tbuckley/cabot-search huggingface dataset:
Clinical and pathological outcomes for patients with T1HG bladder cancer managed with upfront cystectomy with or without neoadjuvant chemotherapy and the impact of the MDACC high-risk features.
Authors: Michael J. Metcalfe, James Edward Ferguson, Roger Li, Lianchun Xiao, Colin P.N. Dinney, Neema Navai, Jay Bakul Shah, Ashish M. Kamat
Journal: Journal of Clinical Oncology (2017)

366 Background: In muscle invasive bladder cancer there is an increased risk for systemic disease identified for patients with certain high risk features (HRF): pre-operative hydronephrosis (POH), lymphovascular invasion (LVI), abnormal exam under anesthesia (AbnEUA), and the presence of variant histology (VH). We sought to identify the effect of these high risk features in the T1HG population. Methods: With IRB approval, a single center retrospective review was performed on all patients at MDACC from 1995-2013 who underwent radical cystectomy (RC) for T1HG urothelial cancer. Patients were stratified according to the presence or absence of HRF defined by the presence of LVI, POH, VH, AbnEUA, prostatic ductal involvement (PDI), and the delivery of neoadjuvant chemotherapy (NAC). Primary outcome included pathologic T (pT) upstage and presence of lymph node positive disease (LN+) at time of RC, as well as survival outcomes. Results: 372 T1HG patients underwent RC, of these 196 (53%) have HRF including: VH (n=98, 25%), LVI (n=44, 12%), PDI (n=31, 8%), POH (n=38, 10%) and/or AbnEUA (n=34, 9%). pT upstage occurred in 43/176 (24.4%) of patients without HRF, in 45/151 (30%) of patients with 1 HRF, and in 38% (17/45) of patients with &gt; 2 HRF (p=0.088). LN+ occurred in 18/176 (10.2%) of patients without HRF, 7.8% (15/151) of patients with 1 HRF and in 17.8% (8/45) of patients with &gt; 2 HRF (p=0.0403). Presence of HRF were not significant for a decreased OS (p=0.076), DSS (0.425), and RFS (p=0.103). No patients without HRF got NAC, and 41/196 (21%) of patients with HRF received NAC. There was no effect of NAC on pT upstage (OR 1.184, 95% CI 0.355-3.954, p=0.7834) or rate of LN+ disease (OR 1.758, 95% CI 0.669-5.606, p=0.2525) on multivariate analysis. There was no effect of NAC on OS (p=0.122), DSS (0.437), or RFS (0.7483). Conclusions: Presence of certain high risk features in the T1HG setting does have increased risk of pT upstage and LN+ disease in patients treated with cystectomy. However, there is no effect seen on survival outcomes. Use of NAC did not significantly alter outcome in our cohort and should be reserved for the muscle invasive setting.
CD44, a cancer stemness marker, to predict poor clinical outcome of esophageal cancer patients after neoadjuvant chemoradiotherapy.
Authors: Yoshinori Fujiwara, Reigetsu Yoshikawa, Masanori Tsujie, Hiroaki Kato, Hiroshi Takeyama, Kotaro Kitani, Masao Yukawa, Masatoshi Inoue
Journal: Journal of Clinical Oncology (2015)

e15068 Background: The major causes of treatment failure in cancer are the development of metastases and drug resistance. Recently, extensive studies have shown hyaluronan (HA) - CD44 interactions are crucial in cancer stemness resulting in therapy resistance. However, their clinical role hasn’t been elucidated yet in esophageal cancer progression. Here, we analyzed whether CD44 expression could predict disease recurrence and prognosis in esophageal cancer patients undergoing neoadjuvant chemoradiotherapy (CRT). Methods: CD44 expression was evaluated in 79 patients with histologically confirmed esophageal squamous carcinomas (ESCC) undergoing preoperative CRT, by immunohistochemical staining. Survival analysis was carried out by the log-rank test using Kaplan-Meier method. Results: Among 79 patients, 38 showed CD44 positive expression (48.1%). Overall survival (OS) was significantly associated with lymph-node metastasis, distant metastasis and CRT, and was further correlated with the absence of both CD44 expression and residual tumor. Furthermore, patients with CD44-positive cancers showed significantly poorer prognoses than those without (Disease-Free Survival; mean DFS time 22.1 vs 73.7 months, 3-yr DFS 18.1% vs 48.9%, P < 0.005, OS; mean OS time 26.3 vs 77.6 months, 3-yr OS 30.8% vs 65%, P < 0.01). Conclusions: Our study has shown that CD44 expression is a strong and independent predictive marker of early relapse and poor prognosis in ESCC after CRT. These findings suggest that CD44 is a rationale therapeutic target for therapy-resistant esophageal cancer cells leading to recurrence.
FOLFIRI.3 (CPT-11 plus folinic acid plus 5-FU) alternating with gemcitabine or gemcitabine (G) alone in patients (pts) with previously untreated metastatic pancreatic adenocarcinoma (MPA): Results of the randomized multicenter AGEO phase II trial FIRGEM.
Authors: Isabelle Trouilloud, Anne Claire Dupont-Gossard, Pascal Artru, Thierry Lecomte, Mélanie Gauthier, Thomas Aparicio, Anne Thirot-Bidault, David Malka, Celine Lobry, Amani Asnacios, Sophie Lacombe, Francine Fein, Daniela Fanica, Olivier Dubreuil, Lysiane Marthey, Aziz Zaanan, Franck Bonnetain, Julien Taïeb
Journal: Journal of Clinical Oncology (2012)

4018 Background: CPT-11 showed modest activity and tolerability in MPA. We developed a new strategy to improve efficacy and tolerability of CPT-11 based regimen in MPA pts. Methods: Chemotherapy-naive pts with histologically proven MPA, bilirubin levels &lt; 1.5 ULN and performance status (PS) 0-1 were randomized in a phase II trial to receive either FOLFIRI.3 (CPT-11 90 mg/m 2 as a 60-min infusion on day (D) 1, leucovorin 400 mg/m 2 as a 2-hr infusion on day 1, followed by 5-FU 2000 mg/m 2 as a 46-hr infusion and CPT-11 90 mg/m 2 , repeated on D3, at the end of the 5-FU infusion, every 2 weeks) for 2 months alternarting with G (1000 mg/m² at a fixed dose rate of 10 mg/m²/min on D1, D8, D15, D29, D36 and D43) for 2 months (arm A) or G alone (arm B). Using Fleming design the primary end point was rate of progression free survival (PFS) at 6 months from (H0) 25% over (H1) 45% needing to include 49 pts/arm. Results: Between 2007 and 2011, 98 pts were enrolled (males: 59, median age: 62 years, PS 0: 32%). Median follow-up was 23 months. Grade 3-4 toxicities per pts (%) in arm A/B were diarrhea 13/0, nausea-vomiting 11/4, neutropenia 51/25 and febrile neutropenia 4/0. No toxic death occurred. Response rate were 40 and 11% as disease control rate (CR+PR+SD) were 73 and 52% in arm A and B, respectively. The primary endpoint of the trial was met with rate of PFS at 6 months of 48% (95% CI: 33-63) in arm A while in arm B PFS was 30% (95% CI: 17 - 44). One year PFS was 23% (95%CI: 11.5-36) and 11% (95%CI: 4-21), respectively. Conclusions: FIRGEM strategy is feasible and efficient with a manageable toxicity profile in good condition pts with MPA. A phase III trial comparing this strategy with the FOLFIRINOX triplet therapy focusing on quality of life should now be performed.
Carbon Monoxide Therapy Reduces Reactive Oxygen Species Production and the Short-Term Hematopoietic Stem Cell Population In Heme-Oxygenase-1 Knockout Mice
Authors: Joan D. Beckman, Paul H Marker, Julia Nguyen, John D Belcher, Robert P Hebbel, Anthony J. Croatt, Karl A. Nath, Gregory M. Vercellotti
Journal: Blood (2010)
Impact of skeletal-related events on pain and analgesic use in patients with solid tumors and bone metastases.
Authors: Lesley Fallowfield, Charles S. Cleeland, Roger Von Moos, Donald Patrick, Jean-Jacques Body, Blair Egerdie, Alison Stopeck, Janet Elizabeth Brown, Gavin M. Marx, Felipe Palazzo, Danail I Damyanov, Ying Zhou, Ada Braun, Arun Balakumaran, Yi Qian
Journal: Journal of Clinical Oncology (2013)

e20514 Background: Skeletal-related events (SREs) including pathological fracture (PF), surgery (SB) or radiotherapy to bone (RB), or spinal cord compression (SCC) occur frequently in patients (pts) with advanced cancer and bone metastases and may cause debilitating clinical sequelae for pts. Pooled results from 3 clinical trials showed denosumab was superior to zoledronic acid (ZA) for prevention of SREs. We now evaluate the burden of SREs through pt-reported pain and analgesic use. Methods: Randomized (1:1) pts in the phase III, double-blind, placebo-controlled trials received denosumab (120 mg SC) or ZA (4 mg IV, adjusted for renal function) monthly. In this posthoc analysis, data from pts with solid tumors in the 2 treatment arms were pooled. At baseline (BL) and each monthly visit, pain was assessed via the Brief Pain Inventory (BPI; 0 no pain to 10 severe pain), and pts’ analgesic use with the Analgesic Quantification Algorithm (AQA; 0 no analgesics to 7 &gt; 600 mg oral morphine equivalent/day). Pain and analgesic use for pts with SREs were assessed from 6 months before to 6 months after the 1 st on-study SRE. A control group was comprised of all pts without SREs; the index time was defined as the median time to each SRE type. SRE impact was assessed using a stratified Cox proportional hazards model adjusting for SREs, as time-dependent covariates, and other baseline characteristics, and reported as HR and 95% CI. Results: 1,925 pts had an on-study SRE (first SRE type: 923 PF; 829 RB, 119 SCC, 54 SB), and 3,618 pts did not. A greater proportion of pts with SREs had a BPI worst pain score &gt; 4 (moderate/severe pain) or an AQA score ≥ 3 (strong opioid use) than did pts with no SREs. The development of SRE was associated with significantly greater risk of pain progression from no/mild pain at BL to moderate/severe pain on study (PF 1.29 [1.07, 1.57], P = 0.009; RB 2.51 [2.03, 3.10], P &lt; 0.001; SCC 3.07 [1.83, 5.13], P &lt; 0.001; and SB 2.75 [1.19, 6.33], P = 0.018). Conclusions: Pts who experienced on-study SREs had increased pain severity requiring stronger analgesic use. Effective treatments that delay or prevent SREs can reduce pain and the need for palliation with opioids. Clinical trial information: NCT00321464, NCT00321620, and NCT00330759.
Patterns of AKT, mTOR, ERK, and STAT3 pathway activation in MGUS, smoldering multiple myeloma, and multiple myeloma.
Authors: Jeremy Todd Larsen, Vijay Ramakrishnan, Linda Wellik, Teresa K. Kimlinger, S. Vincent Rajkumar, Shaji Kumar
Journal: Journal of Clinical Oncology (2015)

8589 Background: Constitutive activation of key signaling pathways supports proliferation in multiple myeloma (MM). However, pathway activation in MGUS and smoldering multiple myeloma (SMM) compared to MM has not been characterized. We examined the levels of phosphorylated Akt, mTOR, ERK, and STAT3 expression by immunohistochemistry (IHC) in MGUS, SMM, and MM and assessed their impact on clinical outcomes. Methods: FFPE bone marrow biopsy samples were obtained during routine clinical care. Primary antibodies used were p-Akt (S473), p-mTOR(Ser2448), p-ERK1/2(Thr202/Tyr204), and p-STAT3 (Tyr705). Staining intensity was scored as: 0 (no staining), 1 ( < 50% of cells), 2 ( > 50%) and 3 (dark staining of all cells). Nominal variables were compared with Fisher's exact test and time to progression (TTP) was calculated with Kaplan Meier analysis. Results: Twenty-one MGUS, 20 SMM, and 18 MM patients were reviewed. Strong expression of p-Akt (2-3+ IHC score) was present in 15% of MGUS cases versus 62% of SMM and 61% of MM patients (p = 0.037). Strong p-mTOR expression was observed in SMM and MM patients compared to MGUS patients (100% and 94% versus 45%; p = 0.001). 61% of MM cases exhibited strong p-ERK expression versus 34% in SMM and 15% in MGUS (p = 0.042). There was non-significant trend toward higher p-STAT3 expression in MM versus SMM/MGUS (39% in MM versus 12% and 10% in SMM and MGUS; p = 0.15). Increased p-mTOR activity correlated with high expression of p-Akt(S473) in all patients (p = 0.023). TTP in SMM patients with high versus low p-ERK activity was significantly shorter (76 months vs 16 months; P = 0.046). No other signaling pathways demonstrated statistical differences in TTP or overall survival. Conclusions: Comprehensive IHC analysis across the spectrum from MGUS to SMM and MM demonstrated increased activity of multiple key signaling pathways as disease progression occurs. Expression of p-Akt(S473) and p-mTOR in SMM and MM is significantly higher than MGUS patients, suggesting an upregulation of these pathways is an early event in pathogenesis. Activation of p-ERK and p-STAT3 was more frequent in MM versus MGUS/SMM, suggesting they may be more active in advanced disease.
Risk factors for complicated grief (CG) and utilization of a hospice bereavement program.
Authors: Elizabeth Henry, Rong Guo, Aziz Ansari, Theresa Kristopaitis, Mark Speyer, Nancy Kiel, Mary Lou Bleeg, Susan DeLongis, Jacalyn Kareb, Marie Shanahan, Sally Taylor, Twana Rundle, Shelly S. Lo
Journal: Journal of Clinical Oncology (2012)

e19588 Background: The Medicare hospice benefit mandates that bereavement services be provided to a surviving caregiver for a period of one year following a patient’s (pt) death. Identifying caregivers at risk for CG is essential so that appropriate interventions can be provided. Methods: Our objective was to identify specific features predicting for CG in surviving caregivers of pts with a malignancy enrolled in an academic based hospice program and determine utilization of Medicare’s bereavement services. Hospice charts for 65 patients whose caregivers were consecutively discharged from bereavement follow-up between January 2009 and December 2011 were reviewed. Assessments for CG features were performed with use of chaplain and social worker visits, and phone calls from a trained bereavement volunteer to caregivers at 6-8 wks and 6 months after a pt’s death. A discharge assessment was completed at 13 months. Results: Fifty (77%) hospice pts had a cancer (ca) diagnosis and tended to have a shorter average length of hospice enrollment than non-ca pts (34 vs 60 days, p=0.11). There was no difference in risk of caregiver CG between ca vs non-ca diagnoses (p=0.12). Twenty-one (42%) of ca pt caregivers were identified at risk for CG. Ca pts ≤ 50 yrs at the time of hospice enrollment were more likely to have caregivers identified at risk for CG compared to those ≥ 50 yrs (3, 100% vs 18, 38%, p=0.07). At risk ca caregivers had a lower average pt age at time of hospice enrollment than lower risk caregivers (mean pt age 67 vs 76 yrs, p=0.03). Eight ca caregivers (38%) identified at risk for CG received intensive bereavement counseling; 13 (62%) subsequently received routine bereavement follow up; none were lost to follow up. Length of enrollment, caregiver employment status and caregiver relationship did not predict for risk of CG. No ca caregivers required intensive bereavement services beyond 12 months post pt death. Conclusions: Young patient age at time of hospice enrollment is associated with an increased risk of caregiver CG.Intensive bereavement counseling was required by 38% of ca caregivers, and none required &gt;1 yr of service. Further study needs to be done to see if caregivers are receiving adequate bereavement support through the hospice benefit.
Ketoconazole as inhibitor of the enzyme CYP17 in locally advanced or disseminated granulosa cell tumors of the ovary (the GreKo I study) (gethi 11-03).
Authors: Laia Garrigos, Alicia Hurtado, Ana Santaballa, Andrés Redondo, Nuria Laínez, Laura Vidal Boixader, Eva Guerra Alia, Victor Rodriguez, Juan Fernando Cueva, Isabel Bover, Isabel Palacio, M Jesus Rubio, Mario Prieto, Jose Antonio Lopez-Guerrero, Nuria Romero, Zaida Garcia-Casado, Elena García-Martínez, Enrique Grande, Jesús García-Donas
Journal: Journal of Clinical Oncology (2014)

5558 Background: Granulosa-cell tumors (GCTs) of the ovary are a rare entity characterized by its genomic stability, presenting a punctual mutation at the FOXL2 gene, 402C→G (C134W), in the vast majority of cases. The protein encoded by this gene directly interacts with the Steroidogenic Factor-1 (SF-1) that regulates the expression of the enzyme CYP17. Since CYP17 inhibition has shown major activity in some cancers, we aimed to test the role of ketoconazole in GCT in a proof of concept trial. Methods: An open-label phase II trial was designed. Main inclusion criteria was adult women with advanced non-resectable GCT. Primary objective was radiological response, centrally assessed. Taking as a basis the two-stage Gehan model, 17 patients would need to be included in the first stage to demonstrate a treatment efficacy of at least 15% (type I error α = 0.05, power of the test (1 - β) = 0.8). Treatment consisted on oral Ketoconazole 400 mg tid plus hydrocortisone 30 mg in morning and 20 mg in evening. 10 institutions, members of the Grupo Español de Tumores e Histologías Infrecuentes (GETHI) were involved. Results: From October 1st 2012 to January 31st 2014 seven patients were included. Recruitment was early finished due to ketoconazole shortage. Median age was 59.5 (range 44 to 63). All patients had 3 to 4 metastatic localizations and had received at least one prior treatment. With a median follow up of 4.6 months (range 2 to 11 months) all cases achieved tumor stabilization as best response. Only one patient has finally progressed thus, median Progression Free Survival (PFS) has not been reached. No grade >2 toxicity has been reported. A preplanned analysis of FOXL2 showed that the case that progressed did not present the pathognomonic mutation 402C→G (C134W) supporting partially the rationale of the study. Mature data with a follow up of 6 months for all cases and complete mutational analysis will be presented at the meeting. Conclusions: CYP17 inhibition seems to be a useful strategy in GCT. These results have prompted a second study (GREKO II) that will assess the role of orteronel, a new generation CYP17 inhibitor, in GCT. Clinical trial information: NCT01584297.
Pre-planned feasibility and safety analyses of docetaxel/S-1 combination in a phase III study comparing docetaxel/S-1with S-1 alone as postoperative adjuvant chemotherapy for stage III gastric cancer (JACCRO GC-07).
Authors: Yoshihiro Kakeji, Yasuhiro Kodera, Kazuhiro Yoshida, Mitsugu Kochi, Masazumi Takahashi, Takayuki Kii, Atsushi Ishiguro, Kiyoshi Ishigure, Akinori Takagane, Takanori Matsui, Masahide Kaji, Wataru Ichikawa, Takeshi Sano, Masahiro Takeuchi, Masashi Fujii, Toshifusa Nakajima
Journal: Journal of Clinical Oncology (2015)

e15000 Background: After the ACTS-GC trial, adjuvant postoperative chemotherapy with S-1 has become the standard for curatively resected stage II/III gastric cancer (GC) in Japan. However, the subset analysis of that trial suggested that S-1 monotherapy was suboptimal to treat stage III GC (HR 0.51, 0.71, and 0.79 for Stages II, IIIA, and IIIB, respectively). A cisplatin/S-1 combination, the standard of care for advanced gastric cancer (AGC) in East Asia, was found to be toxic and intolerable to be given postoperatively. Thus, a docetaxel (DTX)/S-1 combination (DS), found to be another option for AGC by a phase III trial (START trial), was eventually selected as a candidate for the new standard to be explored in JACCRO GC-07, an on-going phase III trial for Stage III GC (UNIN000010337, n = 1,100, primary endpoint: 3-year RFS). Here, we present results of preplanned feasibility and safety analysis involving the first 100 patients who underwent postoperative DS in this study. Methods: Patients with stage III GC who underwent curative D2 gastrectomy were randomly assigned (1:1) to receive adjuvant chemotherapy with either DS or S-1 alone. The DS group received 1st cycle of S-1 monotherapy 80mg/m2 on days 1-14 q3w, and DTX 40 mg/m2 was added intravenously on day 1 of the 2nd to 7th cycle, followed by S-1 monotherapy on days 1-28 q6w up to 1-year postsurgery. The S-1 monotherapy group received oral S-1 on days 1-28 q6w to be repeated for 1-year. The Independent Data Monitoring Committee undertook a review of safety data in the first 100 pts in the DS group at the first interim analysis. Results: Between April 2013 and December 2014, 363 pts were accrued from 106 institutions. Of the first 100 pts allocated to the DS group, 80% (80 pts) completed the first four cycles of DS and exceeded null hypothesis of 60%. Grade 3/4 toxicities were leucopenia 19%, neutropenia 32%, anemia 6%, and anorexia 13%. There was no treatment-related death. Conclusions: Preliminary safety data indicate that DS doublet is safe and well-tolerated. The second interim analysis is currently scheduled in 2016 and the final results will be formally assessed in 2021. Clinical trial information: UNIN000010337.
Combined modality therapy for pancreatic carcinoma - An Australian Pancreatic Cancer Group study of the addition of gemcitabine to concurrent infusional 5-fluorouracil and 3D conformal radiotherapy
Authors: D. Goldstein, G. Van Hazel, C. Underhill, D. Kotasek, J. Harvey, M. Links, J. Shapiro, B. Iacopetta, N. Spry
Journal: Journal of Clinical Oncology (2004)

4100 Background: There is no consensus on the optimal management of locally advanced pancreatic cancer. This open-label phase II study examined whether continuous infusion 5-fluorouracil (CI 5FU) plus 3D conformal planning radiotherapy (RT) is well tolerated and may be combined with gemcitabine (G) pre and post chemoradiotherapy. Methods: Eligible patients (pts) were enrolled in 2 strata: (1) inoperable pancreatic cancer in head or body without metastases (LAD) or (2) resected pancreas cancer at high risk of relapse (Surg). G was given at 1000 mg/m2 weekly for 3 wks followed by 1 wk rest then a 5–6 wk period of RT and concurrent CI 5FU (200 mg/m2/day). The defined target volume was treated to 54Gy in 30# of 1.8Gy in the LAD and 45Gy in 25# in the Surg arm. After a 4-wk rest period, G was reinitiated for 12 wks. Results: 64 pts are on study and results for the first 40 pts are reported (26 females, 14 males; mean age 60 yr, range 39–79; 48% PS 0, 50% PS 1, 3% PS 2). Treatment was well tolerated: 3 pts are still on treatment after 2 cycles of G post RT, 19 completed all planned treatment, 13 discontinued due to disease progression, 4 withdrew and there was 1 treatment-related death. 75% of pts reported CTC grade 3/4 toxicities. 38/40 pts completed the initial G treatment; of these, 36/38 completed RT. 5/38 pts required reduction in 5FU, 10/40 in G pre RT and 32/36 in G post RT. In the LAD arm, 4.8% of pts responded and median TTPD was 6.9 mo (interquartile range (IQR) 5.9–10.3). In the 23 pts who progressed, 6 progressed locally, 14 systemically and 5 site unknown. More recent data shows 61% of LAD (median 13.4 mo, IQR 10.3–18.3) and 65% of Surg pts were alive at 1 yr (median 14.2 mo, IQR 9.5–23). The change in CA 19–9 levels (but not the baseline level) was predictive of outcome. In 17 pts we found no association of outcome with fluorescent-SSCP analysis of K-RAS, 4 p53 mutations or MSI status. Conclusions: This approach to treatment of locally advanced disease is safe and promising with good local control for a substantial proportion of patients and merits testing in a randomized trial against chemotherapy alone. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Amgen; Sanofi Sanofi; Eli Lilly; Oncomethylome Sciences Novartis