tbuckley/cabot-search huggingface dataset:
A phase I/II study of MM-111, a novel bispecific antibody that targets the ErB2/ErB3 heterodimer, in combination with trastuzumab in advanced refractory HER2-positive breast cancer.
Authors: M. J. Higgins, N. Y. Gabrail, K. Miller, S. V. Agresta, S. Sharma, C. McDonagh, J. Murray, K. Andreas, S. Frye, V. M. Moyo, C. Niyikiza, P. D. Ryan
Journal: Journal of Clinical Oncology (2011)

TPS119 Background: The ErbB2/ErbB3 oncogenic heterodimer is the most potent ErbB receptor pairing with respect to strength of interaction, receptor tyrosine phosphorylation, and downstream signaling through mitogen activated protein kinase and phosphoinositide-3 kinase pathways. MM-111 is a novel bispecific antibody fusion protein that specifically targets the ErbB2/ErbB3 heterodimer and abrogates binding of ErbB3's ligand heregulin. In preclinical models of HER-2+ solid tumors, MM-111 inhibits ligand-induced ErbB3 phosphorylation, cell cycle progression, and tumor growth. ErbB2 (HER2) is a well established target of anticancer agents such as trastuzumab and lapatinib for HER2+ cancers, specifically breast and gastric. ErbB3 signaling has emerged as an important mechanism of resistance to ErbB2 (HER-2) targeted agents in clinical use, and preclinical data demonstrates that MM-111 potentiates the antitumor activity of trastuzumab. This first-in-human phase I/II study evaluates the safety and tolerability of MM-111 in combination with trastuzumab and preliminarily explores efficacy in HER-2+ advanced breast cancer (ABC). Methods: This is a phase I/II, open label, multicenter, dose-escalation study that will evaluate the safety, pharmacokinetics (PK), and efficacy of MM-111 + trastuzumab. There is a dose escalation phase followed by an expansion cohort. The dose escalation phase utilizes a standard "3 + 3" design where doses of MM-111 will be escalated until the phase II dose is identified in combination with trastuzumab given at the approved dose and regimen. Once the MTD or phase II dose is identified, an expansion cohort will be enrolled to further evaluate the safety and efficacy of doublet. Key exploratory analyses will include an evaluation of safety and efficacy and levels of expression and/or amplification of HER2 and heregulin. As of January 1 2011, cohorts 1 thru 2 have been completed without DLT. A total of 7 patients have been treated. Enrollment to cohort 3 is ongoing.
Treatment of colorectal cancers with minimally invasive surgical techniques at a dedicated cancer center.
Authors: Sanjay S. Reddy, Elin R. Sigurdson, Jeffrey M. Farma
Journal: Journal of Clinical Oncology (2013)

549 Background: Laparoscopic (LS) and robotic surgery (RS) for colorectal cancer provides a new perspective of the deep pelvis. Our goal was to identify the role of LS and RS for patients with sigmoid and rectal cancer. Methods: We retrospectively analyzed 53 patients treated from 2007-2012. Resection type, previous surgery, neoadjuvant and adjuvant therapy, timing of surgery, lymph nodes (LN) harvested, estimated blood loss (EBL), operative time (OT), complications, and pathology were reviewed. Results: Of 53 patients, 32 underwent LS, and 18 RS. There were 47 patients with adenocarcinoma, 5 with unresectable polyps and 1 with anal melanoma. 62% of patients underwent a recto-sigmoid resection, 23% rectal, and 8% sigmoid. 32% had prior surgery. Neoadjuvant treatment (NAT) was initiated in 31 patients; 3 received chemotherapy without radiation, and 1 short course radiation. An average of 12.8 and 8.4 LN were harvested in the LS and RS groups respectively, with a mean of 9.9 LN after NAT, and 13.9 without. EBL was 155ml (20-650) with LS and 178ml (25-600) with RS. 3 LS cases were converted to an open procedure. Median OT was 270 and 302 minutes for LS and RS groups. Using the Clavien grading system, 12 patients had grade 1-2 complications, 5 grade 3, and 2 grade 4’s within 30 days. Radial margins were positive in 2 patients; one received NAT for a fungating anal adenocarcinoma, and the other had chemotherapy alone. One patient had a positive proximal margin with no prior therapy. Rate of complete pathological response (pCR) was 35%, and 71% were down staged. The mean interval between completion of NAT and resection was 8 weeks (range 4-12), and surgery to adjuvant therapy was 8 weeks (range 4-22). Conclusions: LS and RS surgery for colorectal cancer can be safely performed in conjunction with neoadjuvant and/or adjuvant chemotherapy. NAT should not preclude adoption of these techniques, as we achieved a 35% pCR with minimal operative morbidity allowing patients to proceed to adjuvant chemotherapy in a timely fashion. [Table: see text]
Immune Tolerance with a High Purity Plasma Derived Factor VIII Containing Von Willebrand Factor in Haemophilia A Patients with High Responding Inhibitors.
Authors: Benoit Polack, Philippe Beurrier, Chantal Rothschild, Frédérique Orsini, Albert Faradji, Anne Liennhard, Edith Fressinaud, Jenny Goudemand
Journal: Blood (2004)
RTOG 0438: A phase I trial of highly conformal radiation therapy for patients with liver metastases.
Authors: Alan W. Katz, Kathryn A. Winter, Laura A. Dawson, Michael C Schell, Joon-Hyung J. Kim, Yuhchyau Chen, David Roberge, Christopher H. Crane, Christopher Willett
Journal: Journal of Clinical Oncology (2012)

257 Background: This multi-institutional phase I trial was conducted to determine the maximally tolerated dose (MTD) of hypofractionated, highly conformal radiation therapy (RT) in patients (pts) with liver metastases. Methods: Eligibility criteria included non-surgical pts with ≤ 5 liver metastases; total measurement for all lesions ≤ 8 cm. There were four dose levels (DLs) escalating from 35 Gy to 50 Gy in 5 Gy increments given in 10 fractions with defined normal tissue dose limits. Accrual began at 40 Gy. The clinical target volume (CTV) included all metastases identified on contrast CT/MRI with a 5 mm margin. The planning target margin ranged from 4 to 30 mm around the CTV. For quality assurance the Image-Guided Therapy Center (ITC) remote review tool was used to evaluate treatment planning images and dosimetry information. Dose limiting toxicities (DLTs) were defined as treatment-related grade (Gr) ≥ 4 hepatic, gastrointestinal (GI), thrombocytopenia, or radiation induced liver disease (RILD) within 90 days (dys) of the start of RT. Results: 26 pts were enrolled between 11/05 and 12/10, and 23 were evaluable; 8, 7, and 8 on the 40, 45, and 50 Gy DLs respectively. Two pts assigned to the 50 Gy DL received 35 Gy because of normal tissue constraints, therefore an additional 2 pts were accrued and treated at the 50 Gy DL. The study was temporarily closed for toxicity evaluation after 6 pts on each DL were followed for a minimum of 90 dys from start of treatment. There were no DLTs observed on any of the DLs. Four pts developed treatment-related Gr 3 toxicities; 2 each on the 45 and 50 Gy DLs. On the 45 Gy DL, 1 pt had two Gr 3 GI toxicities: enteritis (37 dys from RT start) and diarrhea (22 dys) while another pt had Gr 3 lymphopenia (23 dys). On the 50 Gy DL, 1 pt had Gr 3 hyperglycemia (74 dys) and another pt had three Gr 3 toxicities: lymphopenia (13 dys), colonic hemorrhage (325 dys), and GI obstruction (325 dys). Conclusions: When normal tissue constraints could be met, treatment of liver metastases with 50 Gy in 5 Gy/fx is feasible and safe in a multi-institutional setting. Further studies looking at higher doses and alternate fractionation regimens are warranted. Supported by RTOG U10 CA21661, CCOP U10 CA37422 and ATC U24 CA 81647 NCI grants.
Risk model for severe anemia in patients with non-hematologic cancer receiving conventional chemotherapy: Results from a multicenter prospective cohort study
Authors: O. Juan, J. Muñoz-Langa, A. Albert, D. Almenar, V. Carañana, S. Olmos, J. Vidal, C. Molins, R. Llorente, V. Alberola
Journal: Journal of Clinical Oncology (2005)

8121 Background: Identification of clinical baseline characteristics that correlate with anemia development could optimize patient care and anemia management. Methods: A risk index for severe anemia, defined as Hb < 8 g/dL or poorly tolerated anemia < 10 g/dL that requires red blood cell transfusion (RBCT), was delineated in a prospective cohort of patients with non hematologic cancer treated with CT ± RT. Data about pts demographics, clinical and tumor characteristics, laboratory parameters and CT agents were collected just before the administration of each course of CT. Risk factors for Severe Anemia (SA) were tested in univariate and multivariate analyses using a logistic regression. A risk model was established using the independent risk factors identified in the multivariate analysis. A total of 450 pts (56% male) were included, 30% had anemia and 64.2% received rHuEPO. Results: Thirty six pts (8%) experienced SA. In multivariate analysis, only the presence of metastases (odds ratio [OR]= 2.8; 95% confidence interval [CI] 1.2 - 7.1), height (OR= 1.1; 95% CI 1.03 - 1.14), number of previous RBCT (OR= 2.1; 95% CI 1.2 - 3.7), baseline Hb level (OR= 0.55; 95% CI 0.39 - 0.77), concomitant RT (OR= 7.25; 95% CI 2.5 - 20.7), and increase platelet count (OR= 1.003; 95% CI 1 - 1.006) and Hb level (OR= 0.46; 95% CI 0.3 - 0.7) after first course of CT were independent risk factors for SA. For these 7 factors, risk coefficients were assigned depending on the value of their OR, and a risk score for each individual patient was obtained by adding the coefficients. The calculated probability of SA was 0%, < 25%, 25–50%, 50–85% and > 85% for patients with a score 0–3, 3–6, 7–8, 9–10 and > 10, respectively. Conclusions: This risk index could be useful to identify patients at high risk for CT-induced SA who might be appropriate candidates for prophylactic rHuEPO treatment. No significant financial relationships to disclose.
Building a provider network based on quality: The Moffitt Oncology Network initiative.
Authors: Timothy Edward Kubal, Douglas D. Letson, Karen K. Fields, Richard M. Levine, Charles F. Andrews, John Turner Hamm, Diana Lachica, Riti Shimkhada, John W. Peabody
Journal: Journal of Clinical Oncology (2014)

49 Background: Before entering into risk bearing contracts with payors, ACOs are challenged to find a basis for forming partnerships. Specialty ACO networks, in particular, must find ways to provide a common, high standard of care among a typically varied set of partners. The Moffitt Oncology Network (MON) Initiative demonstrates a possible solution to forming a value based ACO network across a broad geographical area that is based upon using clinical pathways. Methods: Moffitt Cancer Center (MCC) has developed more than 24 different disease specific pathways. The MCC pathways translate evidence-based guidelines into personalized cancer care throughout the continuum of care from evaluation to treatment. MCC is using these pathways with other hospital systems and physician groups throughout the MON. To enhance the use of pathways in the MON, MCC uses Clinical Performance and Value (CPV) Vignettes. CPV’s, are virtual patient cases related to the specific clinical pathways. The report herein is on pathway implementation in several disease areas (breast, lung and gastrointestinal (GI) cancers) across multiple sites: Lehigh Valley Hospital (Pennsylvania), Norton Cancer Institute (Kentucky), and Space Coast Cancer Center (Florida). Results: Pathway based clinical care was measured at baseline using CPVs across disease and site (Table). A total of 67 breast cancer providers took 131 breast cancer vignettes; 35 lung cancer providers took 104 lung cancer vignettes; and to date 27 GI cancer providers have taken 54 GI vignettes. There is statistically significant variation in performance among providers and between sites. This is manifest in pathway-specified areas of work-up, diagnosis, and treatment. Conclusions: Fostering adoption of clinical pathways is a practical objective that can help guide the formation of an ACO oncology network. This may be useful for forming specialty ACOs that establish a standard of care and set the stage for adopting new payment models with payors. [Table: see text]
Resection of liver metastases from breast cancer: Effect of timing of surgery and estrogen receptor status on outcome.
Authors: D. E. Abbott, A. Brouquet, F. Meric-Bernstam, V. Valero, M. C. Green, H. M. Kuerer, S. A. Curley, E. K. Abdalla, K. Hunt, J. Vauthey
Journal: Journal of Clinical Oncology (2011)

288 Background: The oncologic benefit of resecting liver metastases (LM) in breast cancer patients is unclear. Identifying predictors of improved outcome would be useful in selecting appropriate candidates for surgery. Methods: From 1997 to 2010, 86 breast cancer patients underwent LM resection. RECIST criteria were used to define the best response to chemotherapy as the optimal response at any time during the course of metastatic disease and the preoperative response to chemotherapy as the response immediately before LM resection. Univariate and multivariate analyses were used to identify predictors of survival. Results: Sixty-four patients (74%) had primary tumors that were either estrogen receptor (ER) or progesterone receptor (PR) positive. Fifty-three patients (62%) had solitary LM, and 73 patients (85%) had LM smaller than 5 cm. Sixty-five patients (76%) received preoperative chemotherapy, and 10 patients (12%) received 2 or more chemotherapy regimens before LM resection. Only 2 patients (3%) had progressive disease (PD) as a best response to chemotherapy, whereas 19 patients (29%) had PD as preoperative response to chemotherapy (p &lt; 0.001). No perioperative mortality was observed. At a median follow-up of 62 months, the median durations of overall and disease-free survival were 57 and 14 months. Univariate analysis revealed that ER and PR primary tumor status, best response to chemotherapy, and preoperative response to chemotherapy were associated with overall survival after LM resection. On multivariate analysis, an ER-negative primary tumor (p=.009, hazard ratio [HR] = 3.3, 95% confidence interval [CI] =1.4-8.2) and preoperative disease progression (p=.003, HR = 3.8, 95% CI = 1.6-9.2) were independently associated with worse survival after LM resection. Conclusions: Resection of liver metastases in breast cancer patients with ER positive disease that is responsive to chemotherapy is associated with prolonged survival. Timing of surgery is critical and resection before progression is associated with better outcome. No significant financial relationships to disclose.
The relationship between pathologic nodal disease and residual tumor viability (RV) in patients with locoregionally advanced (LRA) adenocarcinoma (ACA) of the esophagus and gastroesophageal junction (E/GEJ) receiving induction chemotherapy, surgery, and postoperative chemoradiotherapy (CRT).
Authors: Michael J. McNamara, Lisa A. Rybicki, Cristina P. Rodriguez, Gregory M.M. Videtic, Kevin L. Stephans, John Greskovich, Davendra Sohal, Sudish C. Murthy, Siva Raja, Denise I. Ives, Joanna Bodmann, David J. Adelstein
Journal: Journal of Clinical Oncology (2015)

165 Background: A complete pathologic response to induction CRT has been identified as a favorable prognostic factor for patients with LRA ACA of the E/GEJ. Less is known, however, about the impact of pathologic regression after induction chemotherapy. Methods: Between 2/08 and 1/12, 60 evaluable patients with ACA of the E/GEJ enrolled in a phase II trial of induction chemotherapy, surgery, and post-operative CRT. Eligibility required a clinical stage of T3 or N1 or M1a (AJCC 6 th ). Induction chemotherapy with epirubicin 50mg/m2 d1, oxaliplatin 130mg/m2 d1, and fluorouracil 200mg/m2/day continuous infusion for 3 weeks, was given every 21 days for 3 courses and was followed by surgical resection. Adjuvant CRT consisted of 50-55Gy @ 1.8-2.0 Gy/d and 2 courses of cisplatin (20mg/m2/d) and fluorouracil (1000mg/m2/d) over 4 days during weeks 1 and 4 of radiotherapy. RV was defined as the amount of remaining tumor in relation to acellular mucin pools and scarring. Results: Of the 60 evaluable patients, 54 completed induction therapy and underwent curative intent surgery. The Kaplan-Meier (KM) projected 3 year OS for patients with pathologic N0 (n=20), N1 (n=12), N2 (n=13), and N3 (n=9) disease is 73%, 57%, 35%, and 0% respectively (p&lt;0.001). The KM projected 3 year OS of patients with low (0-25%, n=19), intermediate (26-75%, n=26), and high (&gt;75%, n=9) RV was 67%, 42%, and 17% respectively (p=0.004). On multivariable analysis, both the pN descriptor and RV were independently prognostic for OS. In patients with less nodal dissemination (N0/N1), RV was prognostic for OS [3yr OS 85% (0-25% viable) v 51% (&gt;25% viable), p=0.028]. Outcomes were poor, however, for patients with advanced nodal disease (N2/N3) regardless of RV [3yr OS 20% (0-25% viable) v 21% (&gt;25% viable), p=0.55]. Conclusions: RV and the pN descriptor after induction chemotherapy are independent pathologic prognostic factors for OS in patients with LRA ACA of the E/GEJ. Patients with extensive nodal disease, however, have poor outcomes irrespective of viability. Clinical trial information: NCT00601705.
Notch and wnt-beta catenin pathways as targets of γ-secretase inhibitor IX (GSI) mediated therapy in CD44+ gastric cancer (GC) cells.
Authors: Ruben R Plentz, Samarpita Barat, Xi Chen, Cuong Bui, Przemyslaw Bozko, Nisar P Malek
Journal: Journal of Clinical Oncology (2016)

99 Background: GC is the second most common cause of cancer related death worldwide. New palliative therapeutic approaches to treat GC are of urgent need. Targeting cancer stem cells (CSC) could be an effective approach to treat GC. Recent studies have indicated that Notch signaling and wnt-beta-catenin pathways are crucial for CSC development. In this study, we mainly focused on inactivation of both Notch and wnt-beta-catenin pathways in CSC CD44+ GC cells using GSI. Methods: For our experiments we have used the GC cell line MKN45, as it showed expression of both targets (CD44,Hes1). For in vitro experiments proliferation, wound healing, invasion and tumorsphere assays were performed to analyze the migration, invasive and tumorigenic potential of CD44+ sorted GC initiating cells after GSI treatment. Western blot analyses of downstream signaling targets of Notch and wnt-beta catenin were tested after GSI treatment. SiRNA experiments for Notch1 and CD44 were also performed in order to confirm the Notch and wnt-beta-catenin pathway crosstalk. For in vivo analysis sorted CD44+ cells were subcutaneously injected into NMRI-nu/numice and were treated with vehicle or GSI. Results: CD44+ sorted MKN45 cells showed high expression of Hes1 as compared to the CD44- cell population. GSI treatment showed effective inhibition of cell proliferation, migration, invasion and tumor sphere formation of CD44+ cells. Interestingly, amongst all Notch receptors, Notch1 was found to be important in mediating the crosstalk between Notch and wnt-beta-catenin signaling cascades in CD44+ GC cells. Moreover, upon silencing of both CD44 and Notch1 by SiRNA showed effective inhibition of downstream targets and reconfirmed the proposed hypothesis of CD44 mediated Notch and wnt/beta-catenin crosstalk in GC cells. Conclusions: Our study highlights the crosstalk between Notch and wnt-beta-catenin in GC CD44+ cells. GSI could be an alternative drug to treat human GC as it effectively targets the CD44+ GC cells thus, completely reducing all the chances of relapse and metastasis associated with GC. Therefore, GSI therapy can open up new avenues for GC treatment with improved / better clinical outcome.
Cancer in the adolescent and young adult (AYA) population in the United States: Current statistics and projections.
Authors: R. S. Go, J. D. Gundrum
Journal: Journal of Clinical Oncology (2011)

6072 Background: The AYA, defined as people between ages 15 and 40 years, is projected to increase from approximately 104 million in 2000 to 115 million in 2030. Even though cancer is the leading disease-related cause of death, AYA remains a relatively understudied area in oncology. We assessed the current and projected cancer burden in this population. Methods: We obtained data from the SEER program. We excluded benign tumors, myeloproliferative and myelodysplastic neoplasms, as well as in situ cervical tumors. Incidence was reported per 1,000,000 person-years and age-adjusted to the 2000 US standard population. For current statistics, we used 2003-2007 data, while for trend analyses we used 1973-2007 data unless otherwise stated. Results: Currently, the AYA represent approximately 5.3% of annual new cancer cases diagnosed (86,285) and 2.1% of cancer deaths (9,207) in the US. The 10 leading cancers by incidence (both sexes combined) are breast (115.7), melanoma (103.1), thyroid (81.1), testicular (51.7), non-Hodgkin lymphoma (NHL) (39.7), Hodgkin lymphoma (36.8), central nervous system (CNS) (34.1), colorectal (33.9), cervical (32.0), and leukemia (29.9). The incidences are increasing overall and among the top 10 cancers for thyroid, CNS, testicular, breast, melanoma, and colorectal cancers; decreasing for cervical cancer; and relatively stable for NHL, Hodgkin lymphoma, and leukemia. The 10 leading causes of cancer deaths are breast (12.2%), leukemia (12.1%), CNS (9.1%), colorectal (8.0%), lung (6.3%), NHL (5.7%), cervical (4.8%), sarcoma (4.2%), stomach (4.1%), and melanoma (3.5%). Five-year cancer specific survival rates have been increasing for most cancers except for thyroid and cervical, in which the rates remain stable. If more recent trends continue, the AYA is expected to represent 3.4% of annual new cancer cases diagnosed and 1.2% of cancer deaths by 2030. Conclusions: The AYA have distinct cancer incidences and mortality rates. While the proportions of annual new cancer cases and cancer deaths in AYA are expected to decline relative to the other age groups, the cancer burden is anticipated to increase due to projected growth of the US population and an increasing overall incidence.