Effect of oxaliplatin plus 5-fluorouracil or capecitabine on circulating and imaging biomarkers in patients with metastatic colorectal cancer: a prospective biomarker study.

BACKGROUND: Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers. METHODS: A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, Ktrans, increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01-1.20, p = 0.025). CONCLUSIONS: In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, Ktrans, offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.

Don't Shoot the Messenger: Surgical Programs Can Do More to Keep Applicants Informed.

OBJECTIVE: The interview process for applying to general surgery residency is burdened by a high volume of applicants, resulting in unprofessional behavior by both applicants and programs. Sharing more information regarding interview scheduling with applicants may limit fourth year medical student educational disruptions, minimized late cancellations to interview, and improve overall satisfaction with the process. Thus, we set out to determine what information is currently available to applicants. DESIGN: We used publicly accessible sources to determine what information was shared by US general surgery residency programs with applicants. Specifically, we looked at the deadline for applications, United States Medical Licensing Examination Step 1 and 2 score cutoffs, number of interview dates available, specific interview dates, a stated policy to not offering more interviews than slots, dates when applicants can expect to be notified of interview offers, notification of decision to decline, and International Medical Graduate and visa policies. SETTING: This study took place at Maine Medical Center in Portland, Maine, an academic medical center with a general surgery residency program. PARTICIPANTS: Not applicable. RESULTS: Three hundred seventeen programs were examined. Seventy-six percent of programs specified an application deadline, 65% of programs specified a Step 1 cut-off score, 50% of programs specified a Step 2 cut-off score, 61% of programs stated a visa policy, and 50% of programs stated an International Medical Graduate policy. Twenty-five percent of programs disclosed the number of interview dates, 23% disclosed what those interview dates were. About 3.4% of programs gave interview release dates, 2.8% of programs notify applicants of decline to interview, and 0.63% of programs explicitly describe a policy of offering only as many interviews as slots available. Thirty-two percent of programs provided conflicting information. CONCLUSIONS: The information available to applicants from public access sources regarding interview scheduling is minimal, unstandardized, and unreliable. Notably lacking were policies that only offer as many interviews as slots available, dates when applicants can expect to be notified of interview offers, and notification of declines. Providing such information to applicants in a standardized way may improve satisfaction with the interview scheduling process.

Plasma Tie2 is a tumor vascular response biomarker for VEGF inhibitors in metastatic colorectal cancer.

Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer (n = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, Ktrans (R:-0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p = 0.00014; median PFS 248 vs. 348 days p = 0.0008) and the modeling of progressive disease (p < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi.

A phase 1 trial of intravenous 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) in patients with advanced solid tumours.

BACKGROUND: 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) is a water-soluble mitochondrial toxin that binds to adenine nucleotide translocase in the inner mitochondrial membrane, thereby targeting cell proliferation. This phase 1 study investigated safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and pharmacokinetics (PK) of GSAO as a daily 1-h infusion for 5 days a week for 2 weeks in every three. Pharmacodynamics of GSAO was evaluated by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and circulating markers of angiogenesis. METHODS: Patients with advanced solid tumours received GSAO in a dose-escalation trial according to a standard '3 + 3' design that was guided by toxicity and, for the final dose escalation, by arsenic PK data. RESULTS: A total of 34 patients were treated with GSAO across 9 dose levels (1.3-44.0 mg/m(2)). Treatment was well tolerated with few adverse events. An additional three patients were enrolled at the 12.4 mg/m(2) dose level following a DLT of derangement of liver function tests (grade 4). At the 44.0 mg/m(2) dose level, two out of three patients had DLTs (reversible encephalopathy; paroxysmal atrial fibrillation). CONCLUSIONS: The MTD of GSAO was 22.0 mg/m(2)/day. There was no biomarker evidence from DCE-MRI or circulating markers of angiogenesis of an anti-vascular effect of GSAO.

Angiogenesis as a target for the treatment of ovarian cancer.

PURPOSE OF REVIEW: Angiogenesis has been validated as a target in ovarian cancer through four randomized trials that have reported improved progression-free survival (PFS) in patients with ovarian cancer whose conventional treatment was supplemented with concurrent and maintenance administration of the antivascular endothelial growth factor (VEGF) antibody, bevacizumab. These trials [the International Collaborative Ovarian Neoplasm Group trial (ICON7), the Gynecologic Oncology Group trial (GOG218), OCEANS and AURELIA] have shown that the tumour vasculature is a valid target throughout the lifetime of patients with ovarian cancer. This review seeks to address some of the remaining questions surrounding the optimal strategy for the use of bevacizumab in ovarian cancer. RECENT FINDINGS: The first-line trials, ICON7 and GOG218, showed improvements in PFS and in the case of ICON7, an early analysis reported increased overall survival in a predefined group of patients at high risk of disease progression. Trials in recurrent disease, OCEANS and AURELIA, also showed improvements in PFS, raising questions about whether VEGF-inhibiting agents should be confined to first-line therapy, second-line therapy or both. SUMMARY: Both the first-line trials stopped maintenance bevacizumab after 12 and 15 months, respectively; yet, current data suggest that maintenance therapy should continue at least until progression. In addition, current research is focussing on the identification of predictive biomarkers for VEGF inhibitors and candidates have been identified. Thus, the true clinical benefit from VEGF pathway inhibitors in the first-line treatment of ovarian cancer is likely to increase over the next few years.

Trans-fatty acids and cancer: the evidence reviewed.

The present review comes from the authors of the recent Scientific Advisory Committee on Nutrition (SACN) review Update on Trans Fatty Acids and Health, and focuses on assessing the strength of the evidence for a link between trans-fatty acid (trans-FA) intake and cancer. It evaluates a range of human ecological, case-control and prospective studies with trans-FA exposure assessed using either dietary assessment methods or trans-FA levels in tissues. Relevant animal studies are also presented in order to elucidate potential mechanisms. It concludes that there is weak and inconsistent evidence for a relationship between trans-FA and breast or colorectal cancer. Evidence for an association between trans-FA and prostate cancer is limited, but a recent large case-control study has shown a strong interaction between risk and trans-FA intake for the RNASEL QQ/RQ genotype that is present in about 35 % of the population. This potential association requires further investigation. The single study on non-Hodgkin's lymphoma reported a strong positive association, but only used a single assessment of dietary trans-FA made at the start of the study in 1980, and the significant changes in trans-FA intakes between then and the end of follow-up in 1994 limit the reliability of this observation. There is insufficient evidence to allow any differentiation between the effects of trans-FA from animal or vegetable origin on cancer risk.

Microinvasive cervical adenocarcinoma (FIGO stage 1A tumors): results of surgical staging and outcome analysis.

Although studies suggest that microinvasive cervical adenocarcinoma has an excellent prognosis, none has reported treatment-related complications and many have lacked detailed measurement criteria. Our study looks at the rate of lymph node metastases and outcome, including complications, in patients with FIGO 1A1 and 1A2 adenocarcinomas of the cervix. Invasion was strictly defined, and the method of measurement was standardized. Villoglandular, papillary serous and clear cell carcinomas were excluded, as were tumors in which invasion exceeded 7 mm in width or 5 mm in thickness, with tumor thickness measured from the basement membrane of the overlying endocervical or ectocervical surface to the deepest focus of invasive tumor. A mean follow-up of 54 months (range, 5-159 months) was available for 31 of 32 (97%) patients. A total of 29 of 32 patients underwent hysterectomies, 2 patients had radical trachelectomies, and 1 patient was treated by cone biopsy. One patient received adjuvant radiotherapy. A total of 27 of 32 patients had bilateral pelvic lymph node dissections, and no lymph node metastases were identified. No recurrences have been reported to date. One patient died of metastatic ovarian carcinoma 82 months after her diagnosis of cervical carcinoma. Two of 27 (7%) patients have chronic leg edema secondary to lymph node dissection. Given the excellent prognosis of this tumor, the absence of lymph node metastases and a lymph node dissection complication rate of 7%, less radical surgery should be considered in this low-risk patient population.