bluuebunny/crossref_metadata_2025_split huggingface dataset:
Morphoproteomic depiction of constitutively activated mTOR and ERK pathways in adenocarcinoma of the large intestine: A pilot study
Authors: Tan D. , Yao J. , Javle M. , Law A. , Brown R. 
Published: March 2020

14580 Background: Preclinical studies have demonstrated a role for the mammalian target of rapamycin (mTOR) pathway in intestinal tumorigenesis. However, the mTOR and its related ERK pathway in human adenocarcinoma of the large intestine (ALI) have been little examined. Methods: To assess morphoproteomic alterations of ALI, tissue materials from three patients with ALI were analyzed in the present study. Antibody probes used included phosphorylated (p)-mTOR (Ser-2448) and one of its downstream effectors, p-p70S6K (Thr-389); bcl-2, which undergoes mTOR-dependent phosphorylative inactivation; and p-extracellular signal-regulated kinase (ERK)1/2 (Thr-202/Tyr-204), a co-activator of p-p70S6K. The intensity of the chromogenic signal and the cellular compartmentalization (plasmalemmal, cytoplasmic, and/or nuclear) were assessed and scored on a scale of 0–3+. Results: Moderate to strong (up to 2+ or 3+) expression of p-mTOR and its substrate, p-p70S6K, and p-ERK1/2 was present in all three cases. We also found plasmalemmal translocation of p-mTOR and nuclear translocation of p-p70S6K and p-ERK1/2, indicating constitutive activation of these protein analytes and their corresponding signal transduction pathways. We did not detect bcl-2 expression in any of these cases. Conclusions: Morphoproteomic analysis reveals constitutive activation of the mTOR and ERK pathways in ALI as evidenced by the collective commonalities of expression of p-mTOR, p-p70S6K, and p- ERK1/2 and the plasmalemmal translocation of p-mTOR and nuclear translocation of p-p70S6K and p-ERK1/2. The absence of bcl-2 expression in this context is noteworthy. These findings coincide with the preclinical data on the efficacy of rapamycin and a rapamycin analogue against colon cancer cell lines and xenograft models. Although preliminary, these observations of morphoproteomic alterations represent the first in primary human ALI specimens according to a review of the literature. The present pilot study offers a starting point for further studies (we are currently conducting a confirmatory study with larger series of cases) and the design of clinical trials using such small molecule inhibitors(e.g. rapamycin, RAD001) in a combinational strategy against ALI. No significant financial relationships to disclose.
Efficacy and safety of irinotecan-based chemotherapy in poor risk patients suffering from metastatic colorectal cancer
Authors: Deptala A. , Magon M. , Omyla-Staszewska J. , Asendrych A. , Paluszewska M. 
Published: March 2020

14581 Background: Irinotecan (CPT11) combination chemotherapy has provided a significant advancement in the management of patients with metastatic colorectal cancer (MCRC). However, there was some data indicating that poor risk cases might not benefit from longer survival with CPT11-based chemotherapy, mainly due to higher regimen toxicity. Purpose: To evaluate the hypothesis, whether CPT-11- based chemotherapy can produce similar TTP and OS in a group of poor risk MCRC patients in comparison to standard risk MCRC cases. Patients and Methods: Out of 170 CRC patients treated in our departments between 2002 - 2006, 36 poor risk MCRC patients (poor risk group was defined as 2 or more criteria being fulfilled, i.e. PS >1, and/or elevated serum LDH, and/or >1 metastatic site, and/or prior adjuvant chemotherapy), were chosen for this analysis and compared retrospectively with our standard risk MCRC cases. The poor risk arm consisted of 9 females and 27 males, in age between 40–76 [median 63,5]. All the patients were treated with CPT11-based chemotherapy, according to either AIO or de Gramont regimen. Results: In the analyzed poor risk group the confirmed RR (CR+PR) after six months of the treatment was 25,0% what was much lower than in standard risk group (RR = 40%), however did not reach the statistical significance; additional 52,8% of patients achieved SD; 8 patients (22,2%) progressed during therapy. The median TTP was 9 months and the median OS was 15 months, what were not statistically different from the standard risk group; 2-year survival obtained 27,8% of patients. No grade (G) 4 toxicity was observed. The most common adverse events (AE) were diarrhea [25% - 9 pts] and neutropenia [11.1% - 4 pts], but G3 AE were noted only in 2 and 1 person respectively. Conclusions: This analysis showed, that CPT11-based chemotherapy is an effective and safe treatment option even for poor risk patients suffering from MCRC. Although the RR was lower in comparison to standard risk cases it did not translate into shorter TTP as well as OS. Similar to ours results were published in various scientific papers. To define a precise role of various optimization strategies of CPT11-based chemotherapy in MCRC, randomized prospective multicenter studies are mandatory. No significant financial relationships to disclose.
Bevacizumab plus infusional 5-FU, leucovorin and irinotecan (FOLFIRI) for advanced colorectal cancer that progressed after oxaliplatin and irinotecan chemotherapy: A pilot study
Authors: Kwon H. , Lee D. , Kim S. , Oh S. Y. , Choi H. J. , Park K. , Roh M. S. , Kim S. , Kim H. 
Published: March 2020

14593 Background: The humanized monoclonal antibody bevacizumab inhibits angiogenesis, and improves survival when combined with chemotherapy for advanced colorectal cancer. The purpose of this trial is to evaluate the combination of bevacizumab with infusional 5-FU, leucovorin and irinotecan (FOLFIRI) in patients with advanced colorectal cancer pretreated with combination regimens including 5-fluorouracil (5- FU), leucovorin (LV) and irinotecan or 5-FU, LV and oxaliplatin. Methods: A total 14 patients (median age 56 years) with advanced colorectal cancer, all of them had progressed after oxaliplatin and irinotecan based combination chemotherapy, were enrolled in this study. Patients were treated with 2 hour infusion of irinotecan 150 mg/m2 on day 1, plus bevacizumab 5 mg/kg iv infusion for 90 minute on day 2, intravenous (iv) injection of leucovorin 20 mg/m2 followed by a bolus of 5-FU 400 mg/m2 and then 22 hour continuous infusions of 600 mg/m2 given on 2 consecutive days every 14 days. Results: The median cycles of chemotherapy were six (range 3 to 12). The response rate was 28.5%, one patient (7.1%) had a complete response, and three patients (21.4%) had a partial response. Eight patients (57.1%) had stable disease, and two patients (14.3%) progressed. The median time to progression was 3.9 months (95% confidence interval (CI) 2.0–8.7 months), and the median overall survival was 10.9 months (95% CI 9.6–12.1 months). Grade 3/4 neutropenia occurred in 5 patients, among them 2 patients developed neutropenic fever. Grade 3 hematuria and hematochezia occurred in one patient. Grade 2 proteinuria occurred in two patients. However, hypertension, bowel perforation or thromboembolic events were not occurred in total 90 cycles. Conclusions: Bevacizumab with FOLFIRI is well tolerated and improves survival in heavily treated advanced colorectal cancer patients. Further studies are needed to confirm these results. No significant financial relationships to disclose.
Preoperative chemo-radiotherapy in rectal cancer. Effect on down staging and possibility of sphincter sparing surgery
Authors: Mohran T. Z. , Rayad H. A. 
Published: March 2020

14598 Objectives: To evaluate the influence of pre-operative chemo-radiation on resectability of locally advanced rectal cancer and the possibility of performing sphincter- sparing surgery in cases not suitable for this procedures. Methods: 30 patients with rectal carcinoma with either border line respectability or not suitable for primary sphincter sparing surgery. Performance status > 60, adequate bone marrow reserve and adequate hepatic and renal functions. All patients had been staged by radiological studies and endoscopies. Treatment: All patients were treated by combined chemo-radiation. Radiotherapy with dose of 45 Gray in 25 fractions over 5 weeks. Chemotherapy with 5-flurouracil 500 mg/m2 I.V infusion over 2 hours and leucovorin immediately before radiation setting for first 5 days of the first week and the first 5 days of the last week of radiation. Patients were evaluated 4–6 weeks after treatment. Operable patients were subjected to abdominoperineal resection (APR) or low anterior resection (AR). Toxicity was evaluated using WHO Common Toxicity Criteria. Results: 30 patients were included; the median age was 48 years. Partial response was reported in 63.4% of patients and stable disease was reported in 33.3% of patients while progressive disease was reported in only one patient. Low anterior resection (AR) had been performed in 8 patients out of 12 (66.2%) who had initially not suitable for primary sphincter preservation, while abdominoperineal resection (APR) had been performed in 11 patients out of 18 patients (61.1%) who had initially border line resectability. Tumor down staging was achieved in 66% of patients. Tumor stage was identified as the only significant prognostic factors in response. Local control rate at 18 months were 85%. Actuarial overall survival for patient with curative resection at 18 months, were 85%. Toxicities included G3 leucopenia in 10% of patients, Diarrhea G3 in 13.3% of patients. Conclusion: Preoperative chemo-radiotherapy is an effective treatment in inducing down-staging of locally advanced rectal cancer patients and enhances curative resection and sphincter preserving procedures. Keyword: Colorectal cancer; Chemo- radiotherapy No significant financial relationships to disclose.
ABC; An AGITG trial of fixed dose rate (FDR) gemcitabine (gem) and cisplatin for patients (pts) with advanced biliary tract cancer (ABC)
Authors: Goldstein D. , Shannon J. , Brown C. , Tebbutt N. , Ackland S. , Van Hazel G. , Abdi E. , Jefford M. , Gainford M. C. , Adams K. 
Published: March 2020

15015 Background: No standard regimen exists for pts with ABC. Previous studies suggest that FDR optimises gem activity. This study evaluated the activity of FDR gem with low dose cisplatin using a previously identified schedule. Methods: Single arm, multi- centre phase II trial, planned to enrol 45 pts > 18 years, ECOG PS = 2, with previously untreated histologically / cytologically confirmed, inoperable locally advanced or metastatic ABC. Treatment consisted of FDR gem 1000 mg/m2 (10 mg/m2/min) and cisplatin 20 mg/m2 days 1& 8 q21 days until progression or intolerable toxicity. The primary end point was response rate (RR) by RECIST. Secondary end points included tolerability and safety, progression free and overall survival (PFS, OS) and response duration (RD). Results: 50 pts were enrolled from Feb 05 to Oct 06. Mean age was 60y (39–78); 88% had ECOG PS 0–1; 54% were female. Primary sites were gall bladder 45%, biliary tree 51%, ampulla 4%. Distant metastases were present in 63%. Past treatments included biliary stent in 29%, bypass in 6%, and an external drain in 4%. With a minimum follow-up of 12 weeks, best response was a confirmed PR in 11 pts (RR 22%, 95% CI 11 - 36) and SD (after 4 cycles) in 11 pts (22%), 1 (2%) unevaluable. CA19–9 responses occurred in 6 of 33 pts (18%). Median OS was 7 mo (0.3–13), PFS 4.4 mo (0.3–13), and RD 8 mo (5–12). One year survival rate was 30%. The median number of cycles was 4 (1–16). Treatment was delayed at least once in 45% of pts; mean delay 9d. Grade 3/4 (NCI/CTC) toxicities included infection 9%, fatigue 9%, anorexia/nausea 11%, vomiting 9%, anaemia 9%, neutropenia 28%, thrombocytopenia 15%, abnormal ALP 25%, GGT 47%, AST 6%. There was 1 treatment related death (hematemesis with grade 4 thrombocytopenia). Exploratory analysis of CA 19–9 and its association with response assessment and overall survival will be presented in June. Conclusions: This combination was well tolerated. The observed response rate is consistent with the expected 35% rate and may be superior to that expected with gem monotherapy. Further testing of this dose and scheduling is warranted. The authors thank Lilly for an unrestricted grant to conduct this study. [Table: see text]
Clinicopathologic analysis of well, moderately and poorly differentiated gastroenteropancreatic neuroendocrine tumors
Authors: Strosberg J. R. , Coppola D. , Neumann A. , Kvols L. 
Published: March 2020

15028 Background: Pathologic features used to classify neuroendocrine tumors include mitotic rate, pleomorphism and Ki-67 index. Based on these criteria, neuroendocrine tumors are classified into well, moderately, and poorly-differentiated categories. But whereas this nomenclature is conventionally employed, it is not well defined in the field of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). In particular, ‘moderately-differentiated‘ GEP-NETs are not formally recognized as a distinct category, and the clinical behavior of these tumors has not been described. Our classification of GEP-NETs is based on cell mophology and mitotic index, with well-diferentiated tumors displaying monomorphic appearance and rare mitoses (<2/10HPF), poorly differentiated tumors consisting of pleomorphic cells with a high mitotic index (>10/10HPF) and moderately-differentiated tumors displaying intermediate morphology and mitotic rate (2–10/10HPF). Methods: We performed an institutional chart analysis of patients with metastatic GEP-NETs, selecting all poorly and moderately differentiated cases and randomly selecting an equal number of patients with well differentiated tumors. The primary endpoint was overall survival. Results: A total of 83 cases were analyzed (28 well, 28 moderately, and 27 poorly differentiated). Overall survival correlated strongly with histological classification. At 2 years, survival rates among patients with well, moderately and poorly differentiated tumors were 100%, 57% and 22% respectively (p<0.001). De-differentiation of tumors was associated with a decreased rate of pentetreotide scan positivity, decreased rates of neuroendocrine hormone secretion and more widespread organ metastases. Conclusions: The classification of GEP-NETs into three histologic categories (well, moderately and poorly differentiated) correlates strongly with survival. Other features of neuroendocrine tumors (such as secretion of hormones and expression of somatostatin receptors) also correlate with histological classification. ‘Moderately- differentiated‘ neuroendocrine tumors should be recognized as a subset of GET-NETs with a prognosis that is distinct from well and poorly differentiated tumors. No significant financial relationships to disclose.
Cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (HIPEC): Toxicity, survival, and prognostic variables in 130 patients with peritoneal carcinomatosis
Authors: Ceelen W. , Peeters M. , Houtmeyers P. , Breusegem C. , De Somer F. , Pattyn P. 
Published: March 2020

15040 Background: Peritoneal carcinomatosis (PC) has a dismal prognosis. Cytoreductive surgery with HIPEC has been introduced in the management of PC with biologically favourable features. Methods: In an eight year period, 130 patients were treated (53% female, mean age 56±1 years). The origin of PC was colorectal cancer (CRC, 58%), pseudomyxoma peritonei (PMP, 9%), ovarian cancer (17%), primary peritoneal mesothelioma (10%) and gastric cancer (6%). Surgery was followed by HIPEC with mitomycin C (90 min, 35 mg/m2), oxaliplatin (30 min, 460 mg/m2) or cisplatin (90 min, 100–250 mg /m2) depending on tumour histology and previous systemic chemotherapy. The extent of disease was scored using a scale ranging from 0–9, while completeness of cytoreduction (CC) was scored as complete (CC0), nearly complete (CC1, miliary residual disease) or incomplete (CC2, gross residual disease). Target intraperitoneal temperature was 41°C-42°C. Actuarial survival was calculated using the Kaplan Meier method and univariate analysis performed using the log rank method. Results: Open perfusion (coliseum technique) was used in 41% of procedures. Macroscopically complete resection was achieved in 41%. Postoperative 30 day mortality was 1.5% while major morbidity developed in 18% of patients. Morbidity was mainly related to the extent of surgery. Median overall survival (months) was as follows: CRC, 20; PMP, 38; ovarian cancer, 19; gastric cancer, 10; mesothelioma, 9. Median survival was significantly better in CC0 patients (40 months) compared to CC1 (17 months) or CC2 (12 months). Survival was significantly worse in patients with ascites at surgery (p<0.02) and in patients who did not receive adjuvant systemic chemotherapy (p<0.001). The extent of disease score before surgery (p=0.29), performance of a splenectomy (p=0.65), and timing of PC (metachronous or synchronous, p=0.25) were not significantly related to overall survival. Conclusions: Cytoreduction followed by HIPEC offers a significant survival advantage in selected patients with PC with acceptable early toxicity. Survival is significantly associated with disease histology, CC, presence of ascites and adjuvant chemotherapy. No significant financial relationships to disclose.
Evaluation of patupilone as monotherapy in patients with advanced hepatocellular carcinoma (HCC)
Authors: Venook A. P. , Poon R. , Kang Y. K. , Mok T. S. , Chao Y. , de Bedout S. , Harbott A. , Li J. , Johri A. R. 
Published: March 2020

15055 Background: Currently, there is no strong evidence that systemic therapies provide a survival benefit for patients (pts) with hCC. However, preclinical data have shown that the novel epothilone patupilone has potent anti-proliferative activity against 8 HCC cell lines with intrinsic multidrug resistance. This exploratory study tested whether patupilone monotherapy has antitumor activity in HCC patients with intact liver function. Methods: This open-label, single-arm, multicenter, 2-stage phase II study was to enroll 24 pts in the first stage and 41 pts in the second stage, if = 3 complete or partial responses were observed in the first stage. Patients with unresectable and/or metastatic HCC (histologically confirmed) with = 1 measurable lesion were eligible if they had well-preserved hepatic function (Child-Pugh Class A) and life expectancy = 3 months. Patupilone was administered as a single IV infusion at 10 mg/m2 over 20 minutes every 3 weeks. Primary endpoint was objective response. Results: Twenty-five patients were enrolled, 24 were evaluable, and 1 violated protocol. The most common adverse events (AEs) suspected to be study-drug related were NCI CTC grade 1/2 diarrhea, fatigue, and vomiting. Grade 4 serious AEs included hyponatremia (2 pts [8%]), cardiac arrest (1 pt [4%]), diarrhea (1 pt [4%]), and gastrointestinal hemorrhage (1 pt [4%]). Grade 3 serious AEs included diarrhea (3 pts [12%]), hyponatremia (2 pts [8%]), deep vein thrombosis (1 pt [4%]), abdominal pain (1 pt [4%]), and hyperkalemia (1 pt [4%]). Most pts had dose adjustments or delays; 3 discontinued treatment. During the first stage, 1 pt had a confirmed partial response through 4 cycles, and 11 pts (44%) had stable disease for = 2 cycles with a median of 4 cycles (range, 2 to 8 cycles). Median progression-free survival was 3 months (range, 1 to 6 months), and 10 pts (40%) progressed within the first 2 cycles. The study did not progress to stage 2. Conclusions: Patupilone demonstrated an acceptable safety profile. Serious AEs were observed in a minority of patients, and most did not require treatment discontinuation. Patupilone demonstrated only modest antitumor activity in pts with HCC in this study. No significant financial relationships to disclose.
The Study of Tamoxifen and Raloxifene (STAR): Change in patient-reported outcomes (PROs) after the end of treatment
Authors: Ganz P. A. , Land S. R. , Wickerham D. L. , Lee M. , Ritter M. , Vogel V. , Costantino J. P. , Wolmark N. 
Published: March 2020

1506 Background: STAR is a double-blind, placebo controlled, randomized phase III prevention trial to evaluate the efficacy of 5 years of raloxifene (R) compared to tamoxifen (T) in reducing the incidence of breast cancer in high-risk postmenopausal women. STAR was unblinded on 3/30/2006. Primary clinical outcomes, quality of life (QOL) and symptoms (SXs) were reported (JAMA, 6/2006). We now describe changes in QOL and SXs post-treatment. Methods: Endpoints for QOL were the MOS SF-36 physical (PCS) and mental (MCS) component scales and the CES-D. SXs were measured using a modified checklist from the NSABP BCPT. Questionnaires were administered before treatment, every 6 months until 60 months, and then at 66 or 72 months. Participants enrolled in QOL study at selected sites from 1/4/2000–5/31/2001. SX data were collected on all participants in the main trial. The change in PCS, MCS and SX scales after the end of treatment was analyzed with linear regression. Results: From 7/1/1999–11/4/2004, 19,747 participants enrolled in STAR and were eligible for the SX assessment; 4,338 completed both on- and post-treatment assessments. The QOL study enrolled 1983 participants; 400 completed both on- and post-treatment assessments. CES-D scores improved significantly from on- to off-treatment (p=.007), but less so for those stopping treatment early (p=.03). The MCS and CES-D returned to pre-treatment levels; the PCS remained below (p=0.02). These endpoints did not differ by treatment group. Forgetfulness (p=.01), musculoskeletal (p=.01), vasomotor (p<.0001), dyspareunia (p<.0001), bladder (p=.0002), weight gain (p<.0001), gynecological (p<.0001), and leg cramp (p<.0001) scales decreased in severity after treatment. Those who stopped treatment early had a greater decrease in vasomotor SXs (p=.01) but a lesser decrease in gynecological SXs (p=.02). Patients on T had a greater decrease in the vasomotor (p=.02) and bladder (p=.009) scales and a lesser decrease in weight gain (p=.04). Compared to pre-treatment levels, post-treatment vasomotor SXs decreased (p=0.009) and leg cramps increased (p<.0001). Conclusions: QOL and SXs changed significantly after treatment, largely returning to pre-treatment levels. No significant financial relationships to disclose.
A phase I study of neoadjuvant paclitaxel/radiation in patients with potentially resectable adenocarcinoma of the pancreas
Authors: Chakravarthy A. B. , Wu F. Y. , Blanke C. D. , Berlin J. D. , Beauchamp R. D. , Choy H. , Delbeque D. 
Published: March 2020

15067 Background: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of weekly paclitaxel when given with concurrent radiation in the neoadjuvant setting to patients with potentially resectable adenocarcinoma of the pancreas. A secondary goal was to assess the value of 18-fluoro-deoxy-glucose positron emission tomography (FDG-PET) as an early marker of therapeutic response. Methods: Patients received weekly paclitaxel, given as a 3-hour infusion, during the course of radiation. The starting dose of paclitaxel was 30 mg/m2/week. Doses were escalated in increments of 15 mg/m2 in successive cohorts of 3–6 patients. Radiation therapy consisted of 45Gy in 25 fractions over 5 weeks. CT and PET scans were obtained prior to initiating treatment and one month following completion of chemoradiation. Results: Nine patients with resectable pancreatic cancer were enrolled through two dose levels. DLT was defined as grade 3 or greater. There were no DLTs at the first dose level of 30 mg/m2/ week. DLTs consisted of nausea, neutropenia and hepatic toxicity developed at the second dose level of 45 mg/m2/ week. Pre-treatment PET scans revealed uptake in all nine of the patients whereas pre-treatment CT scans detected disease in only 5 of 9 patients. Post-treatment PET scans correlated with pathologic findings in all 9 patients. Conclusions: The MTD for concurrent paclitaxel/radiation in the neoadjuvant setting was determined to be 30 mg/m2/week. DLTs were nausea, neutropenia and hepatic toxicity. FDG-PET may be superior to CT scans as a radiographic marker of treatment response. [Table: see text]