Phase II study of panitumumab combined with capecitabine and oxaliplatin as first-line treatment in metastatic colorectal cancer patients: clinical results including extended tumor genotyping.

This clinical trial assessed the efficacy and toxicity of panitumumab combined with oxaliplatin and capecitabine as first-line treatment in KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. Patients with exon 2 KRAS wild-type mCRC received panitumumab 9 mg/Kg, oxaliplatin 130 mg/m2, and capecitabine 2000 mg/m2 repeated every 3 weeks. The primary endpoint was objective response rate (ORR, minimum 42 responses). We retrospectively assessed mutations in genes implicated in CRC with massively parallel sequencing; ERBB2 and EGFR amplification with fluorescence in situ hybridization, and tumor-infiltrating lymphocyte density. Among 78 patients enrolled, 45 (57.7%) completed 6 cycles. Most common grade 3-4 toxicities were skin rash (19.2%), diarrhea (18%), and neuropathy (6.4%). Among 5 (6.4%) potentially treatment-related deaths, 2 (2.6%) were characterized toxic. Objective response occurred in 43 (55.1%) of the patients (complete 6.4% and partial response 48.7%; stable 17.9% and progressive disease 7.7%), while 3.8% were non-evaluable and 15% discontinued their treatment early. Additional mutations in KRAS/NRAS/BRAF were found in 11/62 assessable (18%) tumors. After 51 months median follow-up, median progression-free (PFS) was 8.1 and overall survival 20.2 months, independently of KRAS/NRAS/BRAF or PI3K-pathway mutation status. Patients with TP53 mutations (n = 34; 55%), as well as those with left colon primary tumors (n = 66; 85%), had significantly better PFS, also confirmed in multivariate analysis. Although the clinical trial met its primary endpoint, according to the current standards, the efficacy and tolerability of the drug combination are considered insufficient. Extended genotyping yielded interesting results regarding the significance of TP53 mutations.ClinicalTrials.gov identifier: NCT01215539, Registration date: Sep 29, 2010.

Prognostic Evaluation of Epidermal Growth Factor Receptor (EGFR) Genotype and Phenotype Parameters in Triple-negative Breast Cancers.

BACKGROUND: Epidermal growth factor receptor (EGFR) aberrations have been implicated in the pathogenesis of triple-negative breast cancer (TNBC) but their impact on prognosis and, therefore, druggability, remain controversial. Herein, we studied EGFR aberrations at different molecular levels and assessed their prognostic impact in patients with operable TNBC treated with adjuvant anthracycline-based chemotherapy. MATERIALS AND METHODS: We evaluated the prognostic impact of EGFR gene status by fluorescent in situ hybridization (FISH), EGFR coding mutations by Sanger and next-generation sequencing, relative EGFR messenger RNA (mRNA) levels by qPCR (upper quartile) and EGFR and p53 protein expression by immunohistochemistry (IHC), in 352 centrally-assessed tumors from an equal number of TNBC patients. RESULTS: Approximately 53.5% of the tumors expressed EGFR, 59.3% p53 and 35.9% both EGFR and p53 proteins; 4.1% showed EGFR gene amplification and 4.4% carried EGFR mutations. The latter were located outside the druggable kinase domain region and presented at low frequencies. Amplification and mutations overlapped only in one case of glycogen-rich carcinoma. EGFR and CEN7 copies were higher in tumors from older patients (p=0.002 and p=0.003, respectively). Patients with amplified tumors (n=11) had excellent prognosis (0 relapses and deaths). Upon multivariate analysis, high EGFR copies conferred significantly favorable disease-free survival (HR=0.57, 95% CI 0.36-0.90, Wald's p=0.017) and high CEN7 copies favorable overall survival (HR=0.49, 95% CI=0.29-0.83, Wald's p=0.008). Patients with EGFR-/p53+ and EGFR+/p53- tumors had significantly higher risk for relapse than those with EGFR-/p53- and EGFR+/p53+ tumors (HR=1.73, 95% CI=1.12-2.67, Wald's p=0.013). CONCLUSION: EGFR gene amplification and mutations are rare in TNBC, the latter of no apparent clinical relevance. Surrogate markers of EGFR-related chromosomal aberrations and combined EGFR/p53 IHC phenotypes appear to be associated with favorable prognosis in patients with operable TNBC receiving conventional adjuvant chemotherapy.

Bilateral aberrant origin of the inferior thyroid artery from the common carotid artery.

The thyroid gland is mainly supplied by the superior and inferior thyroid arteries, with the latter being its principal arterial supply in adults. The inferior thyroid artery usually arises from the thyrocervical trunk, and less frequently from the subclavian artery. Rarely, it may originate from the vertebral artery or the common carotid artery. In the present report, we describe a unique case of a 56-year-old patient, undergoing total thyroidectomy and level VI lymph node dissection for papillary thyroid carcinoma, with aberrant origin of both inferior thyroid arteries from the common carotid arteries.

Prospective comparison of peritumoral and subareolar injection of blue dye alone, for identification of sentinel lymph nodes in patients with early stage breast cancer.

BACKGROUND AND OBJECTIVES: Various techniques are used for the identification of the sentinel node (SLN). We prospectively compare the efficacy of SLN biopsy and the number of SLNs identified, by injecting methylene blue (MB) alone in the subareolar area (SA) or peritumorally (PT) in patients with early stage breast cancer. METHODS: Patients were randomized in two groups (SA or PT injection). A linear regression model was used to estimate the effect of various parameters on the identification rate and on the number of SLNs retrieved. RESULTS: At least one SLN was identified in 61 of 66 (92.4%) procedures in the SA group and in 57 of 60 (95%) procedures in the PT group (P = 0.55). The mean number of SLNs removed with the SA injection method was 1.64 ± 0.6 nodes compared with 2.23 ± 0.7 nodes identified with the PT injection (range: 1-4, P < 0.001). The injection site was the only factor affecting the number of SLNs retrieved. CONCLUSION: The use of MB alone is an efficient method for identification of the SLN. The PT injection route yields a higher number of SLNs than the SA route, comparable with the number of SLNs retrieved, when combined tracing agents and multiple injection sites are used.

Breast angiosarcoma that is not related to radiation exposure: a comprehensive review of the literature.

Breast angiosarcomas that are not related to previous radiotherapy are very rare. Surgical resection is the primary treatment for these tumors, but there is no general agreement on the extent of surgery. The role of multimodality adjuvant treatment also remains controversial. The aim of this study was to summarize the available data from the largest published series of patients in terms of management and outcome. We also sought to identify prognostic factors influencing patient survival. We have included studies presenting detailed data on multimodality therapy and survival of patients with breast angiosarcoma. Ten studies presenting data on 280 patients were included in the review. Seventy-five percent of patients underwent a total mastectomy and 25% had breast-conserving treatment (BCT). In 42% of patients, an axillary node dissection was combined with mastectomy or BCT. Thirty-six percent of patients received chemotherapy and 35% were treated with radiotherapy in an adjuvant or neoadjuvant setting. Survival varied significantly according to tumor size and grade. Adjuvant multimodality therapy may improve the outcome in selected patients with breast angiosarcoma. Tumor size, grade, and margin status are the most important prognostic factors for survival.

Tissue concentration of transforming growth factor beta1 and basic fibroblast growth factor in skin wounds created with a CO2 laser and scalpel: a comparative experimental study, using an animal model of skin resurfacing.

Although a number of ablative-laser techniques based on CO(2) and Er: YAG laser devices have been successfully developed and used in the clinical setting, the bio-molecular processes influencing wound healing after exposure to laser energy are not well elucidated. In this study, we aim to assess the impact of the mechanism of injury on the secretion of transforming growth factor beta1 (TGF-beta1) and basic fibroblast growth factor (bFGF) in various stages of wound healing, in wounds created with a CO(2) laser and scalpel. Ten Wistar rats were used to determine the levels of growth factor proteins TGF-beta1 and bFGF after CO(2) laser- and scalpel-induced skin injury. Tissue was excised on day 0 for untreated skin (control sites), and on days 1, 10, 30, and 90 following laser and scalpel surgery. Specimens were processed for histopathological analysis and for determining the concentration of growth factors by a Western blot technique. The concentration of TGF-beta1 increased markedly, at day 1 postinjury, from a baseline of 130+/-16 mm(2) (mean surface area of blotted-protein lanes) to 261+/-23 mm(2) and 394+/-22 mm(2) for laser-inflicted injury and scalpel wounds, respectively; the latter values were found to differ significantly (p<0.001). The concentration of b-FGF on day 10 postinjury differed significantly (p<0.001) between the laser sites (553+/-45 mm(2)) and the corresponding scalpel sites (418+/-41 mm(2)). Laser energy alters local tissue secretion of TGF-beta1 and bFGF of skin injuries created with the CO(2) laser compared with wounds created with a scalpel. These differences might have an impact on various aspects of wound healing of skin injuries created by a laser.

Gastric decompression and enteral feeding through a double-lumen gastrojejunostomy tube improves outcomes after pancreaticoduodenectomy.

OBJECTIVE: The objective of this study was to assess the feasibility and safety of inserting a double-lumen gastrojejunostomy tube (GJT) after pancreaticoduodenectomy (PD) and to evaluate associated outcomes. BACKGROUND: Gastroparesis is a frequent postoperative event following PD. This often necessitates prolonged gastric decompression and nutritional support. A double-lumen GJT may be particularly useful in this situation: gastric decompression may be achieved through the gastric port without a nasogastric tube; enteral feeding may be administered through the jejunal port. METHODS: Thirty-six patients with periampullary tumors were randomized at the time of PD to insertion of GJT or to the routine care of the operating surgeon. Outcomes, including length of stay, complications, and costs, were followed prospectively. RESULTS: The 2 groups had similar characteristics. Prolonged gastroparesis occurred in 4 controls (25%) and in none of the patients who had a GJT (P = 0.03). Complication rates were similar in each group. Mean postoperative length of stay was significantly longer in controls compared with patients who had a GJT (15.8 +/- 7.8 days versus 11.5 +/- 2.9 days, respectively; P = 0.01). Hospital charges were 82,151 +/- 56,632 dollars in controls and 52,589 +/- 15,964 dollars in the GJT group (P = 0.036). CONCLUSIONS: In patients undergoing PD, insertion of a GJT is safe. Moreover, insertion of a GJT improves average length of stay. At the time of resection of periampullary tumors, GJT insertion should be considered, especially given this is a patient population in which weight loss and cachexia are frequent.

Neoadjuvant treatment for resectable cancer of the esophagus and the gastroesophageal junction: a meta-analysis of randomized clinical trials.

BACKGROUND: There is no general agreement on the effect of neoadjuvant treatment for esophageal cancer on patient survival. METHODS: A meta-analysis was performed to determine the effect of preoperative treatment on survival of patients with resectable esophageal cancer and the effect of preoperative treatment on patient mortality. A standard variance-based method was used to derive summary estimates of the absolute difference in both 2-year survival and treatment-related mortality. RESULTS: Eleven randomized trials involving 2311 patients were analyzed. Preoperative chemotherapy improved 2-year survival compared with surgery alone: the absolute difference was 4.4% (95% confidence interval [CI],.3%-8.5%). Marginal evidence of heterogeneity was eliminated by restricting attention to the four most recent studies, which increased the estimate to 6.3% (95% CI, 1.8%-10.7%). For combined chemoradiotherapy, the increase was 6.4% (nonsignificant; 95% CI, -1.2%-14.0%). Treatment-related mortality increased by 1.7% with neoadjuvant chemotherapy (95% CI, -.9%-4.3%) and by 3.4% with chemoradiotherapy (95% CI, -.1%-7.3%), compared with surgery alone. CONCLUSIONS: There seems to be a modest survival advantage for patients who receive neoadjuvant chemotherapy followed by surgery, as compared with surgery alone. There is an apparent increase in treatment-related mortality, mainly for patients who receive neoadjuvant chemoradiotherapy.