tbuckley/cabot-search huggingface dataset:
Phase I trial of neoadjuvant concurrent chemoradiotherapy with S-1 and weekly irinotecan in locally advanced rectal cancer
Authors: J. Ahn, H. Choi, S. Cheon, S. Shin, K. Keum, B. Min, S. Baik, N. Kim, H. Jeung, J. Roh, H. Chung
Journal: Journal of Clinical Oncology (2007)

14543 Background: S-1 is a novel, orally administered 5-FU analogue and is known of radiosensitizer. The aim of this study was to establish the feasibility and efficacy of S-1 in combination with weekly irionotecan with concurrent pelvic radiotherapy (RT) in patients with locally advanced rectal cancer. Methods: Clinical stage T3–4 or N+(on MRI) rectal adenocarcinoma patients received weekly irinotecan 40mg/m 2 (day1,8,15,22,29) and S-1 at dose levels of 40, 50, 60 and 70mg/m 2 (5days a week from day 1 to 38) according to phase I methodology. Concurrently conventional RT was given at daily fractions of 1.8 Gy on 5 days a week for a total dose of 50.4 (45 + 5.4)Gy. Surgery was performed 4–8 weeks following completion of chemoradiation. Results: A total 16 patients (10M/7F, median age 46 years, ECOG PS0–1) were enrolled between August 2005 and July 2006. One pt withdrew the consent during CCRT. Dose-limiting toxicity (DLT) occurred at 50mg/m 2 of S-1 in one of six pts (G4 cerebral infarction). At dose of 60, 70mg/m 2 of S-1, no DLT occurred. G3/4 toxicties were rare. Fifthteen pts underwent surgery and R0 resection was achieved in 13 pts. Four pts (25.0%) had a pathological complete response. Conclusions: The recommended dose (RD) for further study is S-1 70mg/m 2 with irinotecan and radiotherapy. Neoadjuvant S-1/irinotecan/RT is feasible and well tolerated. Phase II trial is being conducted. No significant financial relationships to disclose.
NanoPro 1000 analysis of Erk1/2, Mek1/2, and Akt isoform phosphorylation in clinical samples from 115 patients.
Authors: Florian Tobias Unger, Jana Krueger, Janina Schaller, Rebecca Giese, Cordula Dede, Alexandra Samsen, Hartmut Juhl, Kerstin David
Journal: Journal of Clinical Oncology (2014)

e22227 Background: Proteomic analysis of cellular signaling networks has strongly gained in importance in the field of cancer research and treatment. For example, the inhibition of the EGFR pathway has been widely integrated into clinical practice for different tumor entities. Although, predictive genetic markers of response to targeted therapy are already in use, heterogeneity in responses has been clinically observed. In order to understand this heterogeneity on the proteome level, the activation status of cell signaling proteins has to be analyzed. Methods: Samples: Patient’s samples were collected according to Indivumed´s SOPs. Patient´s cohort consisted of breast cancer (n=26), non-small cell lung cancer (n=29), colorectal cancer (n= 30) and liver metastases of colorectal cancer (n= 30). Analysis of signaling pathways: Protein phosphorylations of signaling pathway molecules were analyzed using the NanoPro1000 technology (Protein Simple). For quantification of selected signaling proteins (total and phosphorylated Erk1/2, Mek1/2 and Akt), tissue slices were lysed and analyzed in replicates. Results: Statistical analysis of generated data revealed that isoform phosphorylation of Erk1/2, Mek1/2 and Akt significantly differed among individual patients, but not between tumor entities. This indicates that the in-depth analysis of isoform phosphorylation can reveal significant biological differences and might result in therapy relevant, predictive signatures independent of the mutation status. Hence, we established cut-off values for basal signaling molecule phosphorylation, to potentially enable the selection of patients, who will most likely benefit from targeted treatment. Based on the cut-off values we classified patients into statistical significant groups of high, moderate and low signaling molecule phosphorylation. Conclusions: The NanoPro 1000 technology can be used to robustly screen a large cohort of patients for signaling molecule phosphorylation. The analysis of patients on the proteome level may be helpful to identify predictive biomarker for the development of resistance to anti-EGF-receptor treatment and thus further improve personalized medicine.
Factors impacting the diagnosis of stage IV melanoma: A National Cancer Database (NCDB) analysis.
Authors: Josef Beauvais, Gaurav Goyal, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2015)

e17627 Background: Stage IV melanoma carries a poor prognosis, with a 5-year survival rate of approximately 15-20%. The purpose of this study is to use the National Cancer Database (NCDB) to evaluate disparities in presentation with stage IV melanoma. Methods: This is a retrospective study of 20,142 adult patients diagnosed with stage IV melanoma between 2000 and 2012 using the National Cancer Database (NCDB). These represent 4.4% of all staged melanomas in the NCDB. The NCDB consists of approximately 70% of newly diagnosed cases from 1,658 American College of Surgeons accredited hospitals. Chi-square analysis was used to test statistical significance. Results: The factors associated with highest (> 10%) likelihood of presenting with stage IV disease included uninsured status, Medicaid insurance, and black race. Other factors with somewhat increased risk (> 5.4%) include household income less than $36,000, lower education level, age greater than 70, Hispanic ethnicity, and distance from cancer center greater than 100 miles. Factors associated with lower likelihood (< 3.3%) of presenting with stage IV disease include privately insured patients, income greater than $69,000, and higher educational attainment (see table). Conclusions: This is the largest epidemiological study analyzing the impact of these factors on the diagnosis of stage IV melanoma. This study demonstrates that insurance status and race may greatly impact the stage at diagnosis. More stage IV disease is seen in uninsured, Medicaid and black patients while patients with private insurance, higher income and education seem to have fewer stage IV diagnoses. Epidemiology of stage IV Melanoma patients. Overall % of Melanoma Presenting at Stage IV 4.4% Insurance Status* % Stage IV Medicaid 14.7 Not Insured 10.3 Medicare 5.1 Other Government 4.0 Private/Managed 3.3 Household Income (USD, 2012 census)* < 36k 6.2 36k - 44k 5.3 44k - 53k 4.7 53k-69k 4.3 > 69K 3.3 Education (% Without HS Degree)* 23 + 6.5 15-23 5.4 11-15 4.8 6-11 3.9 < 6 3.1 Race/Ethnicity* Black 13.9 Hispanic 9.0 White 4.3 Age* 70 + 5.0 50-69 4.5 30-49 3.5 Distance Traveled (Miles)* ≥ 100 5.4 < 5 5.0 50 to 99 4.6 5 to 9 4.3 25 to 49 3.9 10 to 24 3.8 ≤ 29 2.3 *p-value <.001
CALM study: A phase II study of an intratumorally delivered oncolytic immunotherapeutic agent, coxsackievirus A21, in patients with stage IIIc and stage IV malignant melanoma.
Authors: Robert Hans Ingemar Andtbacka, Brendan D. Curti, Howard Kaufman, Gregory A. Daniels, John J. Nemunaitis, Lynn E. Spitler, Sigrun Hallmeyer, Jose Lutzky, Stephen Schultz, Eric D. Whitman, Karl Zhou, Jeffrey Ira Weisberg, Darren Shafren
Journal: Journal of Clinical Oncology (2014)

3031 Background: Coxsackievirus A21 is an oncolytic immunotherapy consisting of a bio-selected oncolytic strain of Coxsackievirus A21. Following intratumoral injection, preferential tumor infection causes cell lysis and enhancement of a systemic anti-tumor immune response. We present interim findings of the open-labeled, multicenter Phase II Coxsackievirus A21 in Late stage Melanoma (CALM) study. Methods: The CALM study investigated the efficacy and safety of intratumoral Coxsackievirus A21 in 57 patients with treated or untreated unresectable Stage IIIC-IVM1c melanoma. Patients received up to 3 x 108 TCID50Coxsackievirus A21intratumorally on study days 1,3,5 and 8 and then every three weeks for a further 6 injections. Patients displaying immune-related progression-free survival (irPFS) or better at 6 months were eligible for 9 additional injections. Key eligibility criteria were ≥ 18 yrs old, ECOG 0-1, and at least 1 injectable cutaneous, subcutaneous, or nodal melanoma metastasis >1.0 cm. The primary endpoint was to achieve >9 of 54 evaluable patients with irPFS at 6 months. The irPFS was calculated as the proportion of patients demonstrating a Complete Response, Partial Response or Stable Disease by immune-related RECIST 1.1 (irRECIST 1.1) criteria 6 months after the initiation of treatment. Secondary endpoints included 1-year survival, irRECIST1.1 best overall response and safety. Results: The primary endpoint of the study was achieved with 14 of 40 (35%) evaluable patients displaying irPFS at 6 months. The number of patients surviving 1-year from the initial treatment is 13 of 21 (62%). Best overall response rate (irRECIST 1.1) is 24% (9 of 38 evaluable patients). Patients received on average 8.3 series of injections, with the most common side effects being Grade 1 fatigue, chills, local injection site reactions and fever. There were no Grade 3 or 4 product-related AE's. Conclusions: Intralesional Coxsackievirus A21 is a promising novel oncolytic immunotherapeutic agent in the treatment of unresectable Stage IIIC-IV M1c melanoma based on good patient tolerability, with both local and distant tumor responses. A randomized phase 2 clinical trial is planned. Clinical trial information: NCT01227551.
Identification of unipotent megakaryocyte progenitors in human hematopoiesis
Authors: Kohta Miyawaki, Hiromi Iwasaki, Takashi Jiromaru, Hirotake Kusumoto, Ayano Yurino, Takeshi Sugio, Yasufumi Uehara, Jun Odawara, Shinya Daitoku, Yuya Kunisaki, Yasuo Mori, Yojiro Arinobu, Hirofumi Tsuzuki, Yoshikane Kikushige, Tadafumi Iino, Koji Kato, Katsuto Takenaka, Toshihiro Miyamoto, Takahiro Maeda, Koichi Akashi
Journal: Blood (2017)
Baseline carcinoembryonic antigen (CEA) serum levels to predict bevacizumab-based treatment response in patients with KRAS exon wild-type metastatic colorectal cancer (mCRC) receiving 1st-line therapy with FOLFIRI plus cetuximab or bevacizumab (AIO KRK0306, FIRE3 trial).
Authors: Marlies Michl, Ludwig Fischer von Weikersthal, Thomas Decker, Alexander Kiani, Ursula Vehling-Kaiser, Salah-Eddin Al-Batran, Tobias Heintges, Christian Lerchenmueller, Christoph Kahl, Gernot Seipelt, Frank Kullmann, Martina Stauch, Werner Scheithauer, Joerg Hielscher, Michael Scholz, Dominik Paul Modest, Sebastian Stintzing, Thomas Kirchner, Andreas Jung, Volker Heinemann
Journal: Journal of Clinical Oncology (2015)

3581 Background: Recently, Prager et al. proposed the hypothesis that carcinoembryonic antigen (CEA) is involved in tumor angiogenesis and therefore might predict bevacizumab-based treatment response in metastatic colorectal cancer (mCRC) (Cancer Research, 2013; Cancer Science, 2014). The present study aimed to evaluate this hypothesis in the FIRE-3 trial where patients (pts) with KRAS exon 2 wild-type mCRC were randomized to receive first-line chemotherapy with either FOLFIRI + cetuximab (cet) or FOLFIRI + bevacizumab (bev). Methods: Baseline CEA levels were analyzed either as continuous variable (ln) or categorized in two groups ( ≤ / > 25% quartile; ≤ / > 6.2ng/ml) with regard to their predictive impact on PFS and OS in the two different treatment arms. Correlations relied on Cox regression analysis. Survival was estimated by Kaplan-Meier. Results: For analysis of CEA, 522/592 pts (cet: 257 pts; bev: 265 pts) were eligible. When CEA baseline level was evaluated as a continuous variable, CEA (ln) was inversely correlated with PFS (p= 0.02) and OS (p= 0.001) in the bev arm, but not in the cet arm. Using the 25% quartile of CEA as a cut-off, only in the bev arm an effect on OS (24.2 mo vs. 33.3 mo; HR 0.60; Cl95%:0.41-0.88; p= 0.009) and PFS (10.4 mo vs. 11.7 mo; HR 0.67; Cl95%:0.48-0.94; p= 0.02) was observed, but not in the cet arm. Pts with high CEA baseline levels ( > 6.2ng/ml) showed a shorter OS in the bev arm compared to the cet arm (bev: 24.2 mo vs. cet: 30.0 mo; HR 1.52; Cl95%:1.16-2.00; p= 0.002). In pts with low CEA baseline level ( ≤ 6.2ng/ml) no significant survival difference was observed between arms (HR 0.92; Cl95%:0.58-1.44; p= 0.70). Univariate analysis identified CEA as an independent predictor of OS in the bev arm, but not in the cet arm. Conclusions: The present analysis supports the hypothesis that CEA acts as a predictor of bev activity, while outcome parameters in the cet arm are not affected by baseline CEA. Patients with elevated CEA baseline levels appeared to benefit from anti-EGFR directed therapy, while anti-VEGF based treatment was inferior.
A phase II trial assessing pazopanib (paz) as third-line therapy for metastatic renal cell carcinoma (mRCC): Clinical outcome and temporal analysis of molecular profile.
Authors: Sumanta Kumar Pal, Dewan Md Sakib Hossain, Qifang Zhang, Chan Gao, Paul Henry Frankel, Christopher Ruel, Jeremy Jones, Courtney Carmichael, Przemyslaw Twardowski, Robert A. Figlin, Marcin Kortylewski
Journal: Journal of Clinical Oncology (2013)

4571 Background: Paz, an oral vascular endothelial growth factor (VEGF) receptor inhibitor, was assessed in a phase III study conducted in patients (pts) with mRCC who were cytokine-refractory or treatment-naïve (Sternberg et al J Clin Oncol 2010). Clinical outcomes with paz have been associated with a molecular profile (Tran et al Lancet Oncol 2012). The activity of paz in the 3 rd -line setting and temporal changes in molecular profile during paz therapy are poorly understood. Methods: Eligibility was limited to pts with 2 prior lines of therapy (including at least 1 VEGF-directed therapy), ECOG PS 0-2, and clear cell histology. Pts received paz 800 mg/daily on a 28d cycle, and were assessed for response by RECIST 1.1 every 2 cycles. A Simon MinMax 2-stage design was employed, with 80% power of declaring an encouraging overall response rate (ORR) of 23% (type I error=10%). Molecular profiles were assessed on a Luminex platform using the Human Cytokine 30-plex Cytokine Immunoassay (Invitrogen) at baseline, 6 mos and 12 mos. Results: 28 pts (20M, 8F) were enrolled, with a median age of 63 (range, 45-86). All patients received at least 2 lines of prior therapy, and 6 pts (21%) had received 2 prior lines of VEGF-directed therapy. In the pre-specified intent-to-treat analysis, 12/28 pts (43%) had a confirmed response (1 CR, 11 PR), with 1 additional unconfirmed PR. 8 pts (29%) had SD as a best response. Median PFS for the cohort was 17.4 mos (95% CI 14.7-NR). No grade 4 treatment-related toxicities were observed. The most common grade 3 toxicities were hypertension (46%) and proteinuria (14%). At baseline, IL-6 was marginally lower in patients who achieved PR/CR (responders) as compared to those who did not (non-responders; P=0.06). Amongst patients still on therapy at 6 months and 12 months, responders had lower levels of HGF, IL-2R, IL-6, IL-8, and VEGF (P&lt;0.05 for each) at both time intervals. Conclusions: Paz demonstrated an ORR of 43%, representing the highest ORR observed to date in a 3 rd -line trial in mRCC. At 6 and 12 months, differences in molecular profile emerged between responders and non-responders, potentially underscoring mechanisms of drug resistance. Clinical trial information: NCT01157091.
Phase II trial of induction GEMOX followed by a twice-weekly infusion of gemcitabine and concurrent external beam radiation for the treatment of locally advanced pancreatic cancer
Authors: F. Leone, E. Sperti, S. Aliberti, M. Gatti, P. Massucco, A. Magnino, R. Faggiuolo, P. Gabriele, L. Capussotti, M. Aglietta
Journal: Journal of Clinical Oncology (2006)

14019 Background: Combined chemo-radiation therapy may render curative resection feasible in pancreatic cancer deemed unresectable for vascular invasion. We previously demonstrated that primary radiotherapy with concurrent gemcitabine is feasible and allows clinical benefit. However, the percentage of resected patients was low. Methods: Patients with locally advanced pancreatic adenocarcinoma, received induction with 4 cycle GEMOX (gemcitabine 1000 mg/mq, day 1 and oxaliplatin 100 mg/mq, day 2) each 2-week cycle. Patients without disease progression received gemcitabine twice weekly (50 mg/mq/day) for 5 weeks concurrent with upper abdominal radiation (50.4 Gy over 5.5 weeks) and were re-evaluated for resectability. Results: From 7/2003 to 11/2005, 20 patients entered this study, of whom 17 are evaluable for toxicity and 15 for treatment response. Twelve men and 8 women (median age 63 years; range 43–71) received a median of 3.5 cycles GEMOX (range 2–4). Fourteen patients completed the treatment with external beam radiation and received a median of 7 cycles with gemcitabine (range 3–10). In two patients chemotherapy during radiotherapy was omitted for previous toxicity, and one stopped also radiotherapy for gastrointestinal toxicity. No grade IV toxicities or deaths due to therapy were observed. Gastrointestinal grade III toxicities were observed in 3/17 patients (17.6%) after GEMOX and 6/16 patients (37.5%) during radiotherapy. Grades III hematologic toxicity and fatigue occurred in 4/16 (25%) and 2/16 (12.5%) respectively during radiotherapy. A disease control was obtained in 10/15 evaluable patients. One patient progressed after GEMOX and 4 after chemoradiotherapy. Eight patients (53%) appeared to be resectable: 1 patient is planned for surgery, 2 patients were found unresectable at lapaproscopy for peritoneal carcinomatosis or local extension; 5 patients underwent resection and in 4 of them (26%) margins were negative. Conclusions: Induction GEMOX followed by twice-weekly gemcitabine and upper abdominal radiation is feasible in patients with locally advanced pancreatic cancer and seems to induce a high resectability rate. This protocol warrants further evaluation. No significant financial relationships to disclose.
Recurrence patterns in patients with stage IIIC1 versus IIIC2 endometrial adenocarcinoma.
Authors: Catherine Bevan, Christa Irene Nagel, Todd Patrtick Boren, David Scott Miller, Siobhan Marie Kehoe, Debra L. Richardson, Jayanthi Lea
Journal: Journal of Clinical Oncology (2012)

e15501 Background: To identify differences in recurrence patterns between stage IIIC1 and IIIC2 endometrial adenocarcinomas. Methods: A retrospective review was performed with IRB approval of all patients treated for stage IIIC1 and IIIC2 endometrial adenocarcinoma at our institution from 1989-2011. Patients were required to have comprehensive surgical staging including total abdominal hysterectomy, bilateral salpingo-ophorectomy, pelvic and paraaortic lymph node dissection. Descriptive statistics were performed using Microsoft Excel 2011 and Fischer’s exact test, Kaplan-Meier analyses were used to compare disease free (DFS) and overall survival (OS). Results: Eighty-seven patients with stage IIIC endometrial adenocarcinoma were identified, of which 69 were evaluable. The mean age was 59 years and the mean follow up was 32 months. There were 31 patients with stage IIIC1 and 38 patients with stage IIIC2 disease. There was no statistical difference in histology between the two groups: 47 endometrioid, 11 papillary serous, and 11 with other types of adenocarcinoma. Patients with stage IIIC1 disease were more likely to receive pelvic radiation (p=0.0004) and patients with IIIC2 disease were more likely to receive chemotherapy (p=0.014). Median DFS was 28.9 months (range 0-112) and 15.0 months (range 0-166) (p=0.017) and median OS was 31.9 months (range 0-134) and 18.0 months (range 0-166) (p=0.061) for the IIIC1 and IIIC2 groups respectively. Seven of 31 (23%) patients with stage IIIC1 disease recurred: 1 (14%) at the vaginal cuff and 6 (86%) distant. The patient who recurred locally was initially treated with chemotherapy alone. Of the 6 patients with distant recurrences only 1 received chemotherapy. Twelve of the 38 (32%) patients with stage IIIC2 experienced a recurrence: 6 (50%) vaginal/pelvic and 6 (50%) distant. There was a difference between the rates of local versus distant recurrence in patients with IIIC1 and IIIC2 endometrial cancer. Conclusions: IIIC1 patients were less likely to receive systemic chemotherapy and more likely to recur distantly. Our findings suggest a role for adjuvant chemotherapy and radiation in the frontline treatment of both IIIC1 and IIIC2 endometrial cancer.
Inflammatory and locally advanced breast cancer respond similar to operable breast cancer to neoadjuvant chemotherapy: Results from 278 patients with cT4a-d tumors of the GeparTRIO trial
Authors: G. Von Minckwitz, S. Kümmel, P. Vogel, C. Hanusch, H. Eidtmann, J. Hilfrich, B. Gerber, J. Huober, S. D. Costa, S. Loibl
Journal: Journal of Clinical Oncology (2007)

542 Background: Neoadjuvant chemotherapy is the treatment of choice in patients with T4a-c and inflammatory (T4d) breast cancer. However, data on large-scale, multicentre, prospective trials are missing. In the GeparTRIO study (SABCS 2006, abstr. 42) 278 of 2,090 patients with cT4a-c or T4d tumors were included as a separate stratum for inoperable disease for a prospectively planned analysis. Methods: Patients were treated with 2 cycles TAC (docetaxel 75 mg/m 2 , doxorubicin 50 mg/m 2 , cyclophosphamide 500 mg/m 2 , q d 21). If tumor reduction was &gt;50%, patients were randomized to receive 4 or 6 additional TAC cycles. If tumor reduction was less, patients were randomized to 4 additional TAC cycles or to 4 NX cycles (vinorelbine 25 mg/m 2 day 1 + 8, capecitabine 2,000 mg/m 2 day 1 14, q21). Efficacy endpoints were pCR-rate (no invasive and no non-invasive residuals in breast and lymph nodes) (primary), clinical response before surgery and breast conserving therapy (BCT) rate (secondary). Results: 95 (4.6%) T4d, 183 (8.9%) cT4a-c, and 1,767 (86.4%) T1–3 tumors were registered in GeparTRIO within 36 months. Patients with inoperable/operable tumors had a median age of 53.9/49.0 years, median cT size: 7.0/4.0cm, cN+: 75.6/52.0%, ductal: 76.3/78.4%, lobular: 14.0/13.5%, multiple lesions: 28.5/19.5%, grade 3: 34.8/39.9%, hormone receptor (HR) neg: 24.7/36.6%, HER-2 pos: 41.0/35.5%. Response rates for T4d, T4a-c, T1–3 were 8.4, 10.9, 17.5% (pCR, p=0.007), 36.7, 59.4, 72.6% (palpation after 2 cycles TAC, p&lt;0.0001), 64.2, 62.3, 77.8% (palpation before surgery, p&lt;0.0001), 52.6, 51.9, 67.4% (ultrasound before surgery, p&lt;0.0001). BCT was performed in 12.6, 31.7, 69.5% (p&lt;0.0001). Response after two cycles, negative HR content, young age, high grade, ductal type, but not tumor stage or size, were independent predictors for pCR in the total population. Conclusions: Inflammatory and cT4a-c breast carcinomas, compared to cT1–3 tumors, show less favorable tumor characteristics but a comparable pattern of response to TAC/NX. These patients do not need separate neoadjuvant trials. [Table: see text]