tbuckley/cabot-search huggingface dataset:
Phase 1 dose escalation study of MEDI-565, a bispecific T-cell engager that targets human carcinoembryonic antigen (CEA), in patients with advanced gastrointestinal (GI) adenocarcinomas.
Authors: Michael J. Pishvaian, Michael Morse, Jennifer T. McDevitt, Song Ren, Gabriel Robbie, Patricia C. Ryan, Serguei Soukharev, Haifeng Bao, Crystal Shereen Denlinger
Journal: Journal of Clinical Oncology (2016)

320 Background: MEDI-565, a bispecific single-chain antibody, targets human CEA on tumor cells and the CD3 epsilon subunit of the human T-cell receptor complex. In murine models, MEDI-565 showed antitumor activity in CEA-expressing tumors (J Immunother 2009;34:341-52). Methods: This phase 1, multicenter, open-label, dose-escalation study enrolled adults with GI adenocarcinomas (including esophageal, gastric, small intestine, colorectal, biliary tract, and pancreatic). MEDI-565 was given intravenously over 3 h on days 1–5 in 28-day cycles, with 4 single-patient (pt) (0.75–20 μg) and 5 standard 3+3 escalation (60 μg–3 mg; 1.5–7.5 mg with dexamethasone [dex]) cohorts. Primary objective was to determine the maximum tolerated dose (MTD); secondary objectives were to evaluate pharmacokinetics (PK), antidrug antibody (ADA), and antitumor activity. Results: Study enrolled39 pts: mean age 59 y; 56% male; 28 (72%) colorectal, 6 (15%) pancreatic, 5 (13%) other. Dose-limiting toxicities (grade ≥ 3 nonhematologic) were seen in 4 pts (2 at 3-mg; 2 at 7.5-mg + dex): hypoxia (n = 2), diarrhea, and cytokine release syndrome (CRS). Grade 3 treatment-related adverse events (AEs) seen in 5 pts: diarrhea, CRS, increased alanine aminotransferase, hypertension (all n = 1), and hypoxia (n = 2). Treatment-related serious AEs seen in 6 pts: diarrhea, vomiting, pyrexia, CRS (all n = 1), and hypoxia (n = 2). Five pts discontinued treatment due to AEs: diarrhea, CRS, central nervous system metastases, and hypoxia (n = 2). MEDI-565 exposures increased in approximately dose-proportional manner, with clearance (35–77 L/d) and half-life (2–7 h) typical of drug class. ADA had minor impact; 19 pts (48.7%) had ADAs, 5/39 (12.8%) with high titer, with decreased MEDI-565 concentrations in 2 pts. Plasma inflammatory cytokines were elevated posttreatment in several pts at 1.5- and 3-mg (no dex) dose levels. No objective responses were observed; 11 (28%) pts had stable disease as best response. Conclusions: The MTD of MEDI-565 in pts with GI adenocarcinomas was 5 mg with dex. PK was linear, with fast clearance and short half-life. No objective responses were observed. Clinical trial information: NCT01284231.
Phase II study of S-1 in combination with irinotecan in patients with advanced colorectal cancer (CRC)
Authors: Y. Komatsu, S. Yuuki, T. Amano, N. Machida, M. Ozasa, T. Kato, S. Furukawa, H. Akita, M. Asaka, Y. Sakata
Journal: Journal of Clinical Oncology (2005)

3708 Background: The currently recommended first-line chemotherapy for inoperable colorectal cancer is multiple-drug therapy including irinotecan or oxaliplatin. The oral fluorinated pyrimidine compound S-1, even when used alone, has been reported to show considerable efficacy, achieving a response rate of 39.5% in patients with colorectal cancer. Therefore, we planned to conduct a phase II clinical study of combination therapy with irinotecan and S-1, a new oral anticancer drug of the fluorinated pyrimidine type. Methods: The antitumor effect was the primary endpoint, while the safety, progression-free survival time, and median survival time were the secondary endpoints. The subjects were untreated patients with inoperable advanced colorectal cancer aged 20–75 years. Based on the results of our previous phase I/II study in patients with gastric cancer (Proc ASCO 2002 #683), the dosage was established in consideration of safety for outpatient therapy. Irinotecan was administered at a dose of 100 mg/m2 (on days 1 and 15) as an intravenous infusion over 90 minutes, and oral S-1 (40 mg/m2) was administered after breakfast and dinner and then withdrawn for 2 weeks. Results: At the time of abstract submission, 20 patients were enrolled in the present study. There were 13 men and 7 women. The median age was 62 years (range: 34 to 71 years).One patient showed grade 4 neutropenia, but the next course could be given safely after dose reduction. Two patients had grade 3 diarrhea, but therapy could be continued with addition of an antidiarrheal drug. No other serious adverse reactions occurred (either hematological or non-hematological), and all patients could receive therapy safely on an outpatient basis. Interim analysis suggested useful results, with a response rate of 60%(12PR).5pts SD(25%)and 3 pts have PD(15%). Conclusions: Combination therapy with irinotecan and S-1 achieved a high response rate and could be given safely. These findings suggest that the therapy has potential as first-line treatment for inoperable advanced recurrent colorectal cancer. In addition, this regimen could qualify as a candidate for future combination therapy with a molecular-targeting drug. The latest data will be reported at the meeting. No significant financial relationships to disclose.
Identifying the surgical cavity following oncoplastic surgery: Utility of a novel tissue marker.
Authors: John Harman, Stan Govender, Benji Benjamin, John Simpson
Journal: Journal of Clinical Oncology (2013)

76 Background: Oncoplastic surgery has helped improve outcomes following partial mastectomy. However, in most cases, patients still require post-operative radiotherapy, which can cause significant complications. While recent advances have made it feasible to perform external beam radiation in a more targeted and accelerated fashion, these methods are not commonly used in the treatment of breast cancer. This is due to the difficulty in identifying the margins of the surgical site, and can be particularly challenging with oncoplastic surgery (OPS). In this pilot study, we evaluated a new method for marking the margins of the surgical cavity when using oncoplastic techniques. Methods: 15 patients were selected to have a 3-D tissue marker implanted at the time of lumpectomy. All patients were candidates for partial mastectomy, sentinel lymph node biopsy and breast reconstruction using OPS. Post-operative treatment plans including radiation and/or adjuvant chemotherapy were completed as recommended. Patients were followed and imaged with standard breast imaging following completion of their treatment. Results: The marker was easily identified and clearly delineated the margins of the lumpectomy cavity. It allowed for 3-D characterization of the borders surrounding the cavity, and it was easily distinguishable from the seroma and other surgical tissue changes. Respiratory motion was easily tracked using the device making it possible to apply advanced radiation treatment methods such as IMRT and accelerated protocols. When compared to conventional methods of determining the target area, use of the marker resulted in treatment volumes that were reduced by &gt;60%. In appropriate patients, the marker also facilitated the use of an accelerated protocol, decreasing total treatment time from 6 weeks to 5 days. No complications were reported. Conclusions: This novel 3-D marker was consistently visualized, was readily incorporated into standard and advanced dose planning methods, and had appreciable benefits when designing optimal treatment plans. Its unique features were also helpful when using oncoplastic techniques, and proved valuable for long-term follow-up using standard methods of breast imaging.
Evaluation of <i>BRAF</i> mutation as a powerful prognostic factor in advanced and recurrent colorectal cancer.
Authors: T. Yokota, T. Ura, N. Shibata, D. Takahari, K. Shitara, M. Nomura, C. Kondo, A. Mizota, Y. Yatabe, K. Muro
Journal: Journal of Clinical Oncology (2011)

413 Background: Alterations in the RAS/RAF/ERK signaling pathways frequently occur in colorectal cancer (CRC). KRAS mutations preclude responsiveness to EGFR-targeted therapies for CRC patients. However, prognostic significance of KRAS mutation is still controversial. The aim of this study is to investigate clinicopathological features of KRAS mutation in codon 12 and 13 as well as of BRAF mutation, and to validate prognostic impact of KRAS/BRAF mutation in advanced and recurrent CRC. Methods: The population consisted of 230 unselected patients who had undergone first-line chemotherapy for advanced and recurrent CRC between November 2002 and June 2010. Cycleave PCR was performed to detect a point mutation at codon 12, 13 or 61 in KRAS, and the V600E mutation in BRAF. Prognostic factors associated with survival were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. Results: KRAS mutations were present in 34.8% (n= 80) of patients, including 23.5% (n = 54) in codon 12, 11.3% (n = 26) in codon 13, and 0% in codon 61. 6.5% (n = 15) of patients had BRAF mutation. None of the CRC patients carried both KRAS and BRAF mutations. The primary tumor lesions were located on the right side of the colon in 60% of the BRAF mutant patients (p=0.0371). Furthermore, BRAF mutant was significantly associated with the pathological subtypes of poorly differentiated adenocarcinoma/mucinous carcinoma (p&lt;0.0001) and peritoneal metastasis (p=0.0059). The median overall survival for BRAF mutant and KRAS 13 mutant patients was 11.0 and 27.7 months, respectively, which was significantly worse than that for KRAS wild-type (wt)/BRAF wt (40.6 months) (BRAF; HR=3.89, 95% CI 1.83-8.24, p&lt;0.001, KRAS13; HR=2.03, 95% CI 1.10-3.74, p=0.024). After adjustment for significant features by multivariate Cox regression analysis, BRAF mutation was associated with poor overall survival (HR, 3.70, 95% CI, 1.48-9.28; p=0.005), together with performance status 2. Conclusions: This retrospective analysis shows that clinicopathological features of CRC patients with BRAF mutations seem to be distinct from those with wild type BRAF. BRAF mutation is one of the most powerful prognostic factors in advanced and recurrent CRC. No significant financial relationships to disclose.
Association between bone turnover markers and skeletal-related events in patients with breast cancer and bone metastases on treatment with bisphosphonates: ZOMAR study results at nine months of follow-up.
Authors: A. Barnadas, C. De la Piedra, C. Crespo, P. Gomez Pardo, L. Calvo, E. G. Calvo, M. Ruiz-Borrego, J. Rifa, L. Manso, A. Anton, M. Codes, M. Margeli, A. Murias, J. Salvador, M. A. Seguí-Palmer, A. De Juan, J. Gavila, D. Perez, M. Luque, I. Tusquets
Journal: Journal of Clinical Oncology (2011)

594 Background: The presence of bone metastases (BMe) alters the balance of bone remodeling and, consequently, levels of bone turnover markers (BTM). Increased levels of these biomarkers are related to the risk of skeletal-related events (SREs), disease progression and death. Treatment with bisphosphonates reduces the number of SREs through osteoclastic activity inhibition. The aim of this study was to determine the correlation between BTM, bone metastasis development and SREs in patients (pts) with breast cancer (BC) and BMe. Methods: Observational, prospective, multicenter study. Inclusion criteria: pts with BC and BMe; no previous treatment that could interfere with bone metabolism in the last 6 months (mo) prior to inclusion. Urinary aminoterminal telopeptide of collagen I (NTX, Osteomark NTx Urine, Wampole Laboratories, USA), urinary alpha-alpha-isomer of carboxyterminal telopeptide of collagen I (αα-CTX, ALPHA Crosslaps EIA, ids, UK) and serum bone alkaline phosphatase (BALP, OSTASE BAP, ids, UK) were determined at baseline (V0) and every 3 mo. Pts were treated with zoledronic acid (ZA) at inclusion and every 3-4 weeks. Results: Data of BTM at 9 mo of treatment (V3) are presented; 212 patients were analyzed: mean age: 61 years; RE+: 80%; RP+: 66%; HER 2+:17%; previous SRE: 19%. At V0, 54%, 46% and 85% pts presented elevated levels of NTX, αα -CTX and BALP, respectively. A significant decrease was observed in BTM at V3 vs V0, showing normal levels of NTX, αα-CTX and BALP levels in 87, 91 and 48% of pts, respectively (p <0.05). Pts with lowered BTM levels showed fewer SREs (not statistically significant). A significant association was observed between elevated levels of BALP and disease progression throughout follow-up. Conclusions: ZA significantly reduced BTM levels during the first 9 mo of treatment. BALP was significantly associated with disease progression. A tendency to present fewer SREs was observed in the population with lower BTM levels. Longer follow-up is needed to confirm these outcomes.
Clinico-pathologic correlates of BRAF mutation status in 207 consecutive patients with metastatic melanoma.
Authors: G. V. Long, A. M. Menzies, A. Nagrial, L. Haydu, A. L. Hamilton, G. Mann, T. M. Hughes, J. F. Thompson, R. A. Scolyer, R. Kefford
Journal: Journal of Clinical Oncology (2010)

8548 Background: Drugs selectively targeting oncogenic mutant (mut) BRAF show activity against metastatic melanoma (MM) carrying these mutations. Distinguishing clinico-pathologic features of mut BRAF MM may influence patient (pt) selection and stratification in trials of these drugs, but no large studies have comprehensively examined this possibility. Our aim was to identify clinico-pathologic correlates of the BRAF mutation status in pts with MM. Methods: Consecutive BRAF tested pts with MM were followed prospectively. Tumor sections were screened by high resolution melt curve analysis of BRAF exon 15 and abnormal results confirmed by DNA sequencing. Data were collected on demographics, details of the primary melanoma (PM) and diagnostic, prognostic and treatment details from date of first distant metastasis (DM). Chi-square and Mann Whitney U tests were used to assess the association of clinico-pathologic features with BRAF status. Multivariate analysis was performed using a logistic regression model. Results: 97/207 pts (47%) had a mutation in exon 15 of the BRAF gene. Of these 72 (74%) were V600E, 19 (20%) V600K, and 6(6%) another mutation or combination. Pt age at diagnosis of DM was significantly different for mut (median age 56, n = 73) and wt (median age 62, n = 81: p < 0.005) tumours. There was no difference between mut/wt in disease free interval from diagnosis of PM to date of DM, sex, site of metastases at diagnosis of DM, regional lymph node involvement ever, resection of DM with intent to cure, response to chemotherapy (CT) or length of response to CT. ECOG status was not significantly different between mut/wt when adjusted for age. Features of the PM significantly associated (p < 0.05) with BRAF mut were: age at PM ≤ 50 yrs (OR = 3.16, 95%CI: 1.28-7.80); superficial spreading or nodular histopathologic subtype (OR = 3.96, 95%CI: 1.32-11.86); and truncal location (OR = 2.66, 95%CI: 1.09-6.47). Conclusions: The BRAF mutation rate in an Australian MM cohort was 47% and non-V600E activating mutations were more common than previously reported. Characteristics of the preceding PM and age at diagnosis differed in BRAF mut and wt MM pts. Clinical features of metastatic disease were essentially indistinguishable. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline, Roche
Sentinel lymph node (SLN) mapping (M) in colon cancer (CCa) by da Vinci robotic system (DRS): First pilot study.
Authors: Sukamal Saha, Alpesh Korant, Benjamin Abadeer, Andrew Gomez-Seoane, Mohammed Shaik, Madhumitha Krishnamoorthy, Sunil Kaushal, B. K. Ganatra, David Wiese
Journal: Journal of Clinical Oncology (2013)

589 Background: SLNM in CCa has been established as an aid to the pathologist to identify the nodes most likely to harbor micrometastasis. The technique has been well- established by in vivo and ex vivo technique. No such technique has been described by DRS in CCa. Hence, a pilot study was undertaken to identify if SLNM can be performed by DRS during robotically assisted colectomy as in open cases. Methods: Patients (Pts) with CCa were randomly selected for either robotic or open surgery. During each case, 1% methylene blue dye was injected in vivo subserosally around the tumor. Standard oncologic operations were done in each case. The first 1-4 blue nodes near the tumor were tagged with suture as SLNs. Data was collected for demographics, tumor pathology and peri-operative events. Results: There were a total of 11 consecutive robotic pts and 15 open pts. The data was compared between the robotic vs open groups as follows: Primary sites including Cecum (1 vs 3), Ascending Colon (3 vs 4), Transverse Colon (4 vs 5), Sigmoid Colon (2 vs 3); Average number of LNs (18.5 vs 17.6); Average number of SLNs (3.3 vs 3.0), and nodal positivity (50% vs 50%). The success rate was 100% in each group. Conclusions: There are great similarities for SLNM between robotic and open surgeries for CCa in regards to success rate, nodal harvest, SLNs, and nodal positivity. Hence, SLNM should be pursued when robotic surgeries are performed for CCa pts as in open cases. [Table: see text]
Transperineal sector biopsies: Their role in prostate cancer active surveillance.
Authors: Lona Vyas
Journal: Journal of Clinical Oncology (2012)

228 Background: Many men with low risk prostate cancer on transrectal biopsy appear suitable for active surveillance (AS). Under staging and grading at diagnosis can result in delayed treatment and risk of poorer oncological outcomes. In most AS series about 30% men have active treatment at a median of two years for presumed disease progression/choice but this may represent disease mischaracterised at initial biopsy. So it is essential to accurately stratify patients before surveillance. We have routinely offered transperineal sector prostate biopsies (TPSB), using 24-32 cores, to all patients considering AS. Methods: 350 patients with apparent low to intermediate risk prostate cancer after transrectal prostate biopsy (TRUS Bx) underwent transperineal sector biopsies. Results: Median age 64 yrs (38–84). Median PSA 7.2 ug/l (0.14–58). 190 had Gleason 3+3, 115 had Gleason 3+4 and 45 &gt;3+4 disease. 145 (41%) patients elected for definitive treatment, in 112 because there was an upgrade or higher disease volume compared with the original TRUS Bx. 33 patients chose definitive treatment rather than continued AS. 205 (59%) patients entered our AS programme, in 25 follow up data is incomplete leaving 180 for analysis. 61 have had repeat TPSB within our protocol and at a median follow up at 2 years in 56/61 (92%) the Gleason score and volume of disease was unchanged. Only 5/180, 2.8% have had treatment for disease progression and additionally 4/180 (2.2%) have chosen active intervention over continued surveillance, despite no evidence of progression. Conclusions: TRUS biopsies under-estimate Gleason grade or cancer volume compared with TPSB. In our cohort of AS patients only 2.8%, at a median follow up of two years, have transferred to definitive treatment for disease progression. TPSB provides the best method to exclude higher risk disease from AS programmes.
Outcome of intravenous calcium and magnesium (Ca/Mg) in oxaliplatin-containing regimens compared with no Ca/Mg.
Authors: J. Chaves, K. Patel, O. Abdelghany, C. Coleman, J. Lacy, H. S. Hochster
Journal: Journal of Clinical Oncology (2011)

e19681 Background: Peripheral neuropathy (PN) is a cumulative toxicity of oxaliplatin (OX). Retrospective studies have reported that Ca/Mg infusions may reduce the incidence of PN and may allow patients to be treated without dose reductions for a longer duration. The objectives of this study were to retrospectively evaluate the effect of Ca/Mg on the number of treatment cycles, duration of OX therapy, cumulative OX dose, and progression free survival (PFS) in a large university-based practice. Methods: 149 patients treated with OX-containing regimens were retrospectively reviewed for co-administration of Ca/Mg infusions. Ca/Mg was given as 1 gm CaCl2 and 1 gm MgSO4 in 100 ml of IV solution over 30 min pre and post OX. Treatment assignment was at physician discretion. Patients were divided into groups based on histology, stage, and whether Ca/Mg was given. Patients in the “no Ca/Mg” group never received this treatment. All data were retrieved from the YCC EMR and reviewed by the authors. Patients were treated between 5/12/03 and 9/25/09. Results: 149 records were reviewed including 106 with Ca/Mg and 43 without. In patients with stage IV CRC, the Ca/Mg group (n=22) was associated with a statistically significant increased PFS (8.5 vs 4.6 months p=0.0394) compared to those not given Ca/Mg (n=13). There was a trend towards improved treatment duration (5.8 vs 3.8 months p=0.1065), cycles given (10.9 vs 7.8 cycles p=0.173), and total OX dose (677.5 vs 306.2 mg/m2 p=0.1366). In the adjuvant CRC setting, the Ca/Mg group (n=27) also showed a statistically significant improvement in PFS (36.3 vs. 22.8 months p=0.0445) compared to those not given Ca/Mg (n=10). Comparison of these adjuvant groups showed no statistical differences in total OX dose, duration of tx, or total tx cycles. Conclusions: In this retrospective chart review of patients treated with oxaliplatin-based chemotherapy, use of IV Ca/Mg showed a statistically significant increase in PFS in patients with CRC in both the adjuvant and metastatic settings. Despite the limited sample size and statistical power, significance and trends support the use of Ca/Mg to reduce the impact of PN, without signs of interfering with oxaliplatin anti-tumor activity.
Preclinical studies using the linamarase/linamarin/glucose oxidase gene therapy system against human glioma tumors in nude mice and rats.
Authors: M. Izquierdo, W. Girald, J. Gil, R. Gargini
Journal: Journal of Clinical Oncology (2011)

e12524 Background: Glioblastoma multiforme (GBM) is one of the deadliest forms of cancer, with an average survival time of approximately one year despite aggressive surgery, radiotherapy and chemotherapy. Here, we report a therapeutic procedure with potential clinical application, by which the two main energy pathways of the tumor cells, oxidative phosphorylation and aerobic glycolysis, are simultaneously disrupted. Methods: First, the neoplastic cells must receive the plant linamarase gene (lis), which mediates the transformation of linamarin (lin) into cyanide, glucose and acetone. Shortly after, a local treatment with both linamarin and glucose oxidase (GO) is administered to the animal. Results: The treatment triggers autophagy and abrogates tumor growth. After severe mitochondrial insult by lis/lin/GO, the electron transport chain is blocked and hydrogen peroxide production increased. This triggers a degradative phase of these damaged organelles inducing mitophagy that finally leads to cell death. We explored the potential of this powerful mitophagy inducing system in vitro (cell culture) and in vivo (immunodeficient mice and rats) to eradicate human malignant tumors. Conclusions: The procedure destroys glioma cell lines and the highly metastatic stem cells present in the human glioblastoma samples, eradicating also tumors grafted in nude animals.