tbuckley/cabot-search huggingface dataset:
Laparoscopic D2 gastrectomy with complete mesogastrium excision (D2+CME) to reduce cancer leak from mesogastrium in patients with advanced gastric cancer.
Authors: Daxing Xie, Jianping Gong
Journal: Journal of Clinical Oncology (2017)

18 Background: The mechanism underlying tumor recurrence following curative surgery remains unclear. It is believed that intraperitoneal free cancer cells leaked into peritoneal cavity during curative surgery play an important role. In gastric cancer, new strategies should be established towards preventing leakage of cancer cells from the primary tumor involved tissues. Our previous research demonstrated the existence of disseminated cancer cells in the mesogastrium, and we proposed laparoscopic D2 lymphadenectomy plus complete mesogastrium excision (D2+CME) as an optimized surgical procedure for advanced gastric cancer (AGC). By dissecting along the surgical planes and embryonic boundary of mesogastrium, D2+CME is repeatable with less blood lost and improved short-term surgical outcomes. In this study, we further evaluated the oncological effect of D2+CME based on the detection of “cancer leak”. Methods: The peritoneal washings were collected prior to and after tumor resection from 45 patients who underwent D2+CME (D2+CME group) and 46 patients who underwent conventional D2 lymphadenectomy (D2 group). RT-PCR was used to determine the presence of cancer cells. Positive samples are defined as those with CEA mRNA level over threshold (cutoff value). Results: Of 91 peritoneal washing samples obtained before gastrectomy, 84 (41 in D2+CME; 43 in D2 alone) showed no presence of cancer cell. After gastrectomy, CEA positive was detected in 17 of 43 (39.5%) samples with D2 group, however, only 5 of 41 (12.2%) samples in D2+CME group detected positive CEA. The average level of CEA expression in D2+CME group was also significant lower than that in D2 group after gastrectomy (p &lt; 0.05). Presence of “cancer leak” was closely associated with pT stage and surgical procedures. The DFS of patients with CEA positive after gastrectomy was significantly poorer than that of patients with CEA negative (p &lt; 0.05). Conclusions: LaparoscopicD2+CME could reduce the leakage of free cancer cells from the envelop of mesogastrium into the peritoneal cavity during radical gastrectomy, and thus, it might potentially increase the prognosis of AGC patients. Clinical trial information: NCT01978444.
E3 Ligase cIAP2 Mediates Downregulation of MRE11 and Radiosensitization in Response to HDAC Inhibition in Bladder Cancer
Authors: Judith Nicholson, Sarah J. Jevons, Blaz Groselj, Sophie Ellermann, Rebecca Konietzny, Martin Kerr, Benedikt M. Kessler, Anne E. Kiltie
Journal: Cancer Research (2017)

The MRE11/RAD50/NBS1 (MRN) complex mediates DNA repair pathways, including double-strand breaks induced by radiotherapy. Meiotic recombination 11 homolog (MRE11) is downregulated by histone deacetylase inhibition (HDACi), resulting in reduced levels of DNA repair in bladder cancer cells and radiosensitization. In this study, we show that the mechanism of this downregulation is posttranslational and identify a C-terminally truncated MRE11, which is formed after HDAC inhibition as full-length MRE11 is downregulated. Truncated MRE11 was stabilized by proteasome inhibition, exhibited a decreased half-life after treatment with panobinostat, and therefore represents a newly identified intermediate induced and degraded in response to HDAC inhibition. The E3 ligase cellular inhibitor of apoptosis protein 2 (cIAP2) was upregulated in response to HDAC inhibition and was validated as a new MRE11 binding partner whose upregulation had similar effects to HDAC inhibition. cIAP2 overexpression resulted in downregulation and altered ubiquitination patterns of MRE11 and mediated radiosensitization in response to HDAC inhibition. These results highlight cIAP2 as a player in the DNA damage response as a posttranscriptional regulator of MRE11 and identify cIAP2 as a potential target for biomarker discovery or chemoradiation strategies in bladder cancer.
Impact of resistance exercise on metabolic syndrome (MetS) parameters in men receiving androgen deprivation therapy (ADT) for prostate cancer.
Authors: Tanya B. Dorff, Mitchell E. Gross, David I. Quinn, Jacek K. Pinski, E. Todd Schroeder, Susan G. Groshen, Christina Marie Dieli-Conwright, Jacqueline Kiwata
Journal: Journal of Clinical Oncology (2017)

223 Background: Cardiovascular disease is the leading cause of death in men with prostate cancer. ADT is effective treatment, but can induce loss of skeletal muscle, plus increase central fat, lipids, and insulin resistance. These changes in MetS components may contribute to excess cardiac risk. We tested whether a resistance exercise program, designed to increase skeletal muscle mass, could offset adverse changes in MetS parameters during ADT. Methods: Men on ADT for at least 12 weeks were randomized to exercise (EX) or no exercise (NOEX). EX was supervised, periodized resistance training followed by stretching 3x/week for 12 weeks, 45 min/session. NOEX did home-based stretching 3x/week. Baseline and post-intervention measurements included weight, waist circumference, lean body mass, lipids, insulin, glucose, hsCRP. Quality of life (QOL) was evaluated with FACT-P and BFI, and muscle biopsies were obtained pre- and post-intervention. Mean of changes from baseline were compared between groups using ANCOVA. Results: 24 men (mean age 65; range 49-81) completed protocol with 100% compliance (n = 12 EX, n = 12 NOEX). Baseline PSA ranged from 0 – 8.1 ng/mL and did not change; subjects had been on ADT for a mean of 17 months (range 3-84). In multivariable analysis controlling for baseline muscle mass, age, and ADT duration, the mean change in waist circumference after 12 weeks was significantly different between EX (-2.05 cm +/- 2.82) and NOEX (+0.69 cm +/- 2.01) groups (p = 0.011, t-test). There were no significant differences for other parameters. However, consistent patterns were noted in: mean fasting glucose -4.59 mg/dL in EX compared with +1.12 mg/dL in NOEX (p = 0.21, t-test) and diastolic blood pressure -2.17 mmHg in EX vs +2.0 mmHg in NOEX (p = 0.27, t-test). In the EX group 5/12 had MetS at baseline which remained stable while the NOEX group increased from 2/12 with MetS at baseline to 3/12 post intervention. Analysis of QOL and muscle biopsies are ongoing. Conclusions: Supervised resistance exercise for 12 weeks is feasible and decreases waist circumference in men receiving ADT for prostate cancer. Longer follow-up may reveal additional impacts of resistance training on MetS. Clinical trial information: NCT01909440.
Early results of a randomized phase II, compass trial to compare regimen and duration of neoadjuvant chemotherapy for gastric cancer.
Authors: Takaki Yoshikawa, Kazuaki Tanabe, Kazuhiro Nishikawa, Yuichi Ito, Takanori Matsui, Yutaka Kimura, Satoshi Morita, Yumi Miyashita, Akira Tsuburaya, Junichi Sakamoto
Journal: Journal of Clinical Oncology (2013)

4102 Background: Prognosis for stage III gastric cancer was not satisfactory even by D2 gastrectomy and adjuvant chemotherapy. Neoadjuvant chemotherapy is another promising approach. This study investigated the outcomes of two and four courses of neoadjuvant S-1/cisplatin (SC) and paclitaxel/cisplatin (PC) using a two-by-two factorial design for locally advanced gastric cancer. Methods: Patients with stage II schirrhous/junctional tumors, stage III, or resectable stage IV, received S-1 (80 mg/m 2 for 21 days with 1 week rest)/cisplatin (60 mg/m 2 at day 8) or paclitaxel/cisplatin (80 mg/m 2 and 25 mg/m 2 , respectively, on days 1, 8, and 15 with 1 week rest). The primary endpoint was 3-year OS. Key secondary endpoints included pathological/clinical response, R0 resection, and adverse events. Sample size was set at 60 to 80 to achieve 10% improvement of 3-year OS by four courses or by PC with approximately 80% probability of the correct selection. Results: Between Oct 2009 and July 2011, 83 patients were assigned to arm A (2 courses of SC, n=21), arm B (4 courses of SC, n=20), arm C (2 courses of PC, n=21), and arm D (4 courses of PC, n=21). Clinical response (arm A/B/C/D) was 29%/40%/33%/24%. R0 resection (arm A/B/C/D) was 76%/75%/57%/76%. Pathological response (arm A/B/C/D), defined as tumor regression more than two third in the primary tumor, was 43%/40%/29%/38%. Pathological complete response (arm A/B/C/D) was 0%/10%/0%/10%. Major grade 3/4 toxicities (arm A/B/C/D) were anemia (14%/15%/0%/28.6%), neutropenia (10%/15%/14%/33%), nausea (0%/10%/5%/5%), and appetite loss (5%/10%/0%/5%). Pathological complete response by per-protocol analysis (arm B/D) was 17% and 12%. Treatment discontinuation (number of patients, arm A/B/C/D) was disease progression (1/3/0/1), toxicities (1/4/0/3), and others (0/1/0/0). No surgical mortality was observed. Grade 3 morbidity classified by Clavien-Dindo was leakage in 5% (arm A), pancreatic fistula in 5% (arm C), and postoperative hemorrhage in 5% (arm B). Conclusions: Pathological complete response could be induced by four courses of neoadjuvant chemotherapy without a marked increase of toxicities, regardless of a SC or PC regimen. Clinical trial information: UMIN000002595.
Standardized costs and outcome in children treated with gemtuzumab on the AAML0531 trial: A report from the Children’s Oncology Group.
Authors: Richard Aplenc, Brian Fisher, Yimei Li, Todd Allen Alonzo, Robert B Gerbing, Matt Hall, Staci D. Arnold, Yuan-Shung Huang, Alix Eden Seif, Rochelle Bagatell, Lillian Sung, Peter C. Adamson, Alan S. Gamis, Ron Keren
Journal: Journal of Clinical Oncology (2014)

7086 Background: NCI-funded cooperative group oncology group trials report clinical outcomes but do not report cost estimates. The Children’s Oncology Group trial AAML0531 randomized 1,022 de novo AML patients to standard chemotherapy ± gemtuzumab (GMTZ). As previously reported, GMTZ improved event-free survival but did not improve overall survival. The Pediatric Health Information Systems (PHIS) database contains standardized inpatient cost data (SC) on children treated at 43 freestanding pediatric hospitals in the United States. We hypothesized that SC would be similar for both treatment arms during on-protocol therapy but lower in the GMTZ arm during all follow up time (defined as time from on-protocol to last COG follow-up). Methods: Data from AAML0531 and PHIS were probabilistically merged. PHIS SC were defined by hospital costs multiplied by the ratio of cost to charges and adjusted by consumer price index and geographical region. All available SC were extracted for all merged patients and compared with bivariate statistics. Results: Merged patients (n = 373) were representative of the overall trial population. Follow-up time was marginally longer in the GMTZ arm, 223 days vs 238 days, p = 0.1. The overall median SC was $309,785 ($1,943/day) on-protocol and $467,767 ($1,707/day) for all follow-up time. The per day SC did not differ by study arm on-protocol but per day SC were significantly higher in the non-GTMZ arm, $1,877/day vs $1,648/day over all follow-up time, p = 0.03. Table 1 summarizes departmental SC; Room and Board (RB) comprises approximately 50-60% of all SC. Conclusions: Merging of PHIS data with COG data enables estimation of regimen specific SC. GMTZ does not increase SC during protocol therapy but is associated with lower per day SC over all follow-up time. Further work is needed to increase the number of patients with SC data, to examine SC variability, and define drivers of SC. Clinical trial information: NCT00372593. Department Median on protocol Percent* Median overall Percent* Pharmacy 60,866 19.6% 99,881 21% Supplies 3,419 1.1% 5,101 1.1% Laboratory 34,460 11.1% 54,786 11.7% Radiology 4,523 1.5% 7,146 1.5% Clinical 8,282 2.7% 19,142 4% RB 181,774 58.7% 241,794 52% *Percentage of overall median SC.
Everolimus with paclitaxel plus bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (MBC): A randomized, double-blind, placebo-controlled phase II trial of the Sarah Cannon Research Institute (SCRI).
Authors: Denise Aysel Yardley, Linda D. Bosserman, Nancy Walker Peacock, Anne Favret, Susan Kay Morgan, Victor M. Priego, J. David Bass, Paula L. Griner, Howard A. Burris, John D. Hainsworth, Joyce O'Shaughnessy
Journal: Journal of Clinical Oncology (2012)

1018 Background: Constitutive activation of mTOR and amplified PI3K/Akt/mTOR signaling are common in MBC, and increase as treatment-resistance is acquired. Everolimus (E), an mTOR inhibitor, has single agent activity, combines well with paclitaxel (P) and bevacizumab (B), and prolonged PFS when added to AI therapy in BOLERO-2. In this randomized phase II trial, E was added to P/B as first-line treatment of HER2-negative MBC. Methods: Women with untreated HER2-negative MBC were randomized (1:1) to P 90mg/m 2 IV (days 1, 8, and 15) and B10mg/kg IV (days 1 and 15) q28 days with E 10mg PO (Arm 1) or placebo PO (Arm 2) daily. Response assessment was performed q8 weeks until progression or intolerable toxicity. Primary endpoint was PFS. Secondary endpoints: safety, overall response rate, response duration, overall survival. 110 pts allowed detection of improvement in median PFS from 11 to 16 months with 70% power. Results: Between 8/2009 and 6/2011, 112 pts were randomized (Arm 1=55; Arm 2=57). Median age: 58 years (range: 25-79). 88% were ER+ or PR+. Pts received a median 5 treatment cycles (range: &lt;1- 26+); 18 (16%) pts remain on treatment (Arm1, 9; Arm 2, 9). Median PFS were 8.8 months (Arm 1) and 7.1 months (Arm 2) (95% CIs 7.4-9.6; 5.5-9.1 months, p=0.79, HR 0.94). Complete responses were observed in 5% [Arm1, 4 (7%); Arm 2, 2 (4%)] with partial responses in 49% [Arm1, 29 (53%); Arm 2, 26 (46%)]. Responses rates in taxane pretreated pts Arm 1 22%, Arm 2 12%. Hematologic toxicity was similar in both arms; grade 3 mucositis occurred in 13% of E pts. Dose reductions (47% vs 25%) and interruptions (42% vs 26%) were more frequent with E due to mucositis and rash. Treatment discontinuation rates were similar. Conclusions: The addition of E did not result in a significant improvement in the efficacy of weekly paclitaxel/bevacizumab in the first-line treatment of HER2-negative MBC although response rates and median PFS were better with E. Possible explanation for these results may include lower dose intensity in the E arm, treatment of less resistant pts, or intrinsic differences in E activity when added to antiestrogen vs chemotherapy.
Randomized phase II study of 3 versus 6 courses of neoadjuvant carboplatin-paclitaxel chemotherapy in stage IIIC or IV epithelial ovarian cancer.
Authors: Claudio Zamagni, Myriam Perrone, Vincenzo Dario Mandato, Alessandra Bologna, Daniela Rubino, Giorgia Zucchini, Nuria Maria Asensio Sierra, Elena Barbieri, Marta Cubelli, Pierandrea De Iaco, Martino Abrate
Journal: Journal of Clinical Oncology (2014)

TPS5624 Background: The role and the duration of neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian cancer (AOC) are still debated. A phase III randomized trial showed that 3 courses of NACT followed by surgery were not inferior to primary debulking surgery followed by chemotherapy (CHT) for patients (pts) with AOC. Moreover, the absence of residual tumor after surgery was found to be the single most important independent prognostic factor. In our preliminary experience pts with bulky stage IIIC or IV AOC were treated with 6 courses of NACT followed by surgery and we observed a complete cytoreduction rate up to 63% ; the survival data did not suggest a detrimental effect of such strategy. Considering the lack of evidence regarding the best standard of care for pts with AOC, a randomized study of 3 vs 6 courses of NACT was designed to verify if 3 more courses of NACT are associated to an increase of complete cytoreductive surgery rate (CCSR) (primary end-point). Methods: this is a multicenter randomized, phase II study of 3 vs 6 courses of NACT in AOC. The main eligibility criteria are ECOG PS ≥ 2, histologically confirmed FIGO stage IIIC-IV epithelial ovarian cancer, unsuitable for complete primary cytoreductive surgery (inoperability confirmed by open laparoscopy or laparotomy). Pts will receive 3 or 6 courses of i.v. carboplatin AUC 5 and paclitaxel 175 mg/m2 every 3 weeks, followed by surgery.Tumor tissue will be collected for analyses of prognostic and predictive biomarkers, including ESR1 mRNA, HER2 and HER3 expression, BRCA1, BRCA2 and PI3KCA mutations. By hypothesizing a CCSR of 43% in Arm A (3 courses) and 63% in Arm B (6 courses), with a two-sided alpha error of 0.05 and a power of 0.80, 214 pts (107 in each arm) are to be enrolled in 2 years. An interim analysis has been scheduled after the first 120 pts in order to end the enrollment in the phase II and to start a phase III (with survival as primary endpoint) in case of the endpoint for efficacy (CCSR) will be reached at that time. The sample size of the interim analysis was calculated by considering the same alpha error (0.05) but a lower power value (0.50) than those of the global sample size calculation. The first patient was enrolled in January 2014. Clinical trial information: 2013-002520-17.
Body mass index impact on acute myeloid leukemia (AML) outcomes.
Authors: Ahmed Elkhanany, Niamh Keane, Sharukh Hashmi, Kebede Begna, Rajiv Pruthi, William J. Hogan, Shujun Liu, Mark Robert Litzow, Aref Al-Kali
Journal: Journal of Clinical Oncology (2013)

7094 Background: Obesity is associated with comorbidities that could cause negative outcome upon delivering intensive care. In pediatric AML patients (pts), obesity was associated with more toxicity and worse prognosis. Here, we study Body-Mass Index (BMI) impact on clinical outcome of adult AML pts. Methods: A total of 180 adult pts with AML between 2003-2011 were enrolled. Retrospective data included demographics, labs, cytogenetics and outcome. LeukemiaNET Standardization (LNS), complete remission (CR), overall survival (OS) and relapse free survival (RFS) were obtained (Dohner E, Blood 2010). BMI of 25-30 was defined as overweight, while &gt;30 as obesity. Fischer’s and Wilcoxon tests were used for comparatives between groups, cox proportional hazards and logistic regression for associations for OS/RFS and CR, Kaplan-Meier test for OS and RFS estimates via JMP software V9.0. IRB approval was obtained according to Helsinki declaration. Results: The median age was 63 years, with 115 (64%) were men. Of 159 pts, karyotype was favorable, Intermediate I, II and adverse in 21 (13%), 76 (48%), 23 (%14) and 39 (25%) pts respectively. Median BMI was 28.2 (range 16.8-47.8). 48 (26%) had normal BMI, 62 (34%) were overweight, and 70 (38%) were obese. At diagnosis, BMI classes were not associated with age, sex, glucose, white blood count (WBC), platelets, blasts, ECOG status, LNS, FLT3/NPM1 status; nor treatment toxicities, CR rates, or relapse after CR. BMI classes were associated with presence of concomitant comorbidities (p=0.047) and glucose levels (p=0.044). In univariate analysis, overweight (OR=1.8, p=0.16) and obesity (OR=1.9, p=0.13) did not affect CR rates. On adjusting for age, sex, LNS, WBC and blast count at diagnosis, only overweight pts had a significant higher CR (76% vs 63%) rates (OR=2.99, p=0.043). OS and RFS were not associated with BMI in univariate (p=0.51) and multivariate (p=0.32) models. Median OS and RFS were not different across BMI subgroups (p=0.52 and 0.59). Conclusions: BMI subgroups showed no correlation with treatment toxicity, LNS, relapse rates, OS or RFS. This should encourage giving therapy to pts regardless of their BMI status. Overweight was associated with better CR rates despite increased concomitant morbidities.
Liver metastases in mCRPC patients post-therapy with abiraterone (Abi) and/or abiraterone/enzalutamide (Enza).
Authors: Lahiru Ranasinghe, Patrick Cotogno, Elisa M. Ledet, Allie E. Steinberger, Allison H. Feibus, Kyle Degeyter, Bruce Bordlee, Oliver Sartor
Journal: Journal of Clinical Oncology (2017)

250 Background: Liver metastases (mets) are a particularly poor prognostic group among mCRPC patients. The objective of this study is to characterize mCRPC patients who have had treatment with Abi or Enza to identify risk factors that may be associated with subsequent development of liver mets. Methods: A sample of 67 patients (n = 17 liver mets and 50 non-liver met patients matched by treatment history) seen at Tulane Cancer Center were selected for analysis. All patients had prior Abi and or Abi/Enza. Race, age at PCa diagnosis and Gleason Score at PCa diagnosis were assessed. For patients with liver mets, total liver metastatic volume was measured using CT scans and correlated against PSA, LDH and AST values at the time of the scan. Wilcoxon rank sum tests were run analyzing PSA, LDH and AST at the start of Abi treatment, end of Abi treatment as well the duration of Abi treatment, and the nadir PSA for these patients. Results: Patients were predominantly Caucasian, had a median Gleason Score of 8 at diagnosis and were at a median age of 57 for those with liver mets and 62 for non-liver met at PCa diagnosis. Pearson correlation analysis of the total liver lesion volume and lab values revealed a significant correlation for LDH (R = 0.491, &lt; 0.01) and AST (R = 0.368, p &lt; 0.05), but not for PSA. Further evaluation of PSA and AST values at the start and end of Abi treatment as well as at nadir PSA revealed no statistically significant differences between liver met patients and non-liver met patients. However, there was a significant difference (p = 0.015) between LDH levels at the end of Abi treatment with a median of 347 U/L for liver met and 238 U/L for non-liver met patients. Conclusions: LDH and AST levels correlate with extent of liver metastases. Additionally, elevated LDH at the end of Abi treatment is indicative of an increased risk for developing liver metastases. Larger sample sizes and molecular characterization of these tumors are required to gain more insights into this important patient population.