tbuckley/cabot-search huggingface dataset:
First-in-human study of MM-141: A novel tetravalent monoclonal antibody targeting IGF-1R and ErbB3.
Authors: Steven J. Isakoff, Mansoor N. Saleh, Alexey Lugovskoy, Sara Mathews, Akos Gabor Czibere, Anthony Frank Shields, Rastislav Bahleda, Jean-Charles Soria, Monica Arnedos
Journal: Journal of Clinical Oncology (2015)

384 Background: MM-141 is a novel tetravalent bispecific monoclonal antibody that binds IGF-1R and ErbB3 and blocks both ligand dependent and independent IGF-1R/ErbB3/PI3K/AKT/mTOR signaling. MM-141 potentiated gemcitabine, nab-paclitaxel, docetaxel, irinotecan, tamoxifen, and everolimus in preclinical models. A multi-arm Phase 1 study is ongoing and the monotherapy dose-escalation portion of the study is completed. Hepatocellular carcinoma (HCC) patients were enrolled to an expansion cohort of Arm A to receive MM-141 as a monotherapy. Another arm of treatment combined MM-141 with gemcitabine and nab-paclitaxel. Methods: This is a Phase 1 dose-escalation study evaluating safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) properties of MM-141 as monotherapy (n=15) and in combination with everolimus (Arm B) or with nab-paclitaxel and gemcitabine (Arm C). Three HCC patients in the Arm A expansion cohort received MM-141 as a monotherapy at a weekly dose of 20 mg/kg. These patients underwent mandatory pre-treatment and optional post-treatment biopsies. Patients in the dose-escalation portion of Arm C received MM-141 at a weekly dose of 12 or 20 mg/kg or a bi-weekly dose of 40 mg/kg in combination with gemcitabine (1000 mg/m 2 ) and nab-paclitaxel (125 mg/m 2 ). Results: 15 patients with advanced solid tumors were enrolled into the dose escalation portion of Arm A. No dose-limiting toxicities were observed at any of the studied doses. The safety, tolerability, PK and PD profile support weekly and bi-weekly MM-141 dosing. The Arm A expansion enrolled 3 patients with sorafenib-refractory HCC. The analysis of pre- and post-treatment biopsies confirmed that IGF-1R and ErbB3 are expressed in patients previously exposed to sorafenib, and their levels are decreased after MM-141 exposure. Arm C, combining MM-141, gemcitabine, and nab-paclitaxel in a “3+3” dose-escalation design is on-going. Conclusions: MM-141 was well tolerated as a monotherapy and translational analysis of pharmacodynamic parameters suggest appropriate target engagement. Combination data with gemcitabine/nab-paclitaxel will be presented and preparations for a randomized Phase 2 study in front-line pancreatic cancer are underway. Clinical trial information: NCT01733004.
The benefits and burdens of cancer: A prospective, longitudinal cohort study of adolescents and young adults.
Authors: Joelle P. Straehla, Krysta Shutske, Joyce P. Yi-Frazier, Claire M Wharton, Kevin Scott Baker, Kira O'Neil Bona, Joanne Wolfe, Abby R. Rosenberg
Journal: Journal of Clinical Oncology (2016)

243 Background: Much of the literature describing psychosocial consequences of cancer among adolescents and young adults (AYAs) has reported negative outcomes; however, AYAs also have potential for protective, positive outcomes. We aimed to prospectively characterize AYA patient-reported benefit and burden-finding after cancer diagnosis and hypothesized that benefit finding would be a salient coping mechanism. Methods: Semi-structured, 1:1 interviews were conducted with AYA patients after cancer diagnosis at 3 time points over 2 years, to elicit their expectations, hopes, worries, personal strengths, and challenges. A priori coding themes were defined from validated scales: changed sense of self, relationships, philosophy of life, and physical well-being. Verbatim transcripts were coded using content analyses by 3 independent coders for instances of benefit or burden by construct. Raw counts, ratios, and confidence intervals were calculated and compared by patient and time point. Results: Seventeen patients (mean age 17.1 ± 2.7; 8 [47%] male) completed 44 interviews with &gt; 100 hours of transcript-data. Most common diagnoses were sarcoma (n = 8), acute leukemia (n = 6), and lymphoma (n = 3). Twelve patients completed all 3 interviews; reasons for withdrawal included death in all but 2 cases. Mean (±SD) counts of patient-reported benefit were higher than burden at each time point (T1, T2, T3); the benefit: burden ratio was &gt; 1 in 68% of interviews (Table). Of the themes, changed sense of self was the most common benefit identified (44% of all reported benefits [95% CI 37%, 52%]) whereas physical complaints was the most common burden (32% [95% CI 25%, 39%]). Longitudinal analysis of subthemes among patients completing 3 interviews (N = 12) indicated an increase in self-identified positive and negative impact of cancer on personal, social and existential perspectives. Conclusions: AYA patients with cancer identified more benefits than burdens related to their diagnoses at all times studied. There was a shift over time in the distribution of benefit and burden finding constructs which may highlight areas for potential intervention. [Table: see text]
Endoscopic stenting for esophageal leak after minimally invasive esophagectomy.
Authors: Brenda Ernst, Helen J. Ross, Harshita Paripati, Rahul Pannala, William G. Rule, Jonathan Ben Ashman, Kristi L. Harold, Dawn E. Jaroszewski
Journal: Journal of Clinical Oncology (2016)

110 Background: Anastomotic leaks can occur after esophagectomy and optimal management after minimally invasive esophagectomy (MIE) is not well defined. We reviewed endoscopic management of leaks after MIE in patients undergoing trimodality therapy at Mayo Clinic Arizona. Methods: Records of patients undergoing MIE from November, 2006 to February, 2015 were reviewed after appropriate IRB approval. Results: 148 patients underwent MIE including 136 (91.8%) thoracic and 12 (8.1%) cervical anastomoses. Clinically significant anastomotic leaks were observed in 13 (8.8%) patients with 2 (16%) cervical and 11 (8%) thoracic anastomosis at a median of 6.1 days (0-14). 11 (11%) patients treated with neoadjuvant chemoradiotherapy experienced esophageal leak and 2 who did not receive chemoradiotherapy (4%). For treatment of anastomotic leaks, 10 patients underwent VATS with pleural space irrigation and chest tube replacement, and 11 patients underwent stent deployment at the anastomosis for repair. Stents were placed such that the fistula/leak was in the fully covered portion with the greater portion of the stent residing in the esophageal remnant. Stents were removed at a mean of 54 days (28-114). In 2 patients, overgrowth into the stent body required stent-in-stent placement (fully covered) with removal of both stents. Stents were successful at sealing all leaks. Conclusions: Leaks after MIE represent a small, but significant, morbidity in MIE. The majority can be managed by endoscopic stent placement. Stenting is an effective management tool for postoperative leaks in locally advanced esophageal malignancies.
Phase II clinical trial of bevacizumab plus ixabepilone in renal cell carcinoma.
Authors: Mauricio Emmanuel Burotto Pichun, Nicolas Acquavella, Maureen Edgerly, Susan Elaine Bates, Sanjeeve Balasubramaniam, Antonio Tito Fojo
Journal: Journal of Clinical Oncology (2014)

427 Background: Metastatic renal cell carcinoma (mRCC) remains incurable. Seven targeted agents are approved for mRCC, five targeting VEGFR and two m-TOR inhibitors. Most approvals have been based on improvements in progression free survival (PFS). Preclinical data indicates synergism of ixabepilone and bevacizumab. Methods: Patients with histologically confirmed mRCC with at least one previous therapy received ixabepilone [6mg/m 2 /d X 5d] plus bevacizumab [15 mg/kg] every 21 days. The primary endpoint was PFS by RECIST. Secondary endpoints were response rate, overall survival, and safety. In addition to “conventional” efficacy assessments, we calculated the growth rate constant as a measure of efficacy. Results: Thirteen patients have been enrolled. The median number of prior therapies was two (range 1-5). Nine (69%) have stable disease as best response with two (15%) partial responses. Median time to progression (TTP) was 6.39 months. The growth rate constant (g) was 0.0021/day and the regression rate constant (d) was 0.0032/day. Six patients discontinued treatment due to progression; one patient died. Principal toxicities including hypertension, fatigue, anemia and thrombocytopenia led two patients to discontinue therapy. One continues on study after 25 cycles. Accrual continues. Conclusions: Ixabepilone plus bevacizumab has activity in mRCC. A median TTP of 6.39 months compares favorably with 3.9-4.8 months for approved second line therapies. The calculated growth rate of 0.0021/day in this refractory population is indistinguishable from a value of 0.0022/day with single agent bevacizumab in treatment-naive mRCC. However, we cannot discern if this reflects bevacizumab activity even in refractory disease or a beneficial ixabepilone effect. Clinical trial information: NCT00923130.
Efficacy and safety findings from a phase II study of capecitabine (X) as first-line therapy in Japanese patients (pts) with advanced/metastatic colorectal cancer (MCRC)
Authors: K. Shirao, T. Doi, K. Hatake, Y. Arai, K. Yamaguchi, I. Hyodo, T. Tamura, S. Takemiya, H. Takiuchi, Y. Sakata
Journal: Journal of Clinical Oncology (2005)

3693 Background: The oral fluoropyrimidine X (Xeloda) is highly active and well tolerated in pts with MCRC. In a phase II Japanese study (ASCO 2002, abstract 2322), a 4-weekly regimen of X (828 mg/m2 bid d1–21, q4w) was both active and well tolerated in first-line MCRC. However, the standard 3-weekly regimen of X (1250 mg/m2 bid, d1–14, q3w) has demonstrated superior activity and improved safety over the Mayo Clinic regimen of bolus 5-FU/LV as first-line therapy in 2 large randomized phase III trials. Therefore, we conducted a phase II study to investigate the efficacy and safety of the 3-weekly X regimen in Japanese pts with MCRC. Methods: Eligibility criteria: age 20–74; ECOG PS 0–2; measurable disease (RECIST); adequate bone marrow, renal and hepatic function; prior radiotherapy or adjuvant chemotherapies (≥6 months previously) were permitted. Pts received X at 1250 mg/m2 bid on d1–14, q3w. Results: 60 pts were enrolled between January and November 2003. Median age = 59.5 years (range 34–71 years), male/female = 55%/45%, PS 0/1/2 = 70%/28%/2%. All pts were evaluable for efficacy (RECIST) and safety (NCI-CTC, version 2.0). The overall response rate was 35% (95% CI, 23–48%). The median time to progression was 5.6 months (95% CI, 4.3–6.8 months). Median survival has not yet been reached. The most common treatment-related adverse events (all grades) were hand-foot syndrome (HFS, 73%), hyperpigmentation (38%), nausea, diarrhea, stomatitis (all 35%), and anorexia (33%). The most common grade 3/4 treatment-related event (>10% pts) was HFS (13%). Only one pt (2%) developed grade 3 diarrhea. There was no grade 3/4 hematological toxicity (≥10% grade 3/4 shift). Five pts discontinued X due to adverse events. The median dose per cycle was between 69% and 100% of the planned dose. Conclusions: These findings show that the standard 3-weekly regimen of X is both active and well tolerated in Japanese pts with MCRC. The efficacy and safety data are similar to those observed with 3-weekly X in the previous large phase III trials, which provide a clear rationale for replacing 5-FU/LV with X in pts with MCRC. No significant financial relationships to disclose.
Bortezomib, pegylated-lyposomal-doxorubicin and dexamethasone (PAD) as induction therapy prior to reduced intensity autologous stem cell transplant (ASCT) followed by lenalidomide and prednisone (LP) as consolidation and lenalidomide alone as maintenance
Authors: A. P. Palumbo, P. Falco, P. Corradini, C. Crippa, F. Patriarca, F. Rossini, M. Offidani, A. M. Liberati, M. T. Petrucci, M. Boccadoro
Journal: Journal of Clinical Oncology (2008)

8518 Background: New agents have been introduced as induction treatment prior to ASCT and as consolidation or maintenance thereafter to improve complete response (CR) rates. In this study, we evaluate Bortezomib as induction preASCT, followed by consolidation/maintenance with Lenalidomide in elderly myeloma pts. Methods: Newly diagnosed MM pts aged 65–75 years were eligible. The induction included four 21-day PAD cycles (bortezomib1.3mg/m2 days 1,4,8,11, pegylated-liposomal-doxorubicin 30mg/m2 day 4 and dexamethasone 40mg days 1–4,8–11,15–18 for cycle 1 and days 1–4 for cycles 2–4). Cyclophosphamide (3g/m2) plus G-CSF was used to harvest stem-cells. Pts were then conditioned with tandem Melphalan 100mg/m2 and stem-cell support (MEL100). After ASCT pts received four 28-day LP cycles (Lenalidomide 25mg/day on days 1–21 plus Prednisone 50mg every other day) followed by Lenalidomide alone (10mg/day on days 1–21 every 28 days) as maintenance. Primary endpoints were safety (any Grade-3 non-hematologic toxicity<30%) and efficacy (near complete > response rate, nCR, >35%). According to Simon procedure, 100 pts were planned to be enrolled. Results: Ninety-four pts have been enrolled. After the 4 PAD cycles 95% of pts achieved at least partial response (PR), 60% at least very good partial response (VGPR), 23% at least nCR, and 13% CR. After tandem MEL100, 95% of pts showed PR, 80% at least VGPR, 60% at least nCR, and 33% CR. After LP consolidation regimen all patients achieved PR, 89% at least VGPR rate, 78% at least nCR, and 56% CR. During PAD, 25% of pts experienced grade3–4 hematologic toxicity, 17% grade3–4 peripheral neuropathy and 11% grade3–4 infections. During LP consolidation one DVT and one discontinuation due to prolonged anemia and thrombocytopenia were recorded. Conclusion: PAD as induction pre ASCT followed by LP as consolidation induced a high response rate with a 56% CR rate recorded at the end of a reduced intensity ASCT regimen for elderly patients. Updated results and molecular remission data will be presented at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celgene, Johnson & Johnson
Future life expectancy in 35 industrialised countries: projections with a Bayesian model ensemble
Authors: Vasilis Kontis, James E Bennett, Colin D Mathers, Guangquan Li, Kyle Foreman, Majid Ezzati
Journal: The Lancet (2017)

Projections of future mortality and life expectancy are needed to plan for health and social services and pensions. Our aim was to forecast national age-specific mortality and life expectancy using an approach that takes into account the uncertainty related to the choice of forecasting model.We developed an ensemble of 21 forecasting models, all of which probabilistically contributed towards the final projections. We applied this approach to project age-specific mortality to 2030 in 35 industrialised countries with high-quality vital statistics data. We used age-specific death rates to calculate life expectancy at birth and at age 65 years, and probability of dying before age 70 years, with life table methods.Life expectancy is projected to increase in all 35 countries with a probability of at least 65% for women and 85% for men. There is a 90% probability that life expectancy at birth among South Korean women in 2030 will be higher than 86·7 years, the same as the highest worldwide life expectancy in 2012, and a 57% probability that it will be higher than 90 years. Projected female life expectancy in South Korea is followed by those in France, Spain, and Japan. There is a greater than 95% probability that life expectancy at birth among men in South Korea, Australia, and Switzerland will surpass 80 years in 2030, and a greater than 27% probability that it will surpass 85 years. Of the countries studied, the USA, Japan, Sweden, Greece, Macedonia, and Serbia have some of the lowest projected life expectancy gains for both men and women. The female life expectancy advantage over men is likely to shrink by 2030 in every country except Mexico, where female life expectancy is predicted to increase more than male life expectancy, and in Chile, France, and Greece where the two sexes will see similar gains. More than half of the projected gains in life expectancy at birth in women will be due to enhanced longevity above age 65 years.There is more than a 50% probability that by 2030, national female life expectancy will break the 90 year barrier, a level that was deemed unattainable by some at the turn of the 21st century. Our projections show continued increases in longevity, and the need for careful planning for health and social services and pensions.UK Medical Research Council and US Environmental Protection Agency.
Venous thromboembolism (VTE) risk in patients with localized urinary tract tumors (UTT).
Authors: Jorge Ramos, Yu-Ning Wong, Simon J. Crabb, Guenter Niegisch, Joaquim Bellmunt, Sylvain Ladoire, Syed A. Hussain, Jack Baniel, Ali Reza Golshayan, Thomas Powles, Jonathan E. Rosenberg, Ugo De Giorgi, Ulka N. Vaishampayan, Neeraj Agarwal, Sumanta K. Pal, Lauren Christine Harshman, Andrea Necchi, Federica Recine, Matt D. Galsky, Evan Y. Yu
Journal: Journal of Clinical Oncology (2016)

422 Background: VTE is common in cancer patients, but there is limited data in patients with UTT. We previously demonstrated that non-urothelial histology, cardiovascular disease (CVD) or CVD risk factors or renal dysfunction increased VTE risk in metastatic UTT. In this study, we assessed the frequency and risk factors for VTE in localized disease. Methods: Data was collected via an electronic data capture platform from 29 centers. Patients diagnosed with &lt; cT2, &gt; N1, or M1 disease at diagnosis were excluded. Patients without a date of diagnosis, last follow up, or VTE data were excluded. Cumulative, unadjusted VTE incidence was calculated from time of diagnosis, excluding VTEs diagnosed in the metastatic setting. Chi-squared analyses were used to assess differences in VTE rates for various patient, therapy, and tumor-related factors. Significant covariates were incorporated into a multivariate, logistic regression model. Results: 1131 patients were eligible for analysis. Perioperative chemotherapy was utilized in 46.9% (530/1131) of patients. 70.8% (801/1131) underwent definitive surgical intervention. There were 64 VTEs (cumulative incidence 5.7%). Treatment with chemotherapy (p = 0.609) or surgery (p = 0.886) did not increase VTE risk. In the univariate analysis, non-urothelial histology (p = 0.025), CVD or CVD risk factors (p = 0.004), renal dysfunction (p = 0.023), and radiation to the primary tumor (p = 0.048) were statistically significant factors. Multivariate analysis demonstrated that non-urothelial histology and CVD or CVD risk factors were associated with increased VTE risk (table). Conclusions: The VTE incidence of 5.7% in localized disease is lower than our previously reported rate in the metastatic setting (8.2%). Consistent with our findings in metastatic UTT, non-urothelial histology and CVD or CVD risk factors increase VTE risk in localized disease. Additional analyses to control for baseline demographics in patients treated with surgery and chemotherapy will be performed. [Table: see text]
A multicenter phase II study of irinotecan (CPT-11) and bolus 5-fluorouracil (5FU)/l-leucovorin (l-LV) in patients with metastatic colorectal cancer
Authors: H. Fujishima, A. Makiyama, O. Miyanaga, A. Ueda, T. Esaki, K. Mitsugi, E. Baba, H. Kusaba, M. Harada, S. Nakano
Journal: Journal of Clinical Oncology (2005)

3742 Background: A previous phase I trial in patients (pts) with metastatic colorectal cancer (CRC) demonstrated that weekly CPT-11 and bolus 5FU/l-LV administered for 3 weeks every 28 days (modified Saltz regimen) showed a promising activity without severe toxicity. We conducted a multicenter phase II trial of this regimen in pts with metastatic CRC to evaluate the objective response rate (ORR), safety profile, time to progression (TTP), and overall survival (OS). Methods: 27 pts with metastatic CRC, measurable disease, ECOG PS less than 3, and adequate organ functions were enrolled. Prior chemotherapy was allowed. Pts received weekly doses of CPT-11 (100 mg/m2) and bolus 5FU (500 mg/m2) plus l-LV (20 mg/m2) for 3 weeks. Cycles were repeated every 28 days. Results: 25 pts (10 treated and 15 untreated pts) were evaluable for response and toxicity; M/F, 12/13, median age 63 years (45–73), ECOG PS 0–1, 96%. Metastatic sites were liver 48% (n=12), lung 40% (n=10), and lymph node 36% (n=9). To date, 213 cycles were administered (median 8.5, range 2–36). There were 10 PR (40%) and 13 SD (52%), and 2 PD, resulting in ORR of 40% (CI 95%: 20.8–59.2%) and disease control rate (PR+SD) of 92%. The response rates of the pts with or without previous treatments were 20% and 53.3%, respectively. Median TTP and OS have not been achieved yet, but were 6.9 months and 17.2 months, respectively for 16 early registered pts. Neutropenia was the only NCI-CTC grade 3/4 hematological toxicity, which occurred in 52% of pts. Non-hematological toxicity was mostly grade 1/2 with only one patient (4%) having a grade 3 diarrhea. No treatment related death has been encountered. Conclusions: This weekly CPT-11/5FU/l-LV administered for 3 weeks every 28 days has manageable toxicity profile and a substantial anti-tumor activity, specifically for chemotherapy-naive patients with metastatic CRC. No significant financial relationships to disclose.
Preoperative prediction of peritoneal metastasis in gastric cancer as an indicator for neoadjuvant treatment.
Authors: Koichiro Mori, Yuji Toiyama, Masaki Ohi, Yuka Nagano, Ryo Uratani, Satoshi Oki, Masato Okigami, Hiromi Yasuda, Susumu Saigusa, Koji Tanaka, Yasuhiro Inoue, Yasuhiko Mohri, Masato Kusunoki
Journal: Journal of Clinical Oncology (2016)

14 Background: Although Gastric cancer (GC) mortality has been reduced by advances in new treatments and in chemotherapy, it still has a poor prognosis and high mortality. One of the reasons for poor prognosis is that at the time of diagnosis advanced GC with metastatic disease is often detected and it is frequently accompanied by peritoneal metastasis. Imaging studies are frequently used to predict peritoneal metastasis, however, these modalities did not obtain consistently high sensitivity and specificity in assessing peritoneal metastasis. Therefore, we investigated whether the combination of several serum markers and clinical factors could be used for preoperative prediction of peritoneal metastasis in GC as an indicator for neoadjuvant treatment. Methods: A total of 493 patients with GC were enrolled in our Hospital. Preoperative serum tumor markers [carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19-9], systemic inflammatory marker C-reactive protein (CRP), host immune markers [neutrophil and lymphocyte counts and their ratio (NLR)], albumin as a nutritional marker, and objective preoperative clinical factors were available as indicators of postoperative peritoneal metastasis. Results: This study included a total of 344 men and 149 women who were classified according to UICC TNM Classification: 264 patients had stage I disease, 79 stage II, 78 stage III and 72 stage IV. Specific clinical factors, including tumor size, histopathology of biopsy sample, and tumor morphology, were significantly correlated with peritoneal metastasis. CA19-9, lymphocyte count and NLR were also predictive factors for peritoneal metastasis. Multivariate analysis identified the clinical factors tumor morphology and histopathology, and laboratory markers CA19-9 and lymphocyte count as independent factors predictive for peritoneal metastasis. Next, a combination of independent predictive factors achieved high predictive accuracy (0.882) for peritoneal metastasis preoperatively. Conclusions: A combination of preoperative tumor features and serum parameters is an alternative method to preoperatively discriminate patients with GC with peritoneal metastasis from those without.