tbuckley/cabot-search huggingface dataset:
Targeting mTOR and VEGF in CRPC: Preliminary results of a phase I/II trial of temsirolimus (T) and bevacizumab (B) in docetaxel-refractory metastatic CRPC.
Authors: Jorge A. Garcia, Paul Elson, Matthew M. Cooney, Allison Janine Tyler, Robert Dreicer
Journal: Journal of Clinical Oncology (2012)

e15208 Background: Despite the availability of novel agents in the docetaxel-refractory setting, their activity is often short lived as all pts eventually progress. Activation of the PI3K/AKT/mTOR/VEGF/CXCR6 pathway regulates proliferation, differentiation, and malignant transformation in PCa progression. mTOR inhibition inhibits CXCL16, IL8/VEGF levels and other CXCR6 targets including CD44 and matrix metalloproteinase 3. Combination strategies capable of blocking the CXCR6/VEGF/AKT/mTOR signaling pathway could become a more effective therapeutic strategy for CRPC. Methods: Eligible docetaxel-refractory CRPC pts had serologic or objective PD after 1 or 2 prior chemotherapies. Pts with CNS metastases or active spinal cord compression were excluded. A staged-cohort design to study primarily safety of the combination was undertaken. Once the MTD was established a two-stage phase 2 trial was implemented. An underlying ORR &gt;20% was deemed sufficient to warrant further study, whereas an ORR rate &lt;5% would not. Starting doses of T and B were 15mg wk and 5mg/kg e/2 wk. Exploratory endpoints included CTCs, VEGF levels and Th1 cytokine production. Results: To date 22 of a total planned 28 pts are enrolled, median age was 64 and half of the pts were ECOG 1. Most pts had bone disease and the median PSA was 205 ng/mL. Pts have received a median of 4 cycles of treatment (range: 1-12). All pts have discontinued therapy; 48% PD, 38% AEs and 5% consent withdrawal. PSA reductions were observed in 30% of pts. No RECIST defined PR was seen. The most common AEs included anorexia (67%), mucositis (53%), fatigue (57%) and myelosuppression in over 60% of pts. CTC analysis and VEGF/TOR and cytokine levels are currently underway. Conclusions: The combination of T and B demonstrated significant toxicity in a heavily pretreated CRPC pt population. Minimal antitumor activity was observed. Exploratory studies and their correlation with clinical outcome are underway.
Association of chemotherapy regimen with venous thromboembolic risk in patients with urothelial tract cancer.
Authors: Jorge Ramos, Sarah Holt, George Schade, Matt D. Galsky, Jonathan L. Wright, John L. Gore, Evan Y. Yu
Journal: Journal of Clinical Oncology (2017)

314 Background: Cisplatin chemotherapy (CTX) is associated with increased risk of venous thromboembolism (VTE); however, other agents have also been hypothesized to increase risk. We assessed the association of VTE with different CTX regimens in urothelial tract cancer patients. Methods: We identified &gt; 66 year-old patients diagnosed with urothelial tract cancers (excluding renal pelvis) from the Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database from 1998 to 2011. CTX regimens included gemcitabine/cisplatin (GC), methotrexate/vinblastine/doxorubicin/cisplatin (MVAC), or gemcitabine/carboplatin (GCarbo). We calculated VTE rates within 120 days of CTX initiation and compared VTE by CTX regimen with multivariable logistic regression models adjusted for patient and cancer characteristics. Results: Of 5050 identified patients, VTE occurred in 13.1% (660/5050). VTE rates were 15.3% (265/1737) and highest for GC; 8.8% (23/262) and 12.2% (372/3051) of MVAC and GCarbo patients experienced VTE, respectively. Adjusted for patient demographic and cancer-specific variables, MVAC and GCarbo were associated with lower odds of VTE compared with GC (see Table). Conclusions: Compared with GC, MVAC and GCarbo are associated with a decreased rate of VTE. This finding suggests that gemcitabine may add to the increased thrombosis risk from cisplatin. Patients treated with GC should be counseled about this association. Sensitivity analyses to assess VTE risk of different CTX regimens in the perioperative setting will be presented. [Table: see text]
Surgical intervention in early-stage pancreatic adenocarcinoma.
Authors: Javaneh Jabbari, Aabra Ahmed, Ryan W Walters, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2017)

443 Background: Bilimoria et al (2007) reviewed 9,559 patients from the 1995-2004 National Cancer Database (NCDB) showing that 38.2% of patients with early-stage pancreatic cancer without any identifiable contraindications failed to undergo pancreactomy. We used the 2004-2013 NCDB to look at the role of surgery in initial care plans of patients with stage I pancreatic adenocarcinoma. We also assessed differences in practice in this regard at different types of cancer centers. Methods: We analyzed 12,927 patients diagnosed with stage I pancreatic adenocarcinoma between 2004-2013 from the NCDB. Survival differences between patients who received surgery at the primary site versus patients not offered surgery were estimated by the Kaplan-Meier method. Differences in surgery were compared using chi-squared analysis. Results: Of the stage I patients, 27.3% had surgery, 52.8% were not offered surgery, 9.3% were not offered surgery due to risk factors, 4.4% refused surgery. Patients who received surgery had an increased median survival time compared to patients who were not offered surgery (30.2 months versus 7.1 months, p &lt; 0.05). Patients at academic/research programs were most likely to have surgery compared to those at community cancer programs who were least likely to have surgery (39.8% versus 22.9%, p &lt; 0.05). Conclusions: Patients who had surgery of the primary site had a significantly longer median survival time than those that were not offered surgery. Patients were most likely to be offered surgery if they were at an academic/research facility. Future studies should examine other factors that could possibly influence whether a patient is offered surgery or not for early-stage pancreatic adenocarcinoma. [Table: see text]
Abstract A39: Expression of DNA methylation-related proteins in metastatic breast cancer
Authors: Lee Yukyung, Kim Eun-Sol, Koo Ja Seung
Journal: Cancer Research (2017)

Abstract Purpose: To investigate the expressions of methylation-related proteins (5-methylcytosine [5-meC] and DNA [cytosine-5-]-methyltransferase 1 [DNMT1]) in metastatic breast cancers of variable sites and their associations with clinicopathologic factors. Methods: A total of 126 metastatic breast cancers (31, 36, 11, and 48 bone, brain, liver, and lung metastases, respectively) were made into tissue microarrays, and immunohistochemical staining was performed for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER-2), Ki-67, 5-meC, and DNMT1. Molecular classification was made on the basis of the immunohistochemical staining results of ER, PR, HER-2, and Ki-67, as luminal A, luminal B, HER-2-positive, and triple-negative breast cancers. Results: Methylation-related proteins were differentially expressed based on the metastatic sites. Tumoral and stromal 5-meC showed the lowest expression in bone metastases (P &amp;lt; 0.001), while tumoral DNMT1 showed the lowest expression in bone metastases and the highest expression in brain metastases (P &amp;lt; 0.001). Expression of DNMT1 correlated with ER-negativity (P = 0.004), PR-negativity (P = 0.011), HER-2-positivity (P = 0.016), higher Ki-67 labeling indices (P = 0.016), and non-luminal A type (P = 0.017). Univariate analysis revealed that DNMT1-positivity was associated with shorter overall survival in patients with bone (P = 0.017) and lung metastases (P = 0.028). Conclusion: In metastatic breast cancer, methylation-related proteins are differentially expressed according to the metastatic sites. Tumoral and stromal 5-meC showed the lowest expression in bone metastases, while tumoral DNMT1 expression was low in bone metastases and the highest in brain metastases. Citation Format: Lee Yukyung, Kim Eun-Sol, Koo Ja Seung. Expression of DNA methylation-related proteins in metastatic breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A39.
Stem cell rescue from irradiation of multiple tumor sites combined with high-dose chemotherapy, followed by reduced intensity conditioning and allogeneic stem cell transplantation in patients with advanced pediatric sarcomas: Preliminary results of the MetaEICESS 2007 protocol.
Authors: Stefan Burdach, Uwe Thiel, Angela Wawer, Irene Teichert von Luettichau, Franziska Blaeschke, Thomas GP Grunewald, Marc Steinborn, Barbara Roeper, Michael Molls, Christoph Salat, Thomas Klingebiel, Peter Bader, Ewa Koscielniak, Peter Lang, Uta Dirksen, Heribert Jurgens, Hans-Jochem Kolb
Journal: Journal of Clinical Oncology (2015)

10525 Background: Advanced pediatric sarcomas are associated with poor prognosis. These truly rare diseases include Ewing’s sarcomas (ES), metastatic to more than one bone or early relapse as well as stage IV rhabdomyosarcomas (RMS). We assessed toxicity, relapse free survival (RFS) and overall survival (OS) of advanced ES and RMS patients treated a single institution with the MetaEICESS 2007 protocol. Methods: From 2007 to 2015, 9 patients, 7 with ES ( ≥ three bones/organs or marrow involved at diagnosis, n = 4 or relapse < 24 months after diagnosis, n = 2) and 2 with stage IV RMS patients were enrolled. The protocol comprised induction-chemotherapy, whole-body MRI/PET directed radiotherapy to the primary tumor and to all metastases, surgery, tandem high-dose chemotherapy with autologous rescue and allogeneic stem cell transplantation (allo-SCT). Data was censured on february 1st 2015. Radiotherapy was delivered to the primary tumor (n = 8, total dose 50-60 Gy), to the lungs (n = 4, 15-18 Gy), and to lymph node and osseous metastases (n = 3 and n = 7, 45-50 Gy). Target volumes ranged from 453 – 9.407 cm³ (median of 2.762 cm³). One patient received proton, all others photon irradiation. Results: 5 patients are surviving in CR at a median of 27 months (range 0-62) after allo-SCT. Median RFS after allo-SCT was 17 months (range 0-62). 8 patients had reached complete remission (CR) before allo-SCT, three of whom relapsed thereafter, predominantly outside the radiotherapy treatment fields. 4 patients received donor lymphocyte infusions (DLI), of whom two patients showed clinical responses. One patient had to be retransplanted after initial graft rejection, 3 patients suffered ADV reactivation, 3 patients developed acute- and 1 patient chronic GvHD. Conclusions: The MetaEICESS 2007 protocol constitutes a feasible option for patients with advanced pediatric ES and RMS. A larger cohort is mandatory to verify OS or RFS improvement over current protocols.
Increasing Hypoxemia and Dyspnea in Mild Chronic Obstructive Pulmonary Disease
Authors: Boris Medarov, Haroon Chaudhry, Thomas Myint
Journal: JAMA (2017)

A man with chronic obstructive pulmonary disease and worsening dyspnea has pulmonary hypertension by right heart catheterization, a nonocclusive left femoral and popliteal thrombus, and a large mismatch defect on V/Q scan. What would you do next?
Inverse probability of treatment weighting analysis of upfront surgery versus neoadjuvant chemoradiotherapy followed by surgery for pancreatic adenocarcinoma with arterial abutment.
Authors: Tsutomu Fujii, Suguru Yamada, Kenta Murotani, Hideki Takami, Masamichi Hayashi, Mitsuro Kanda, Goro Nakayama, Hiroyuki Sugimoto, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera
Journal: Journal of Clinical Oncology (2017)

440 Background: Combined arterial resection during pancreatectomy can be a challenging treatment, and outcome would be more favorable if the tumor becomes technically removable from the artery. Neoadjuvant chemoradiotherapy (NACRT) is expected to achieve locoregional control and enable margin-negative resection. To investigate the effects of NACRT in patients with pancreatic adenocarcinoma (PDAC) which were deemed borderline resectable through preoperative imaging due to abutment of the major artery, including the superior mesenteric artery (SMA) or common hepatic artery (CHA), but were still considered to be technically removable. Methods: Comparisons were make between 71 patients who underwent upfront surgery and 21 patients who underwent NACRT followed by surgery in the strategy to preserve the artery, using unmatched and inverse probability of treatment weighting analysis (UMIN000017115). Results: Fifty patients in the upfront surgery group and 18 in the NACRT group underwent curative resection (70% vs 86%, respectively; P = 0.1609). The results of the propensity score weighted logistic regressions indicated that the incidences of pathological lymph node metastasis and a pathological positive resection margin were significantly lower in the NACRT group (odds ratio, 0.006; P &lt; 0.0001 and odds ratio, 0.007; P = 0.0005, respectively). Among the propensity-score matched patients, the estimated 1- and 2-year survival rates in the upfront surgery group were 66.7% and 16.0%, respectively, and those in the NACRT group were 80.0% and 65.2%, respectively. Conclusions: It was suggested that chemoradiotherapy followed by surgery provided clinical benefits in patients with PDACs in contact with the SMA or CHA. Clinical trial information: 000017115.
Phase I, double-blind, placebo-controlled, ascending single subcutaneous dose, safety, tolerability, and pharmacokinetic study of sustained release granisetron (APF530).
Authors: John Barr, Erin O'Boyle, Martin Johnson
Journal: Journal of Clinical Oncology (2013)

e20587 Background: Although several 5-HT 3 antagonists are approved for chemotherapy-induced nausea and vomiting, agents with longer duration of therapeutic benefit are needed. APF530 incorporates a polymer that allows for controlled and sustained release of granisetron. Methods: Adult males were randomized to receive subcutaneous (SC) APF530 125 mg, 250 mg, 500 mg, or 1 g (groups A-D, respectively) and simultaneous placebo. Groups B-D subsequently received intravenous (IV) granisetron ≥ 7 days after APF530 dosing. Safety, tolerability, pharmacokinetics (PK), and absolute bioavailability of granisetron from APF530 were examined. Results: 26 subjects were randomized. All APF530 doses were well tolerated; most adverse events (AEs) were mild injection site reactions (pain on palpation, erythema); all resolved. Other AEs included headache (IV, SC), upper abdominal pain (SC), and constipation (SC). PK parameters were generally dose proportional (Table). APF530 elicited slow sustained absorption of granisetron; t max was 8-10 h, and some subjects had secondary plasma peaks at 24-96 h. Systemic levels were reached within 30 min. Based on AUCall, granisetron was shown to be completely bioavailable from the SC dose formulation of APF530. Conclusions: APF530 safety profile was similar to that of granisetron, with the addition of mild injection site reactions. Granisetron was completely bioavailable at all APF530 doses. PK parameters were generally dose proportional. Absorption of granisetron from APF530 was prolonged compared with that from IV granisetron. Clinical trial information: NCT01416259. [Table: see text]
Breast cancer screening: Biology of tumors detected by analog and digital mammography.
Authors: Caroline Drukker, Marjanka Schmidt, Emiel J. Rutgers, Fatima Cardoso, Karla Kerlikowske, Laura Esserman, Leen Slaets, Jan Bogaerts, Laura J. van 't Veer
Journal: Journal of Clinical Oncology (2013)

587 Background: Population-based screening might be associated with a higher likelihood of a (ultra)low risk tumor assessed by the 70-gene signature (MammaPrint) (ultralow defined as indexscore &gt;0.6, no distant metastasis observed at 5 years in the original 78 patients). The aim of this study is to determine the proportion of biologically (ultra)low risk tumors among the screen-detected tumors and to evaluate the impact of the analog versus digital screening technique. Methods: All Dutch breast cancer patients enrolled in the MINDACT trial (EORTC-10041), who were invited for the Dutch screening program (biennial, age 50-75), were included (n=1409). The proportions of 70-gene signature high, low and ultralow risk were calculated for patients with screen-detected (n=775), interval (n=390), and symptomatic, non-screening (n=244) carcinomas, taking into account analog vs. digital technology. Co-variants such as age, tumor size, grade, histological type, ER, HER2 and nodal status were included in the analyses. Results: Among the screen-detected tumors, 31.5% had a high risk, 31.2% a low risk and 37.3% an ultralow risk 70-gene signature result, compared to 47.4%, 28.5% and 24.1% among the interval carcinomas, respectively (p=0.001). Among the screen-detected carcinomas, 40.6% were detected using analog (n=315) and 59.4% using digital mammography (n=459). When using digital imaging a shift was seen among the screen-detected tumors in the proportions of high risk tumors from 27% to 35% and ultralow risk from 42% to 34%, low risk proportions remained the same (31%)(p=0.011). No such difference was seen for other tumor characteristics. Conclusions: Screen-detection was found to be associated with a higher likelihood of a biologically low risk tumor. The transition from analog to digital mammography resulted in a smaller proportion of ultralow risk and a larger proportion of high risk tumors among the screen-detected carcinomas.
Phase 1 trial of OCV-C02, a peptide vaccine for metastatic colorectal cancer patients refractory to all standard chemotherapies.
Authors: Satoru Iwasa, Hiroya Taniguchi, Kentaro Yamazaki, Takayuki Yoshino, Chika Kiryu, Ei Leen Liew, Yoshiharu Naka, Yuh Sakata
Journal: Journal of Clinical Oncology (2017)

706 Background: OCV-C02 is a peptide vaccine consisting of 2 peptide epitopes derived from ring finger protein 43 and translocase of outer mitochondrial membrane 34. In colorectal cancer (CRC), they are upregulated in approximately 80% of tumor tissues. This study was conducted to assess safety, preliminary efficacy and immunological responses to OCV-C02. Methods: Key eligibility criteria for this open label, sequential cohort, dose escalation study were patients (pts) with unresectable metastatic CRC (mCRC) refractory to all standard chemotherapies and HLA-A*24:02. Pts in cohorts 1 to 4 received OCV-C02 0.3, 1, 3 and 6 mg/body respectively, subcutaneously, on days 1, 8, 15 and 22 of the 28-day treatment cycle. Cycle was repeated in pts without progressive disease, until occurrence of unacceptable toxicity or disease progression. Primary endpoint was dose limiting toxicity (DLT) that was defined as treatment-related ≥ grade 3 or 4 hematological or ≥ grade 3 non-hematological adverse events (AEs) observed from days 1 to 29 of Cycle 1. Secondary endpoints were treatment emergent AEs (TEAEs), efficacy and immunological responses. Efficacy was evaluated by overall response rate, disease control rate (DCR), time to treatment failure (TTF) and overall survival (OS). Immunological responses were evaluated by cytotoxic T lymphocytes (CTL) and delayed-type hypersensitivity (DTH). Results: A total of 24 pts were treated. No DLT occurred in cycle 1 and no major safety issues throughout the trial. All pts had ≥ 1 TEAE. Frequently reported TEAEs included injection site reaction (25%), vomiting (25%), decreased appetite (20.8%) and pyrexia (16.7%). More than 50% of TEAEs were of grade 1 or 2 in severity. None achieved complete or partial response. Six pts had stable disease and DCR were 16.7%, 50% and 33.3% for cohorts 2, 3 and 4, respectively. TTF was 1.8, 0.9, 2.3 and 1.6 months and OS was 7.9, 11.6, 8.4 and 7.4 months for cohorts 1, 2, 3 and 4, respectively. CTL and DTH responses following vaccination were observed across the 4 cohorts. Conclusions: OCV-C02 at 0.3 to 6 mg/body exhibited a safe and well tolerated profile, and showed immunological responses in mCRC pts refractory to all standard chemotherapies. Clinical trial information: NCT01801930.
Treatment outcome of acute myeloid leukemia (AML) in HIV+ patients.
Authors: Irene Ang Dy, Matthew Patchett, Alicia McDonald, Peter H. Wiernik
Journal: Journal of Clinical Oncology (2012)

6595 Background: AML is diagnosed more frequently in HIV+ patients than previously. The results with standard AML treatment in such patients have not been evaluated. We evaluated whether the results justify standard aggressive treatment of AML in HIV+ patients. Methods: We identified 5 HIV+ patients at our institution who were subsequently diagnosed with AML and 68 previously reported HIV+ patients with AML through PubMed from 1986-2011. The median age at the time of AML diagnosis was 40 years (range 7-70 years). Of the 26 patients with known karyotype, 7 had favorable, 7 intermediate and 12 had unfavorable cytogenetics. The majority of treated patients received standard intensive induction therapy and complete responders (CR) received consolidation therapy. HIV was pre-, post-, and concurrently diagnosed in 47, 2 and 19 AML patients respectively. The Kaplan-Meier method examined whether CD4 count, AML treatment and CR attainment affected overall survival. Cox proportional hazard modeling, adjusted for age and CD4 count determined whether AML treatment and CR attainment were associated with death from AML. Results: The final analysis included pre- and concurrently HIV diagnosed AML patients (n=66). HIV infection occurred at a median of 5 years (range 0.25-28 years) prior to the diagnosis of AML in 47 patients. The most common FAB types were M4 (22.6%) and M2 (22.6%). CR was achieved in 71.7% (n=33/46) of treated patients and 51.5% (n=17/33) of them relapsed with a median CR duration of 9.2 months. Median survival of patients with CD4 count &lt; 200 and ≥ 200 was 7 vs. 13.4 months (p=0.03); median survival of untreated and treated patients was 1.0 vs.13.2 months (p &lt; 0.001) and median survival of treated patients who did and did not achieve CR was 2 vs. 21 months respectively (p &lt; 0.001). All treated patients and those who achieved CR were less likely to die from AML than untreated patients and those who failed to respond (H.R=0.05; 95% CI, 0.01-0.17 and H.R. = 0.11; 95% C.I, 0.04-0.35, respectively). Conclusions: Standard AML treatment and CR were associated with longer survival in HIV+ patients regardless of CD4 count. More than half of patients studied achieved CR. HIV+ AML patients should be offered standard AML therapy.