tbuckley/cabot-search huggingface dataset:
Association of PD-1 and PD-L1 protein expression in matched primary and metastatic renal cell carcinoma tumors.
Authors: Brian I. Rini, Jennifer Yearly, Hari Dhakal, Christopher Przybycin
Journal: Journal of Clinical Oncology (2015)

418 Background: Therapy targeting programmed death (PD)-1 and PD-L1 proteins has activity in metastatic renal cell carcinoma (mRCC). Expression of these proteins on tumor and infiltrating immune cells is associated with a higher response to drugs inhibiting this pathway. However, these associations have been made based on primary tumor expression, while therapy is directed against metastatic deposits. Methods: Patients with mRCC and metastases (all clear cell; 3 with sarcomatoid changes) who had undergone resection of both the primary and at least one metastatic tumor were included. Samples were evaluated for PD-1 and PD-L1 expression by immunohistochemistry using anti-PD-1 clone NAT105 and Merck proprietary anti-PD-L1 clone 22C3. Stained sections were scored for PD-1 and PD-L1 using a semi-quantitative 0 to 5 scale (0 = negative, 1 = rare, 2 = low, 3 = moderate, 4= high, 5 = very high). PD-1 expression was limited to cells with lymphoid morphology, PD-L1 expression was evaluated for both tumor and non-tumor (inflammatory, endothelial) cells. Linear regression analysis was performed to assess significance of correlations. Results: Fifty matched primary and metastatic RCC tissue sets were analyzed with 48 evaluable matched pairs. PD-1 score greater than 3 (considered positive) was detected in 9 primary tumors (18%) and 9 metastatic sites (18%). PD-L1 score greater than 3 was detected in 9 primary tumors (18%) and 12 metastatic sites (24%). There was a correlation between PD-1 scores for primary and metastatic pairs (R 2 =0.194; p&lt;0.002) and between PD-L1 scores for primary and metastatic pairs (R 2 =0.319; p&lt;0.0001). There was an association between PD-1 score and PD-L1 score for primary tumors (R 2 =0.513; p&lt;0.0001) and for metastatic sites (R 2 =0.449; p&lt;0.0001). For PD-1 score, there were 10 pairs (21%) in which either the primary or metastatic site score was ≥3, but the matched pair was &lt; 3. For PD-L1 score, there were 9 pairs (19%) in which either the primary or metastatic site score was ≥3, but the matched pair was &lt; 3. Conclusions: The expression of PD1 and PD-L1 in primary clear cell RCC tumors is correlated with metastatic site expression, although there are a substantial percentage of tumors with discordance.
A single multidisciplinary center's experience in the management of hepatitis C virus-induced hepatocellular carcinoma in 184 patients.
Authors: A. K. Varia, S. Guha, M. Hassan, A. O. Kaseb
Journal: Journal of Clinical Oncology (2010)

e14594 Background: The incidence of hepatocellular carcinoma (HCC) is increasing in the United States, and the predominant risk factor is cirrhosis induced by hepatitis C virus (HCV). Over the past 10 years, HCC treatment options have changed, and several centers have adopted a multidisciplinary approach. We compared HCV-related HCC treatment modalities and outcomes between patients diagnosed before and after 2001 at our institution. Methods: From 1997 to 2006, 184 patients with HCC were included in a retrospective analysis and divided into two periods; 1=between 1997 and 2001 and 2 = between 2002 and 2006. We analyzed the data related to the patients' characteristics, Barcelona Clinic Liver Cancer (BCLC) staging, and treatment received. Patients were divided based on the treatment algorithms: local, surgery, systemic, and mixed-modality therapy. Kaplan-Meier curves were used to estimate median survival, and comparisons between the different treatment modalities received along with the patients' outcomes were made using the log-rank, Wilcoxon, and Pearson chi-squared tests. Results: In period 1, 64 patients were identified (44 male:20 female) and 120 patients were identified in period 2 (95 male:25 female). For patients in both periods (period 1/period 2) who received treatment, BCLC staging was as follows; stage 0: 1/0, stage A: 11/8, stage B: 8/13, stage C: 23/54, and stage D: 1/4. We observed a significant change in the distribution of treatment modalities received (p value=0.001), with an increase in the use of local and surgical approaches in period 2. We also observed a trend towards improved median survival in those who received mixed- modality therapy in period 2 as compared to those in period 1 who received mixed modality therapy. Conclusions: In this single-center retrospective analysis of patients with HCV-related HCC, there was a significant change in the distribution of treatment modalities between the two periods. There was a greater increase in the local and surgical treatments performed in the second period, which was associated with a trend toward improved survival, reflecting the importance of adopting a multidisciplinary approach in HCC management. No significant financial relationships to disclose.
Radiotherapy in locally advanced pancreatic cancer: SEER experience.
Authors: Amit Mahipal, Monique Z. Sajjad, Aaron Denson, Ravi Shridhar, Gregory M. Springett, Sachin Batra
Journal: Journal of Clinical Oncology (2015)

364 Background: Pancreatic cancer is the fourth most common cause of cancer deaths in the US. Despite the fact that the radiotherapy in addition to chemotherapy is frequently employed, the role of radiation therapy in the treatment of locally advanced pancreatic cancer (LAPC) remains controversial. The majority of the data evaluating the efficacy of this approach is derived from small randomized trials. Methods: The Surveillance, Epidemiology and End Results (SEER) registry dataset from 2004-2011 was queried to identify patients with locally advanced pancreatic adenocarcinoma. Pts with survival &lt;2 months, unknown radiation status and those who received post-operative radiation were excluded. Multivariate analysis of prognostic factors related to survival was performed using a Cox proportional hazard regression model. Results: We identified 4,460 patients that met the inclusion criteria; 59% of pts received radiation and 41% did not. The two groups were similar with respect to gender, race and tumor differentiation. Pts in the radiation group were younger (ages&lt;65: 49% vs. 38%), had smaller tumor size (largest dimension &lt;4.5 cm: 80% vs. 75%), lesser lymph node involvement (33% vs. 36%) and lower rate of surgical resection (4% vs. 9%). Radiation treatment, age, tumor grade and surgical resection were significantly associated with survival on univariate analysis. Patients who received radiation therapy had better survival (median OS: 11 vs. 7 months; HR: 0.77; 95% CI 0.69-0.78). On the multivariate analysis, radiation was independently associated with improved survival (Table). Conclusions: In this population-based registry, radiation therapy was associated with improved survival in patients with LAPC in both univariate and multivariate analysis. Larger randomized trials are needed to confirm these findings. The optimal schedule and type of radiation therapy remains unknown. [Table: see text]
Effect of the ERα agonist GTx-758 on bone turnover markers in men with advanced prostate cancer.
Authors: Evan Y. Yu, Thomas E. Keane, Ronald Tutrone, Laurence Belkoff, Joel Bass, Franklin Chu, Mike Gambla, Franklin Gaylis, James Bailen, Robert H. Getzenberg, Christopher Coss, Michael L. Hancock, James T. Dalton, Mitchell S. Steiner
Journal: Journal of Clinical Oncology (2013)

222 Background: Men with advanced prostate cancer are being treated with androgen deprivation therapy (ADT) for longer periods of time. The use of ADT can be limited by estrogen deficiency side effects, including a loss of bone and a higher incidence of fractures. GTx-758 is an ERα agonist that lowers serum free testosterone greater than an LHRH agonist. Herein we compare the effects of GTx-758 and leuprolide on markers of bone turnover, C-terminal telopeptides and bone specific alkaline phosphatase, in men with advanced prostate cancer treated with ADT. Methods: In a Phase II study (G200705), men with advanced prostate cancer (n=159) received 1000 mg or 2000 mg of GTx-758 daily or leuprolide. Serum samples were collected and analyzed by a reference laboratory. C-terminal telopeptides (pg/ml) and bone specific alkaline phosphatase (U/L) were measured as indicators of bone turnover. All p values describe the comparison of the GTx-758 treatment groups to the leuprolide treated men at day 120. Results: Men receiving the 1000 mg and 2000 mg doses of GTx-758 had lower C-terminal telopeptide levels with a mean percentage change of -56.9 ± 12.5 and -54.8 ± 23.1, respectively, as compared with an increase of 46.0 ± 48.9 percentage in the men receiving the leuprolide (p&lt;0.001). Similarly, bone specific alkaline phosphatase levels were lower in men treated with GTx-758, with mean percentage changes of-28.5 ± 11.7 and -19.8 ± 14.7, respectively, compared with an increase of 8.1 ± 24.3 percent in the leuprolide treated group (p&lt;0.001). As a result of an increased risk of venous thromboembolic events (VTEs) at these higher doses of GTx-758, the trial was stopped prior to its completion and not all of the men on the study reached the 120 day treatment dates (71 evaluable). Conclusions: Patients receiving GTx-758 experienced a significant decrease in markers of bone turnover indicating potential improvement and not a loss of bone on ADT. Since changes in bone mineral density are a major side effect that can negatively affect the quality of life in men on ADT, the improvements in bone turnover observed in men treated with GTx-758 could be significant. A Phase II clinical trial utilizing lower doses of GTx-758 (G200712) is currently being performed. Clinical trial information: NCT01326312.
Safety and oncologic outcomes of robotic-assisted esophagogastrectomy.
Authors: Sebastian G. De La Fuente, Jill M. Weber, Sarah E. Hoffe, Ravi Shridhar, Khaldoun Almhanna, Richard C. Karl, Kenneth Meredith
Journal: Journal of Clinical Oncology (2012)

93 Background: The introduction of robotic systems to surgical oncology has allowed improved visualization with more precise manipulation of tissues. In esophageal cancer patients, this is crucial since most patients undergo neoadjuvant therapy (NT) prior to surgical resection. We report our initial experience in patients undergoing robotic-assisted Ivor-Lewis esophagogastrectomy (RAIL) for oncologic purposes at a large-referral center. Methods: A retrospective review of all consecutive patients undergoing RAIL from 2010-2011 was performed. Basic demographics such as age, gender, and body mass index (BMI) were recorded. Oncologic outcomes include tumor type, location, NT, post-operative tumor margins, and nodal harvest. Immediate 30-day postoperative complications were also recorded. Results: We identified 50 patients who under went RAIL with median age of 66 (42-82 years). The mean BMI was 28.6 ± 0.7, 67% of patients received NT and 54% had an ASA classification of 3. The mean and median number of lymph nodes retrieved during surgery was 20 ± 1.4 and 18.5 (8-63) respectively. R0 resections were achieved in all patients. The mean estimated blood loss was 146 ± 15 ml and there were no conversions to an open procedure. Postoperative complications occurred in 13 (26 %) of patients. Complications included atrial fibrillation 5 (10%), pneumonia 5 (10%), anastamotic leak 1 (2%), conduit staple line leak 1(2%), and chylous thorax 2 (4%). There were no wound infections documented. The median ICU stay and length of hospitalization (LOH) were 2 and 9 days respectively. Total mean operating time calculated from time of skin incision to wound closure was 453 ± 13 minutes. The mean operative time significantly decreased over time (first 23 cases 479 min vs. second 23 cases 428 min, p&lt;0.05). Similarly the frequency of complications decreased significantly after 28 cases: 10 (35%) vs. 3 (13%) p=0.04. There were no in hospital mortalities. Conclusions: We demonstrated that RAIL for esophageal cancer can be performed safely with acceptable oncologic outcomes. RAIL may be associated with fewer complications after a learning curve, and shorter ICU stay and LOH.
Toxicity analysis of lymph node irradiation for prostate cancer patients treated with IMRT.
Authors: Matthew E. Johnson, Tianyu Li, Alexander Kutikov, Mark K. Buyyounouski, Mark L. Sobczak, Rosalia Viterbo, Eric M. Horwitz
Journal: Journal of Clinical Oncology (2014)

41 Background: The radiation target for intensity modulated radiation therapy (IMRT) in high-risk prostate cancer (HRPC) includes both the prostate and seminal vesicles (SV). Inclusion of the regional lymph nodes (LN) has considerable variation in daily practice. Currently used prescriptions are 80 Gy to prostate and proximal SV, with 56Gy to the distal SV with (P/SV+LN) or without the pelvic LN (P/SV). The same P/SV prescription is used for intermediate risk prostate cancer (IRPC). We report the association between inclusion of the LN and toxicity for men treated from 2001 to 2009. Methods: 1,160 men treated for HRPC and IRPC with IMRT were identified in our clinical database. All patients had simulation with both CT and MRI, and utilized daily image guidance. Toxicity data were obtained from chart review. Statistical analysis was performed utilizing log rank test. Results: 408 patients were in the P/SV+LN group. There was no difference between the groups in regard to age, race, RT duration, or smoking. Median prescription dose was 78 Gy in both groups. Median follow-up was 44 months. A higher rate of late GI toxicity was seen in the group of patients treated to P/SV+LN (p&lt;0.01), see Table. No difference was seen in toxicity &gt;grade 2 for acute GU (33.1% vs. 30.2%, p=0.31), acute GI (5.9% vs. 3.5%, p=0.05), or late GU toxicity (13.7% vs. 13.0%, p=0.74) for P/SV+LN vs. P/SV alone at 5 years. MVA was performed for late GI toxicity controlling for radiation dose, length of radiation course, and use of androgen deprivation. Inclusion of LN RT remained a significant predictor of late GI toxicity (HR=2.0, p=0.02). For those with late GI toxicity, the most common symptoms were bleeding (69.5%), increased frequency of bowel movements (26.6%), fecal incontinence (15.7%), and proctitis (14.9%). Conclusions: Delivery of 56 Gy to the pelvic LN results in a significant increase in grade 2 or higher late GI toxicity with a HR of 2.0 in the setting of treatment with IMRT. A decision to treat the pelvic LN in HRPC should be weighed against the increase in late GI toxicity. [Table: see text]
FOLFOX4 relative dose intensity and factors associated with dose reduction or stop: A cohort study.
Authors: F. Canoui-Poitrine, M. Laurent, E. Paillaud, P. Caillet, M. Verlinde-Carvalho, N. Reynald, T. Vesval, A. Le Thuaut, S. Bastuji-Garin, S. Culine
Journal: Journal of Clinical Oncology (2011)

e19668 Background: Randomized controlled trials suggest similar efficacy and tolerance of chemotherapy in elderly cancer patients compared to younger. The objective was to assess in real-world setting FOLFOX4 relative dose intensity (RDI) and identify factors associated with dose reduction or stop. Methods: Between January 2007 and February 2010, 86 consecutive patients with colorectal cancer treated by FOLFOX4 were included and followed for first dose reduction (≥15%) or stop during 12 cycles for adjuvant chemotherapy (n=58) and 6 cycles for palliative chemotherapy (n=28). Data regarding patient characteristics and doses were collected using hospital chemotherapy database. Among a subgroup of patients ≥ 70 years, Comprehensive Geriatric Assessment parameters were assessed. Analysis used Kaplan-Meier survival curves, log-rank tests and Cox model. Results: Mean age was 65.3 (±11.5; 44.2% ≥ 70 years), 52.3% were women and 54.4% had a performance status (PS) at 0. Median RDI was 0.89 (Q1: 0.74 – Q3: 0.97). Respectively for FOLFOX4, 5FU and oxaliplatine, 48.4% (95% CI: 35.6-63), 26.7% (12-44.8) and 47.2% (37-61) had a dose reduction or stop within 3 months. Age ≥ 70 years (p logrank=0.007), female sex (p=0.03) and PS of 1 or more (p=0.03) were associated with dose reduction or stop. In multivariate analysis, female sex (adjusted HR = 2.34; 95%CI:1.04-5.57) and age (adjusted HR for one year increase = 1.04; 95% CI:1.00-1.09) remained associated with dose reduction or stop. Neuro-and hematotoxicity were the leading causes of dose reduction or stop of oxaliplatine (48.9%) and 5FU (38.5%) respectively. Patients ≥ 70 years had more often neurotoxicity related to oxaliplatine (46.4% vs 14.8%; p=0.003) than younger whereas no significant difference was found for 5FU. Dependency (adjusted HR=7.35; 95% CI:1.19-45.5; p=0.03) and impaired mobility (6.18; 95%CI:1.16-33.07; p=0.033) were associated with dose reduction or stop after adjustment for age. Conclusions: age was independently associated with FOLFOX4 dose reduction or stop. This can be partly explained by a greater toxicity in elderly for oxaliplatine but not for 5FU. Among elderly, dependency and impaired mobility may be associated with FOLFOX4 dose reduction or stop.
Long-term immune responses elicited by a DNA vaccine encoding prostatic acid phosphatase (PAP) in patients with nonmetastatic castrate-resistant prostate cancer.
Authors: Douglas G. McNeel, Jordan T. Becker, Jens C. Eickhoff, Laura E. Johnson, Glenn Liu, Brian M. Olson
Journal: Journal of Clinical Oncology (2013)

135 Background: We have previously reported a phase I/II trial with a DNA vaccine encoding PAP in patients with stage M0 CaP. Vaccination was found to be safe and immunologically active. Th1-biased PAP-specific immune responses were associated with increases in PSA doubling time (DT). In the current trial, we sought to evaluate the immunological efficacy of immunizations performed over a 1-2-year period of time, with the goal of identifying a preferred schedule. Methods: Patients (pts) were randomized to a schedule of 6 immunizations at 2-wk intervals followed by quarterly booster immunizations, or a schedule determined by frequent immune monitoring. Immune monitoring was by IFNγ and granzyme B ELISPOT and antigen-specific T-cell proliferation. Pts continued immunization until evidence of radiographic progression, toxicity, two years, or 24 total immunizations, whichever occurred first. Results: 17 pts were enrolled, of whom 11 completed at least 1 year on treatment, and 4 completed 2 years. 3 pts remain on study. 1 pt experienced a grade 3 allergic reaction (angioedema) after 11 immunizations; no other events &gt; grade 2 were observed. 6/16 evaluable pts developed durable immune responses, defined as statistically significant PAP-specific T-cell responses by at least two separate measures that were at least 3-fold the baseline response and detectable at &gt;1 post-treatment time point. 2 pts in the immune-monitoring arm developed immune responses after 6 immunizations that were detectable at each quarterly time point up to 2 years. 5/15 evaluable pts were observed to have a &gt;3-fold increase in PSA DT; the 2 with the greatest increase in PSA DT developed PAP-specific IFNγ-secreting T cells detectable at multiple time points after immunization. Conclusions: Repetitive immunization with this vaccine appears safe and immunologically active. Presence of durable Th1-biased antigen-specific immune responses is a mechanistically rational biomarker, and may be associated with favorable increases in PSA DT observed in 2 separate trials. Impact of vaccination on time to radiographic disease progression awaits results from an ongoing randomized clinical trial. Clinical trial information: NCT00849121.
An early-phase study of azacitidine and lenalidomide for untreated elderly acute myeloid leukemia (AML) patients.
Authors: D. A. Pollyea, H. E. Kohrt, R. Rajwanshi, L. Gallegos, C. Berube, S. E. Coutre, J. R. Gotlib, M. Liedtke, B. S. Mitchell, B. C. Medeiros
Journal: Journal of Clinical Oncology (2010)

TPS280 Background: Induction therapy results in suboptimal outcomes in elderly AML patients (pts). CpG hypermethylation of tumor suppressor gene (TSG) promoters can reduce expression and contribute to these poor outcomes. Azacitidine (aza) prevents DNA methyltransferase from methylating CpG cytosines, allowing transcription of previously silenced genes. Lenalidomide (len), an immunomodulatory agent, upregulates SPARC, a hypermethylated TSG with reduced expression in AML (Pellagatti A, et al. PNAS USA. 2007;104:11406). In addition, len was recently shown to activate demethylation of the promoter histone of p21, allowing expression of this TSG (Escoubet-Lozach L, et al. Cancer Res. 2009;69:7347). Therefore, we hypothesize that the low-intensity combination of aza and len will be a well-tolerated, mechanistically logical regimen that can synergistically upregulate TSG expression in elderly AML pts. Methods: Pts ≥60 with newly diagnosed untreated AML are eligible. In phase I, cohort 1 receives 75 mg/m2 aza SC/IV on days 1-7. After 3 weeks off, pts receive the same dose and schedule of aza, plus len, 5 mg PO on days 8-28 of a 42-day cycle. Cohorts 2, 3, and 4 receive 10, 25, and 50 mg of len, respectively, with the same dose and schedule of aza, for 42-day cycles. Once the maximum tolerated dose (MTD) is determined, the MTD cohort will roll over to an expanded phase II efficacy study. Sub-MTD cohort pts may continue at the same dose if they respond and tolerate the regimen. Pts may receive a maximum of 12 cycles. Disease assessments in both phases occur after cycles 1, 3, 6, and 12 by bone marrow biopsy. Using a Simon two-stage design with α= 0.05, power= 0.8, null hypothesis=20% complete remission (CR) (based on reports of use of aza alone) and alternative hypothesis=40% CR, phase II requires 33 pts. The primary endpoints for phase I and II are MTD and CR rate, respectively. Correlative studies to identify molecular features that predict responsiveness, including investigations of Cdc25C and PP2Acα phosphatase expression, TET2 mutations, and genome expression profiling, are planned. As of January 1, 11 pts, 6 with secondary AML, have enrolled in phase I (5, 3, and 3 in cohorts 1, 2, and 3), receiving a median of 2 cycles. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene Celgene