, further decreases serum testosterone for castrate resistant prostate cancer patients. Radium Ra 223 dichloride (Ra-223), an alpha-emitting radioisotope is a calcium mimetic, forming complexes with hydroxyapatite at sites of bone metastasis (mets). This study evaluates the combinatorial use of concurrent AA + Ra-223 in CRPC patients with symptomatic bone mets. Methods: In this open-label, phase II study (NCT02097303), 30 patients with symptomatic bone mCRPC with no visceral mets were enrolled. All evaluable patients are treated with Rad-223 every 4 weeks x 6 doses, and concomitant AA 1000 mg + prednisone 5 mg BID. The primary endpoint is efficacy. Secondary endpoints include safety, time to measurable disease progression and SRE's, PSA and ALP progression, progression to further antineoplastic therapy and performance status changes. Patients are assessed at screening, weeks 1, 5, 9, 13, 17, 21 and 25. Data will be presented according to all metrics detailed, and by subject and visit. Time to event variables will be summarized using the Kaplan-Meier method to estimate the median, 25th and 75th percentiles, minimum and maximum and the 95% confidence interval for the median time to event. Kaplan-Meier plots will also be generated. This trial is ongoing and closed to enrollment. Clinical trial information: NCT02097303. Results: Pending. Last patient last visit scheduled to occur in December, 2015. Conclusions: Pending. Clinical trial information: NCT02097303.
Cardiac toxicity associated with dose and gender in patients undergoing chemoradiation for esophageal carcinoma.
Authors: Lauren Marie Tait, Joshua E. Meyer, Erin McSpadden, Jonathan D. Cheng, Philip Agop Philip, Walter J. Scott, Frank Baciewicz, Neal J. Meropol, Anthony Frank Shields, Kevin Crawford, Steven J. Cohen, Antoinette J. Wozniak, Shirish M. Gadgeel, Minsig Choi, Andre A. Konski
Journal: Journal of Clinical Oncology (2012)

112 Background: The purpose of this study was to identify factors associated with symptomatic cardiac toxicity in patients treated with chemoradiotherapy (CRT) for esophageal carcinoma. Methods: One-hundred and forty-four patients with adenocarcinoma or squamous cell carcinoma were treated from 7/2002 - 6/2011 at 2 academic institutions with pre-operative, definitive or palliative CRT. Chemotherapy and radiation therapy was administered at the discretion of the treating oncologist. Altogether, 120 patients had sufficient dose volume histogram (DVH) data for analysis and ≥3 month follow up from treatment completion. Association of cardiac toxicity with a number of variables was investigated, including heart disease, cardiac bypass/angioplasty, diabetes, insulin use, smoking, and tumor location (upper/middle vs. lower/GE junction). T-test assessed risk of cardiac toxicity secondary to age. Percentage of heart volume receiving &gt;20, 30, 40, and 50 Gy (V20-V50) and its association with cardiac toxicity was evaluated for each patient. Fisher’s exact test was used to test for an association between dose volume parameters and cardiac toxicity. Results: Patient population included 93 males and 27 females with a mean age of 63 years. Any cardiac toxicity occurred in 27 patients, 8 of which were symptomatic. T-test comparing age to toxicity was not significant; however, female patients were 3.57 times more likely to have cardiac toxicity ([95% Confidence Interval 1.42-9.01], p=0.005). A significant difference in V40 existed between patients with cardiac toxicity and those without (p=0.05). Patients above the median cut-off for V40 (54%) had 2.48 increased odds of developing cardiac toxicity ([95% Confidence Interval 1.02-6.02], p=0.04). None of the other investigated variables were associated with an increased risk of developing cardiac toxicity. Conclusions: Female patients were found to have an increased risk of cardiac toxicity subsequent to receiving CRT for esophageal carcinoma. V40 greater than 54% was associated with increased cardiac toxicity. These data suggest exercising increased care when designing radiation fields in women undergoing CRT for esophageal carcinoma.
Association between clinical response and toxicities with drug exposure in an alternative dosing regimen of sunitinib.
Authors: Ravindran Kanesvaran, Yi Ling Teo, Xiu Ping Chue, Noan-Minh Chau, Min-Han Tan, Hwee Lin Wee, Han Kiat Ho, Alexandre Chan
Journal: Journal of Clinical Oncology (2014)

439 Background: An alternative dosing (AD) regimen of 37.5mg daily in repeated 4-weeks on, 2-weeks off cycle has been proposed to ameliorate frequent dose modifications due to toxicities as observed with the approved dosing regimen of sunitinib for metastatic renal cell carcinoma (mRCC). This study aims to determine the effect of drug exposure (sunitinib and active metabolite, SU12662) on clinical response and toxicities in patients receiving this AD regimen. Methods: All mRCC patients initiating AD sunitinib were invited to participate in this study. In week 4 of each cycle, toxicities were assessed and plasma steady-state levels (C max ) were quantified using high-performance liquid chromatography. Clinical response was assessed after 2 treatment cycles; and was used with drug exposure and toxicities data for dose adjustments. Results: 36 patients with a mean age of 59.1 ± 10.1 years were recruited. Majority were males (81%) and Chinese (86%). Among the 24 and 16 analyzable cases for cycle 1 and 2, median total C max were 0.088 and 0.094 µg/ml respectively. Sixteen patients completed 2 treatment cycles; 7 (44%) partial response, 5 (31%) stable disease and 4 (25%) progressive disease. A dose increment to 50mg daily was performed for a patient with disease progression. Common grade 2 and above toxicities were hypertension, hand foot syndrome (HFS) and mucositis. Higher drug exposures were observed among patients who achieved clinical response and among those who experienced at least grade 2 toxicities. Conclusions: Drug exposure could likely be associated with clinical response and toxicities in this AD regimen. [Table: see text]
Phase II trial of preoperative chemoradiotherapy with irinotecan and infusional 5-fluorouracil in locally advanced operable rectal carcinoma
Authors: V. Alonso, A. Salud, P. Escudero, P. Bueso, M. Mira, J. Valencia, S. Polo, A. Ruiz de Lobera, J. Lao, R. Lastra
Journal: Journal of Clinical Oncology (2005)

3542 Background: The aim of this phase II trial was to assess the impact of preoperative external radiation therapy combined with 5-Fluorouracil (5-FU) and irinotecan (CPT-11) on pathologic tumor response, sphincter preservation and tumor control in patients with locally advanced rectal carcinoma. Methods: Thirty-nine patients with locally advanced rectal carcinoma (T3/T4 or N+) received radiotherapy (50.4 Gy/28 fractions) and chemotherapy with continuous infusion of 5-FU 200 mg/m2/day on days 1–5 + CPT-11 50 mg/m2 on day 1 every week (weeks 1–6). Surgery with TME was performed between 6–7 weeks after the end of the treatment. Adjuvant chemotherapy with 5-FU + Folinic Acid (NCCTG) x 4 cycles was administered after surgery. Results: Patients have been recruited between February 2004 and November 2004. 29 male/10 female. Median age 68 years (range 43–80). Clinical stage (determined by EUS+CT or RMI): cT3 35p/cT4 4p/cN+ 24p. Tumor location (from anal verge): ≤ 5 cm in 18p, >5 cm in 21p. Surgery (performed in 25 patients) consisted of low anterior resection in 15p and abdominal perineal resection in 10p. One patient refused surgery (not included in assessment). Tumor downstaging was observed in 21p (84%), 21 (88%) had negative lymph nodes, including 5p with complete pathological response (20%) and six with only microfoci of tumor remaining (24%). Conclusions: Preliminary results show that preoperative chemoradiotherapy with infusional 5FU+CPT-11 is a well tolerated regimen for locally advanced operable rectal cancer leading to a high probability of tumor downstaging. No significant financial relationships to disclose.
A phase II trial of gemcitabine plus cisplatin (GP) in patients with inoperable biliary tract cancer (BTC)
Authors: J. O. Park, W. K. Kang, T.-Y. Kim, M. A. Lee, M.-J. Ahn, H.-K. Kim, N. S. Lee, H. Y. Lim, B. J. Park, J. S. Kim
Journal: Journal of Clinical Oncology (2005)

4133 Background: BTC is an aggressive cancer with median survival time rarely exceeding 6 months. While most BTC is unresectable, there is currently no standard systemic chemotherapy. Recently, phase II studies have shown promising preliminary activity of gemcitabine in BTC, both as a single agent and in combination with cisplatin. Therefore, we conducted a phase II trial to evaluate the efficacy and toxicity of gemcitabine and cisplatin in combination for patients with advanced or metastatic BTC. Methods: Patients with unresectable and histologically confirmed cholangiocarcinoma or gallbladder cancer were enrolled. Eligible patients had no prior systemic therapy, ECOG performance status ≤2, adequate organ function, and measurable disease. Patients received gemcitabine 1250 mg/m2 on days 1 and 8 plus cisplatin 70 mg/m2 on day 1 every 3 weeks. Results: From March 2003 to August 2003, 39 patients were enrolled; there were 24 males and 15 females with a median age of 60 years (range, 36–68). Primary tumor sites were intrahepatic bile ducts (19), extrahepatic bile ducts (2), gallbladder (17), and ampulla of vater (1). Of the 35 patients evaluable for efficacy, 6 partial responses were reported for an objective response rate of 17.1% (95% CI, 4.7%–29.6%). Ten patients (28.6%) had stable disease, 16 (45.7%) progressed, and 3 (8.6%) had not been evaluated. Median time to progression was 3.5 months (95% CI, 2.3–4.6 months), and the median overall survival was 8.3 months (95% CI, 4.6–9.4 months). In a subgroup analysis, patients with gallbladder cancer had a higher response rate (4 PR of 14 patients; 28.6%, 95% CI, 4.9%–52.2%) and longer survival (9.1 months; 95% CI, 4.1 - Not coverage). Of the total 148 cycles (median 4 cycles; range, 1–8), most common grade 3/4 hematologic toxicities were neutropenia (35.8%) and thrombocytopenia (16.9%) without treatment-related mortality. The most common grade 3/4 non-hematologic toxicities were nausea (3.4%) and vomiting (2.7%). Conclusions: The combination of gemcitabine and cisplatin demonstrated modest activity with manageable toxicity for patients with advanced BTC and showed a more favorable outcome for patients with gallbladder cancer. This study was sponsored by Eli Lilly. No significant financial relationships to disclose.