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Background Alternative splicing of vascular endothelial growth factor A (VEGFA) results in VEGFAxxxb antiangiogenic isoforms that fail to activate angiogenesis. Bevacizumab, widely used in patients with metastatic colorectal cancer (CRC), binds both VEGFA and VEGFAxxxb isoforms. Patients and Methods Formalin-fixed, paraffin-embedded primary tumors from metastatic CRC patients treated with first-line FOLFIRI (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) + bevacizumab (n = 285) or FOLFIRI only (n = 75) were collected. The relative expression of VEGFA121a, 121b, 145a, 145b, 165a, and 165b was assessed with custom TaqMan-MGB assays and quantitative PCR. Results At a median follow-up of 101.5 months, left-sided primary CRC was a favorable prognosticator (median survival, 29.2 vs. 18.2 months; P = .015). Positive high VEGFA145b was an unfavorable factor for progression-free survival (PFS; hazard ratio [HR] = 1.66; 95% confidence interval [CI], 1.13-2.44; P = .009) in patients who received FOLFIRI + bevacizumab, without prognostic significance in FOLFIRI-only patients (HR = 0.70; 95% CI, 0.34-1.44; P = .33). The adverse effect on PFS of 145b was more pronounced in patients with right-sided colon cancer (HR = 2.62; 95% CI, 1.35-5.12; P = .005), especially in those who received bevacizumab (HR = 2.85; 95% CI, 1.31-6.21; P = .008). In patients with right-sided colon primary tumors, isoform 121b correlated with inferior PFS (HR = 1.73; 95% CI, 0.94-3.18; P = .076) and overall survival (OS; HR = 2.0; 95% CI, 1.08-3.72; P = .028). In patients with left-sided primary tumors, positive high 165b correlated with superior PFS (HR = 0.76; 95% CI, 0.59-0.99; P = .044) and OS (HR = 0.68; 95% CI, 0.52-0.90; P = .006). At multivariate analysis, right-sided primary tumor was associated with inferior PFS (HR = 1.28; 95% CI, 1.00-1.64), while 145b consistently retained predictive significance for lack of benefit in PFS with bevacizumab (HR = 1.71; 95% CI, 1.16-2.53). Multivariate analysis for OS showed that VEGFA165b expression was favorable in patients with left-sided but unfavorable in patients with right-sided primary tumors (Pinteraction Conclusion The antiangiogenic isoform VEGFA145b messenger RNA may predict resistance to bevacizumab. Differences in biological relevance and prognostic significance of various VEGFA isoforms were found for right- versus left-sided primary tumors.

Background - aim: Information on the prognostic role of cytotoxic CD8+ T cells in the era of modern adjuvant CT is limited. The primary objective of the present report is to assess the prognostic impact of CD8+ cells in patients with intermediate or high-risk EBC (T1-3N1-2M0) treated with dds-CT. Secondary endpoints are safety, disease-free survival (DFS) and overall survival (OS). Patients and Methods: Patients (N=1,000) were treated with 4 cycles of Epirubicin, 75mg/m2, and Cyclophophamide, 600mg/m2 every 2 weeks followed by 4 cycles of Docetaxel (D), 100mg/m2 every 3 weeks with G-CSF support in all cycles. Trastuzumab was initiated concurrently with D and continued for a total of 1 year. Hormonal and radiation therapy were given post CT, as indicated. Formalin-fixed paraffin-embedded tumors were available for 642 patients (64.2%) and were centrally assessed for immunohistochemical subtypes (IHC4; N=526), stromal TILs density by morphology (N=636), as well as stromal and intratumoral cytotoxic CD8+ T cell numbers (N=554). TILs and CD8+ were assessed as continuous variables for associations and as 10% increments for outcome. Results: In total, 901/1,000 pts (90.1%) completed 8 cycles of CT. Severe (gradeIII-IV) toxicitiesincludedneutropenia (5.6%), leucopenia (3.6%), lymphopenia (2.1%), hand-footsyndrome (2.1%), and hepatotoxicity (1.8%). Febrileneutropenia occurred in 1.6% of the patients. The 5-year DFS and OS rates were 89.5% and 93.1%, respectively. Luminal A tumors were classified in 26.2%, Luminal B in 35.2%, luminal HER2 in 9.5%; HER2-enriched in 7.2%; and, triple-negative (TNBC) in 21.9% of informative patients. Among subtypes, stromal TILs density was higher in HER2-enriched and TNBC (p Conclusions: In this study, dds-CT was well tolerated and active in patients with EBC. We confirm the presence of morphologically assessed higher TILs density, and of higher cytotoxic CD8+ T cell numbers in hormone receptor negative EBC, as well as the favorable prognostic impact of higher stromal TILs density in TNBC. In comparison to stromal TILs density, higher stromal CD8+ may confer favorable prognosis irrespectively of EBC subtype. Stromal CD8+ seems to be a marker worth further standardizing for reporting on immune cell infiltrates in EBC. Citation Format: Kourea HP, Koletsa T, Kotoula V, Koliou G-A, Batistatou A, Pentheroudakis G, Arapantoni-Dadioti P, Zagouri F, Bobos M, Sotiropoulou M, Papoudou-Bai A, Chrisafi S, Efstratiou I, Aravantinos G, Nicolaou I, Gogas H, Visvikis A, Christodoulou C, Petraki C, Koutras A, Psyrri A, Pectasides D, Fountzilas G. Prognostic significance of CD8+ tumor-infiltrating lymphocytes (TILs) in patients with early breast cancer (EBC) treated with dose-dense sequential adjuvant chemotherapy (dds-CT). An observational study (ACTRN12616001043426) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-13.

Background/Aim: KRAS mutations are reported in 20-25% of non-small cell lung cancer (NSCLC) and their prognostic role is unclear. We studied KRAS and EGFR genotyping in Greek NSCLC patients. Patients and Methods: KRAS and EGFR genotypes were centrally evaluated in 421 NSCLC patients (diagnosed September 1998 -June 2013) and associated with clinicopathological parameters. Outcome comparisons were performed in 288 patients receiving first line treatment. Results: Most patients were male (78.6%), >60 years old (63.9%), current smokers (51.1%), with adenocarcinoma histology (63.9%). EGFR and KRAS mutations were found in 10.7% and 16.6% of all histologies, respectively, and in 14.9% and 21.9% of adenocarcinomas. At 4.5 years median follow-up, KRAS status was an independent negative prognostic factor for overall survival (OS, p=0.016). KRAS mutations conferred 80% increased risk of death in patients receiving first-line treatment (p=0.002). Conclusion: The presence of KRAS mutations is an independent negative prognosticator among Greek NSCLC patients and an independent response predictor to first line treatment.

BACKGROUND/AIM: PTEN-loss and PIK3CA mutations have been addressed as markers of PI3K activation in breast cancer. We evaluated these markers in early high-risk breast cancer (EBC) focusing on PTEN immunohistochemistry (IHC) issues, particularly in HER2-positive disease. MATERIALS AND METHODS: We examined PTEN-loss and PIK3CA mutations in 1265 EBC patients treated with adjuvant chemotherapy within two clinical trials. Two different methods for the evaluation of PTEN IHC were used, one upfront binary (loss; no-loss) and the other initially multi-scale allowing for the classification of "grey zone" tumors with low and very low PTEN protein expression. RESULTS: PTEN-loss (33.4% and 22.1%, depending on the IHC method) and PIK3CA mutations (29.6%) were associated with ER/PgR/HER2-negative and ER/PgR-positive disease, respectively. Concordance of the two IHC methods was moderate (Cohen's kappa 0.624). PTEN-loss discrepancy and intra-tumor heterogeneity concerned "grey zone" tumors that were prevalent among HER2-positive cancers. PTEN-loss independently conferred higher risk for relapse and death. Compared to single PIK3CA mutations,single PTEN-loss was independently associated with increased risk for relapse and death. Depending on the evaluation method, in HER2-positive cancer, PTEN-loss was without- or of marginal unfavorable prognostic significance. CONCLUSION: In EBC, PTEN-loss is an independent predictor of poor outcome. When occurring singly, PTEN-loss and PIK3CA mutations have opposite prognostic impact. In HER2-positive disease, assessment of PTEN-loss by IHC appears unreliable and the marker is without clear prognostic significance.

Background We explored the clinical significance of tumor genotypes and immunophenotypes in non-metastatic colorectal cancer (CRC). Methods In primary tumors (paraffin blocks) from 412 CRC patients treated with adjuvant chemotherapy, we examined pathogenic mutations (panel NGS; 347 informative); mismatch repair (MMR) immunophenotype (360 informative); and CD8+ lymphocyte density (high – low; 412 informative). The primary outcome measure was disease-free survival (DFS). Results We evaluated 1713 pathogenic mutations (median: 3 per tumor; range 0-49); 118/412 (28.6%) tumors exhibited high CD8+ density; and, 40/360 (11.1%) were MMR-deficient. Compared to MMR-proficient, MMR-deficient tumors exhibited higher CD8+ density (chi-square, p

Background/Aim: Ovarian cancer (OVCA) is characterized by genomic/molecular intra-patient heterogeneity (IPH). Tissue histology and morphological features are surrogates of the underlying genomic/molecular contexture. We assessed the morphological IPH of OVCA tumor compartments and of lymphocytic infiltrates in multiple matched samples per patient. Materials and Methods: We examined 294 hematoxylin & eosin (H&E) OVCA tumor whole sections from 70 treatment-naïve patients who had undergone cytoreductive surgery. We assessed morphological subtypes as immunoreactive (IR), solid – proliferative (SD), papilloglandular (PG), and mesenchymal transition (MT); subtype load per patient; stromal tumor-infiltrating lymphocyte (sTIL) density as average per sample; and, as maximal sTIL values (max-TILs) among all samples per patient, ovaries and implants. Results: Among all 294 tumor sections, the most frequent primary morphological subtype was PG (n=150, 51.0%), followed by MT (71, 24.1%), SD (48, 16.3%) and IR (15, 5.1%). Subtype combinations were observed in 67/294 sections (22.8%) and IPH in 48/70 patients (68.6%). PG prevailed in ovaries (p

This study essentially aims to contribute to the immunohistochemical investigation of the use of pituitary tumor transforming gene (PTTG) as a marker of cell proliferation or advanced tumor grade in meningiomas of various WHO grades. In all, 51 cases were recovered in total, 21 Grade-I, 23 Grade-II and 7 Grade-III meningiomas. Mitotic index (MI), Ki-67/MiB-1 positivity percentage and PTTG expression were analyzed in correlation to each other as well as to the tumor WHO grades. All three biomarkers showed a high diagnostic significance and a strong association with WHO grades. In comparison, PTTG expression was on a par with the other two indices, and performed very well regarding identification of advanced grade tumors. PTTG may be considered an important diagnostic tool and serve in the future as a novel prognosticator of the biological behavior of all grade meningiomas as well as a useful high-risk patient selection tool.

Background-aim: HER2-positive breast cancer (BC) features high rates of tumor infiltrating lymphocytes (TILs) and mutations (mut) in various genes, more frequently in TP53. We investigated associations between TILs and mutations in HER2-positive BC and their impact on patient outcome in early and metastatic BC (EBC and MBC, respectively), which remain largely unexplored. Methods:In 352 primary paraffin tumors from patients with HER2-positive disease, we examined amino acid changing mutations (20% variant frequency). Study groups were: (A) 218 EBC, including 117 patients treated with adjuvant chemotherapy only (CT) and 101 patients treated with CT and trastuzumab (CTT); (B) 134 MBC, including 95 patients who relapsed upon adjuvant CT without trastuzumab (R-MBC) and 39 patients who were first diagnosed with metastatic disease (de novo MBC). TILs were assessed as percentage of stromal tumor area. Clinical endpoints were disease-free survival in 5 years (5yr DFS) for EBC, and time-to-progression (TTP) from 1st line CTT treatment start for MBC. Results: 243/352 tumors (69%) carried at least one mut; 27/352 (8%) of tumors >10 up to 150 mut (hypermut); 192/352 (54%) at least one possibly clonal mut. Mean mut number and TP53 mut in particular were highest in R-MBC and lowest in EBC; mean TILs density followed the opposite pattern (all p3 compared to 0-3 positive nodes (OR 3.83, CI 1.76-8.34, p=0.001); lower risk for relapse was observed for higher TILs irrespectively of treatment (OR 0.93, CI 0.90-0.97, p=0.001), for TP53 mut (OR 0.39, CI 0.18-0.87, p=0.022) and for clonal TP53 mut in CTT-treated patients (OR 0.10, CI 0.02-0.58) but not in CT-treated patients (interaction p=0.084). The presence of any clonal mut (hazard ratio [HR] 2.77, CI 1.42-5.38) and of clonal TP53 mut (HR 2.24, CI 1.20-4.17) conferred worse TTP in de novo but not in R-MBC; these interactions remained significant upon multivariate analysis (interaction p=0.007 and p=0.061, respectively). Higher TILs in the absence of clonal mut conferred longer TTP (HR 0.75, CI 0.56-0.99) but no such effect was observed for tumors with clonal mut (multivariate interaction p=0.052). Classic independent predictors of unfavorable TTP in MBC were younger age (p=0.002), absence of hormone receptors (p=0.001) and poor performance status (p=0.044). PIK3CA mut did not remain significant in any of the examined settings. Conclusions: The expected pattern of higher TILs associated with mutation number and clonality was not observed in HER2-positive BC; the favorable effect of TILs only in the absence of clonal mut in MBC may imply exhausted immune response. Clonal TP53 mut may serve as a predictor for trastuzumab benefit in EBC but as an adverse prognosticator in trastuzumab-treated de novo MBC, which, if further validated, is of potential clinical relevance.Background-aim: HER2-positive breast cancer (BC) features high rates of tumor infiltrating lymphocytes (TILs) and mutations (mut) in various genes, more frequently in TP53. We investigated associations between TILs and mutations in HER2-positive BC and their impact on patient outcome in early and metastatic BC (EBC and MBC, respectively), which remain largely unexplored. Methods:In 352 primary paraffin tumors from patients with HER2-positive disease, we examined amino acid changing mutations (20% variant frequency). Study groups were: (A) 218 EBC, including 117 patients treated with adjuvant chemotherapy only (CT) and 101 patients treated with CT and trastuzumab (CTT); (B) 134 MBC, including 95 patients who relapsed upon adjuvant CT without trastuzumab (R-MBC) and 39 patients who were first diagnosed with metastatic disease (de novo MBC). TILs were assessed as percentage of stromal tumor area. Clinical endpoints were disease-free survival in 5 years (5yr DFS) for EBC, and time-to-progression (TTP) from 1st line CTT treatment start for MBC. Results: 243/352 tumors (69%) carried at least one mut; 27/352 (8%) of tumors >10 up to 150 mut (hypermut); 192/352 (54%) at least one possibly clonal mut. Mean mut number and TP53 mut in particular were highest in R-MBC and lowest in EBC; mean TILs density followed the opposite pattern (all p3 compared to 0-3 positive nodes (OR 3.83, CI 1.76-8.34, p=0.001); lower risk for relapse was observed for higher TILs irrespectively of treatment (OR 0.93, CI 0.90-0.97, p=0.001), for TP53 mut (OR 0.39, CI 0.18-0.87, p=0.022) and for clonal TP53 mut in CTT-treated patients (OR 0.10, CI 0.02-0.58) but not in CT-treated patients (interaction p=0.084). The presence of any clonal mut (hazard ratio [HR] 2.77, CI 1.42-5.38) and of clonal TP53 mut (HR 2.24, CI 1.20-4.17) conferred worse TTP in de novo but not in R-MBC; these interactions remained significant upon multivariate analysis (interaction p=0.007 and p=0.061, respectively). Higher TILs in the absence of clonal mut conferred longer TTP (HR 0.75, CI 0.56-0.99) but no such effect was observed for tumors with clonal mut (multivariate interaction p=0.052). Classic independent predictors of unfavorable TTP in MBC were younger age (p=0.002), absence of hormone receptors (p=0.001) and poor performance status (p=0.044). PIK3CA mut did not remain significant in any of the examined settings. Conclusions: The expected pattern of higher TILs associated with mutation number and clonality was not observed in HER2-positive BC; the favorable effect of TILs only in the absence of clonal mut in MBC may imply exhausted immune response. Clonal TP53 mut may serve as a predictor for trastuzumab benefit in EBC but as an adverse prognosticator in trastuzumab-treated de novo MBC, which, if further validated, is of potential clinical relevance. Citation Format: Kotoula V, Giannoulatou E, Kouvatseas G, Tikas I, Lazaridis G, Charalambous E, Efstratiou I, Bobos M, Tsolaki E, Zagouri F, Christodoulou C, Pentheroudakis G, Koutras A, Papakostas P, Kosmidis PA, Pectasides D, Fountzilas G. Mutation characteristics and tumor infiltrating lymphocytes in early and metastatic HER2-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-07.

Background/Aim: PTEN-loss and PIK3CA mutations have been addressed as markers of PI3K activation in breast cancer. We evaluated these markers in early high-risk breast cancer (EBC) focusing on PTEN immunohistochemistry (IHC) issues, particularly in HER2-positive disease. Materials and Methods: We examined PTEN-loss and PIK3CA mutations in 1265 EBC patients treated with adjuvant chemotherapy within two clinical trials. Two different methods for the evaluation of PTEN IHC were used, one upfront binary (loss; no-loss) and the other initially multi-scale allowing for the classification of “grey zone” tumors with low and very low PTEN protein expression. Results: PTEN-loss (33.4% and 22.1%, depending on the IHC method) and PIK3CA mutations (29.6%) were associated with ER/PgR/HER2-negative and ER/PgR-positive disease, respectively. Concordance of the two IHC methods was moderate (Cohen’s kappa 0.624). PTEN-loss discrepancy and intra-tumor heterogeneity concerned “grey zone” tumors that were prevalent among HER2-positive cancers. PTEN-loss independently conferred higher risk for relapse and death. Compared to single PIK3CA mutations, single PTEN-loss was independently associated with increased risk for relapse and death. Depending on the evaluation method, in HER2-positive cancer, PTEN-loss was without- or of marginal unfavorable prognostic significance. Conclusion: In EBC, PTEN-loss is an independent predictor of poor outcome. When occurring singly, PTEN-loss and PIK3CA mutations have opposite prognostic impact. In HER2-positive disease, assessment of PTEN-loss by IHC appears unreliable and the marker is without clear prognostic significance.

Background-Aim: Breast cancer is a heterogeneous disease and despite recent scientific progress there is still need for the identification of biomarkers associated with risk for relapse, as well as for markers identifying patients who will benefit from specific treatments. The aim of the present study was to investigate the role of MYC, as a clinically meaningful biomarker, in the outcome of breast cancer subtypes. Patients and Methods: We have pooled the patients and the respective breast carcinomas from two randomized anthracycline-based adjuvant phase III trials, consecutively conducted by the Hellenic Cooperative Oncology Group (HE10/97 and HE10/00). The HE10/97 trial included a non-paclitaxel arm. Tissue microarrays were constructed from 1,060 formalin-fixed paraffin-embedded tumor tissue samples that were collected retrospectively in the first and prospectively in the second trial. MYC was evaluated by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in 986 cases. Results: In total 61.0% of the cases showed positive cytoplasmic MYC immunostaining, while 26.5% showed positive nuclear staining. 65-80% of the patients were characterized as non-amplified or loss/normal-low gain in all FISH cut-offs examined. A weak association was observed between FISH and nuclear protein expression of MYC. High histological grade was associated with MYC protein overexpression and gene amplification. In terms of disease-free survival (DFS), low (2.5-5 copies) and high (≥5 copies) gain of MYC was of adverse prognostic value compared to loss/normal ( Treatment with paclitaxel was found to differentiate the effect of MYC: CEP8 ratio ≥1.3 and polysomy 8 in terms of DFS and OS in our total cohort. Among patients with CEP8 ratio ≥1.3 and polysomy 8, those treated with paclitaxel performed significantly better than those not treated, while among patients not treated with paclitaxel, those with CEP8 ratio ≥1.3 and polysomy 8 performed much worse than those with CEP8 ratio Conclusions: Our data suggest that MYC has prognostic and predictive value in patients with breast cancer. MYC amplification and MYC protein overexpression are detected in breast cancer patients and are of adverse prognostic value for DFS and OS. Polysomy 8 is also associated with worse prognosis. Treatment with paclitaxel in the adjuvant setting benefits breast cancer patients with MYC:CEP8 ratio ≥1.3 and polysomy 8. Citation Format: Batistatou A, Razis E, Bobos M, Tsolaki E, Timotheadou E, Alexopoulou Z, Goussia A, Gogas H, Koutras A, Karina M, Pentheroudakis G, Efstratiou I, Petraki K, Sotiropoulou M, Pavlakis K, Koletsa T, Kotoula V, Fountzilas G. Associations of MYC protein expression and gene status with breast cancer subtypes and outcome in patients treated with anthracycline-based adjuvant chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-50.

Tissue genomic heterogeneity (t-HET) in patients with epithelial ovarian cancer (OVCA) is related to tissue plasticity, i.e., flexibility to adapt to adverse molecular environments. Here, we interrogated the presence and clinical relevance of OVCA t-HET.We applied high-depth (2000×) sequencing on 297 paraffin tissue samples (fallopian tubes, ovaries, intra-abdominal metastases) from 71 treatment-naïve patients who subsequently received first-line platinum-based chemotherapy. Based on tissue mutation patterns, we distinguished tissue genotypes into: no mutation (33/297 samples; 11.1%), stable (173; 58.2%) and unstable (91; 30.7%). We profiled genotypes per patient and assessed t-HET in 69 patients. Predicted pathogenic mutations refer to germline and/or tissues.Among all 71 patients, 46 (64.8%) had pathogenic BRCA1 mutations and 15 (21.7%) had BRCA1/2 disruption (i.e., pathogenic mutations with position-LOH). We classified 29 patients with t-HET (42%), all with pathogenic BRCA1; t-HET was observed in 64% with such mutations (p 0.001). As opposed to non-t-HET, matched tissues in t-HET shared pathogenic BRCA1 (p 0.001) but not BRCA2 and TP53. Germline BRCA1 mutations in tissues exhibited position-LOH; heterozygous status; or, partial loss of the inherited allele accompanied by additional clonal mutations. Patients with t-HET had worse outcome (log-rank p = 0.048 [progression-free]; p = 0.037 [overall survival]), including 12/15 patients with disrupted BRCA1/2 and 3 BRCA1 carriers with partial germline loss in tissues.Pathogenic BRCA1 mutations appear necessary but may not be sufficient for the establishment of t-HET. t-HET may be associated with worse outcome, including in patients with disrupted BRCA1/2, which is usually considered as a favourable marker. OVCA t-HET may need to be addressed for treatment decisions.

The efficacy and safety of the FOLFIRI (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) regimen combined with aflibercept has not been studied in the first-line management of patients with metastatic colorectal cancer (mCRC).In the context of a prospective single-arm trial (NCT02129257), patients with mCRC received standard doses of a maximum of 12 cycles of FOLFIRI combined with aflibercept (4 mg/kg body weight delivered intravenously) every 2 weeks, followed by aflibercept maintenance. Endpoints were 12-month progression-free survival rate, efficacy, and toxicity.Seventy-three fit patients were enrolled onto the study between 2014 and 2016. Median relative dose intensities administered were 0.80 for irinotecan and 1.0 for aflibercept. The most common grade 3/4 adverse events were neutropenia (13 patients, 18%), febrile neutropenia (3 patients, 4%), diarrhea (11 patients, 15%), hypertension (19 patients, 26%), proteinuria (8 patients, 11%), infections (8 patients, 11%), and mucositis (6 patients, 8%), with no toxic deaths. The objective response rate was 46.6%, significantly associated with the presence of right-sided primary, synchronous metastases, and a relapse-free interval of 12 months (odds ratio = 3.00, 2.92, and 3.75 respectively, P ≤ .05). Intermediate infiltration by stromal core lymphocytes correlated with progression-free survival (hazard ratio = 0.40, [95% confidence interval (CI), 0.19-0.83], P = .014). At a median follow-up of 24.5 months, 12-month progression-free survival rate was 21.9% (median overall survival 20.9 months [95% CI, 16.6-29], median progression-free survival 8.4 months [95% CI, 7.4-9.3]).The FOLFIRI + aflibercept regimen is active and tolerable; however, it failed to improve historical benchmarks of efficacy in chemonaive patients with mCRC. Preliminary data hint that this regimen has cytoreductive activity in disease with adverse biology.

Background-Aim: The aim of the present study was to explore the efficacy of dose-dense sequential adjuvant chemotherapy followed by trastuzumab in HER2-positive patients according to the immunohistochemically (IHC) defined subtypes. Patients and methods: A total of 771 formalin-fixed paraffin-embedded (FFPE) tumor tissue samples, prospectively collected from 990 eligible patients with high-risk N0 or N1 operable breast cancer participating in a phase III trial (HE10/05), were centrally assessed in tissue microarrays by IHC for 6 biological markers, that is, estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki67, cytokeratin 5 (CK5) and EGFR. All cases were further evaluated for HER2 amplification by FISH. Patients were classified as: luminal A (ER/PgR-positive, HER2-negative, Ki67low, N=382, 49.5%); luminal B (ER/PgR-positive, HER2-negative, Ki67high, N=136, 17.6%); luminal-HER2 (ER/PgR-positive, HER2-positive, N=125, 16.2%); HER2-enriched (ER-negative, PgR-negative, HER2-positive, N=63, 8.2%); triple-negative (TNBC) (ER-negative, PgR-negative, HER2-negative, N=65, 8.4%); and basal core phenotype (BCP) (TNBC, CK5-positive and/or EGFR-positive, N=53, 6.9%). Results: At a median follow-up of 60.5 months, the 3-year disease-free survival (DFS) and overall survival (OS) rates for the total patient population were 88.3% and 96.0%, respectively. The 3-year DFS rates for luminal A, luminal B, luminal-HER2, HER2-enriched, TNBC and BCP patients were 91.1%, 88.2%, 86.4%, 93.7%, 87.7%, and 89.4%, respectively, while the corresponding 3-year OS rates were 95.8%, 95.6%, 97.6%, 95.2%, 95.4%, and 95.0%, respectively. No significant differences were detected for either 3-year DFS or OS in the immunohistochemically defined subtypes, except a trend for significantly worse DFS in patients with luminal-HER2 tumors compared to patients with HER2-enriched tumors (log-rank, p=0.069). Conclusions: In the post-trastuzumab era, at a relatively short follow-up, the luminal-HER2 patients show a trend for worse DFS compared to patients with HER2-enriched tumors treated with dose-dense sequential adjuvant chemotherapy followed by trastuzumab. No other significant differences were detected, with follow-up however being continued. Citation Format: George Fountzilas, Eleni Timotheadou, Georgia Gourgioti, Petroula Arapantoni-Dadioti, Sotiris Lakis, Anna Batistatou, Triantafyllia Koletsa, Olympia Tzaida, Mattheos Bobos, Alexandra Papoudou-Bai, Eleftheria Tsolaki, Sofia Chrisafi, Elena Fountzilas, Ioannis Efstratiou, Helen Gogas, Flora Zagouri, Dimitrios Pectasides. Prognostic value of immunophenotypically defined subtypes in patients treated with dose-dense sequential adjuvant chemotherapy in the trastuzumab era. A Hellenic Cooperative Oncology Group study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-09-07.

Leiomyomas of the chest wall are very rare. In a review of the current literature twelve cases were found, of which only one concerns of an intercostal leiomyoma of the chest wall. We report a case of 1 year old male child with intercostal leiomyoma who presented with a painless rigid swelling of the right chest wall. The radiological control revealed a solid mass in the right anterior sixth intercostal space. En-bloc excision of the mass by abrading of the sixth rib through right anterior thoracotomy was performed. Histopatological analysis showed a localized intercostal leiomyoma. The patient has a close follow-up for 6 months without evidence of recurrence. This is the first case of a primary intercostal leiomyoma in a child which was excised totally without reconstruction of the chest wall.

Langerhans cell histiocytosis (LCH) is a rare hematologic disorder that results from the clonal multiplication and accumulation of immature dendritic Langerhans cells. Its reported incidence rate varies, but is considered to be 2.6-8.9 per million children who are

Pancreatic cancer is one of the most fatal malignancies ranking fourth among the leading causes of cancer death with diagnosis at late stages carrying a dismal prognosis. The aim of our retrospective study was to describe the nature and the incidence of gene mutations and genomic instability in advanced pancreatic adenocarcinomas of a Greek patient population fully annotated with clinicopathological data. We used a targeted next-generation sequencing (NGS) panel encompassing genes commonly mutated in pancreatic tumours in a patient population managed with either nab-paclitaxel regimens or targeted compounds modulating the epidermal growth factor receptor (EGFR)/AKT/mTOR axis. We identified KRAS, TP53, SMAD4 and CDKN2A as being the most prevalent mutations in the study population with the exception of an intriguingly lower incidence regarding KRAS mutants. Homologous recombination gene mutations were found to be mutually exclusive with CDKN2A mutations. The coexistence of both KRAS and TP53 mutation seems to adversely affect the outcome of the patients whether treated with targeted therapy against EGFR/Akt/mTOR axis or cytotoxic drugs. The poor prognosis observed, correlated to late presentation, specific molecular mutations and to high mutational load warrant prospective validating studies and research into the mechanistic pathophysiology of pancreatic tumours for more effective therapeutic targeting.

Regression of congenital nevi is usually associated with loss of pigment or halo formation. In rare cases, regression is characterized by sclerosis and hair loss. We describe a rare case of a sclerotic hypopigmented large congenital melanocytic nevus in which a localized scleroderma-like reaction process of regression seemed to have started in utero and progressed throughout early childhood.

Background Stromal tumor infiltrating lymphocytes (TILs) density is an outcome predictor in triple-negative breast cancer (TNBC). Herein we asked whether TILs are related to coding mutation load and to the chemical class of the resulting mutated amino acids, i.e., charged, polar, and hydrophobic mutations. Methods We examined paraffin tumors from TNBC patients who had been treated with adjuvant chemotherapy mostly within clinical trials (training cohort, N = 133; validation, N = 190) for phenotype concordance; TILs density; mutation load and types. Results Concordance of TNBC phenotypes was 42.1% upon local / central, and 72% upon central / central pathology assessment. TILs were not associated with mutation load, type and class of mutated amino acids. Polar and charged mutation patterns differed between TP53 and PIK3CA (p50% TILs tumors (training p = 0.003; validation p = 0.015). Conclusions TILs density is unrelated to mutation load in TNBC, which may be regarded as an unstable phenotype. If further validated, hydrophobic mutations along with TILs density may help identifying TNBC patients in higher risk for relapse.

Wnt and epidermal growth factor receptor (EGFR) pathway abnormalities and de-stabilization of cell adhesion are all important aspects of the pathogenesis of triple-negative breast cancer (TNBC). Herein we investigated how the expression of related protein markers may affect the outcome of patients bearing TNBC treated in the adjuvant setting. Immunohistochemistry for beta-catenin, Myc (Wnt pathway), E-cadherin, P-cadherin (cell-adhesion), EGFR and cytokeratin 5 (CK5) (identification of basal-like tumors) was carried out in 364 centrally confirmed TNBCs. Survival analysis was performed with Cox-regression models according to dichotomized continuous protein expression data and marker interactions. In 352 evaluable tumors, 81.5% were basal-like TNBC. E-cadherin and P-cadherin were positively associated, with co-expression being present in 68% of tumors. Individual markers did not affect patient outcome. However, a statistically significant interaction was shown such that low expression of beta-catenin in the cell membrane, defined as expression below the median of the H-score distribution, was associated with unfavourable disease-free survival among tumors that expressed EGFR, but not in the absence of EGFR expression (interaction p=0.0085). The interaction persisted after correcting for clinicopathological variables. A considerable number of TNBC co-expresses E-cadherin and P-cadherin, while membranous localization of beta-catenin may predict patient outcome in an EGFR-dependent manner. This novel interaction seems worthy for validating with regards to its biological and clinical relevance.

Study Objective: To estimate the diagnostic performance of magnetic resonance imaging (MRI) in detection of myomas and adenomyosis of the uterus. Design: Prospective cohort observational study (Canadian Task Force classification II-2). Setting: Department of obstetrics and gynecology, tertiary academic hospital. Patients: One hundredfifty-three consecutivewomen with an enlarged uterus accompanied by gynecologic symptoms and/or with an asymptomatic pelvic mass. Intervention: Total abdominal hysterectomy. All patients underwent MRI before the operation. Measurements and Main Results: The sensitivity, specificity, positive, and negative predictive value of MRI for the diag- nosis of uterine pathology was calculated using histologic findings as the standard criterion for final diagnosis. Receiver op- erating characteristics curves were constructed to describe the diagnostic performance of MRI. In the diagnosis of myomas, MRI demonstrated sensitivity of 94.1%, specificity of 68.7%, PPVof 95.7%, and NPVof 61.1%. In the diagnosis of adeno- myosis, MRI demonstrated sensitivity of 46.1%, specificity of 99.1%, PPVof 92.3%, and NPVof 88.5%. The area under the curve (AUC) for the diagnostic performance of MRI in the detection of myomas and adenomyosis was 0.81 and 0.73, respec- tively. Uterine sarcoma was diagnosed in 5 patients; in these cases, MRI demonstrated sensitivity of 60.0%, specificity of 99.2%, PPVof 75.0%, and NPVof 98.4%. The AUC for MRI in the diagnosis of uterine sarcomas was 0.80. Conclusions: MRI exhibits a high AUC for the diagnosis of both adenomyosis and myomas. The PPVof MRI in the diagnosis of adenomyosis and myomas of the uterus is high as well. MRI seems to be a useful technique in everyday clinical practice in the diagnostic approach of these common conditions, enabling clinicians to select the most appropriate management. Journal of Minimally Invasive Gynecology (2012) 19, 620-626 2012 AAGL. All rights reserved.

International audience; Trastuzumab (T) is effective in metastatic breast cancer (MBC) with HER2 overexpression and/or amplification, but resistance to T develops in a significant number of HER2-positive patients. Understanding the mechanisms of resistance is critical to the care of these patients. Formalin-fixed paraffin-embedded tumor tissue samples were collected from 256 patients with T-treated MBC. Clinical information was collected retrospectively from the patients' medical records. Central review of HER2 status by fluorescent in situ hybridization (FISH) and/or immunohistochemistry (IHC) revealed that of the 227 eligible patients only 139 (61%) were truly HER2-positive. PTEN, ER, PgR, and Ki67 were evaluated by IHC, while PTEN status was evaluated by FISH as well. PIK3CA mutations were identified with single nucleotide polymorphism (SNP) genotyping. Median time to progression (TTP) was 14.4 months for the HER2-positive and 10.3 for the HER2-negative patients (log-rank, = 0.22). Survival from the initiation of T (survivalT) was 50.4 months for the HER2-positive and 35.3 for the HER2-negative subgroups ( = 0.006). Higher risk of progression was associated with HER2-positive status and the presence of PIK3CA mutations ( = 0.014). PTEN loss, as determined by IHC, was associated with lower survivalT in the whole population ( = 0.029) and in the HER2-positive population ( = 0.017). PIK3CA mutations and/or PTEN loss status were evaluated together as a single parameter, to estimate the impact of activation of the PI3K/AKT molecular pathway, and it was significantly associated with both decreased TTP ( = 0.003 in the total population, = 0.004 in HER2-positive patients) and survival (survivalT, = 0.011 in total, = 0.006 in HER2-positive). In this trastuzumab-treated breast cancer population, PIK3CA activating mutations were associated with shorter TTP and PTEN loss with decreased survival. The activation of the PI3K/AKT pathway from either defect was associated with both TTP and survival, indicating the adverse effect of this pathway's status on trastuzumab efficacy.

e15606Background: Right- and left-sided colorectal cancers (CRC) demonstrate a distinct clinical behavior. Whether this heterogeneity is associated with specific molecular profiles has yet to be de...

Metronomic taxane administration has putative antiangiogenic properties. Herein, we examined the baseline tumor angiogenic profile of patients with metastatic breast carcinoma (MBC) in a prospective-retrospective translational research study. The interplay between the angiogenic factors expressed in the tumors and their prognostic value in MBC were investigated.Tumor tissues from patients with MBC treated with weekly docetaxel (n=159) were examined by immunohistochemistry for VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, VEGFR-3 and osteopontin (OPN) and by mRNA analysis for expression of VEGF-A, VEGFxxxa, VEGFxxxb, VEGF-C, thrombospondin-1 (THBS-1), hypoxia-inducible factor-1α (HIF-1α) and von Hippel-Lindau (VHL) genes. Associations between these parameters and outcome were statistically analyzed.Statistically significant correlations were identified between almost all biomarkers examined in continuous form, particularly at the mRNA level: VEGF-A with VEGFxxxa (rho=0.70); VEGF-C with VEGFxxxa, VEGFxxxb and VHL (rho=0.51, 0.60 and 0.44 respectively); HIF-1α with VEGF-C and THBS1 (rho= 0.48 and 0.45). High VEGF-A mRNA was associated with worse survival (p=0.0279) and marginally with progression free survival (PFS). Intratumoral co-expression of VEGFR-1 and VEGFR-2 proteins was associated with more favorable survival (p=0.0337). In multivariate analysis, only high VEGF-A mRNA levels retained their prognostic role for worse PFS and survival (PFS: HR=2.34, 95% CI=1.25-4.40, p=0.0080; survival: HR=3.15, 95% CI=1.48-6.72, p=0.0029).In MBC, this study confirms the adverse prognostic effect of high intratumoral VEGF-A mRNA and reveals the combined VEGFR-1/VEGFR-2 protein expression as a potentially favorable prognosticator, which merits further evaluation in larger studies.

The urokinase plasminogen activator (uPA) and the plasminogen activator inhibitor 1 (PAI-1) are associated with an aggressive course in breast cancer and are used to determine whether chemotherapy is needed in node-negative patients. The objective of the study was to evaluate the prognostic value of uPA and PAI-1 protein expression in advanced breast cancer patients treated with trastuzumab. Formalin-fixed paraffin-embedded tumor tissue samples were retrospectively collected from 230 patients with advanced breast cancer treated with trastuzumab and 130 patients treated with 1st line taxanes. uPA, PAI-1, ER, PgR, HER2 and Ki67 protein expression was evaluated by immunohistochemistry. Central review of HER2 status revealed that only 144 (63 %) of the trastuzumab-treated patients were truly HER2-positive. Median survival was 50.7 months for the HER2-positive and 30.1 months for the HER2-negative patients (p = 0.006) treated with trastuzumab. In multivariate Cox regression analysis of the trastuzumab cohort, a significant interaction was found, in terms of survival, between HER2 status and PAI-1 protein expression in the stroma (Wald’s p = 0.002). Positive PAI-1 protein expression in the stroma of HER2-negative patients was associated with lower risk of death (HR 0.35, 95 % CI 0.19–0.65, Wald’s p = 0.0008). Such an association was not observed in HER2-positive patients treated with trastuzumab or in the non-trastuzumab (validation) cohorts. Our results suggest that positive stromal PAI-1 protein expression may identify a subgroup of HER2-negative advanced breast cancer patients who might benefit from treatment with trastuzumab. Further studies are warranted to validate these findings in larger cohorts.

Background The PI3K-AKT pathway is frequently activated in breast cancer. PIK3CA mutations are most frequently found in the helical (exon 9) and kinase (exon 20) domains of this protein. The aim of the present study was to examine the role of different types of PIK3CA mutations in combination with molecular biomarkers related to PI3K-AKT signaling in patients with early breast cancer. Methods Tumor tissue samples from 1008 early breast cancer patients treated with adjuvant chemotherapy in two similar randomized trials of HeCOG were examined. Tumors were subtyped with immunohistochemistry (IHC) and FISH for ER, PgR, Ki67, HER2 and androgen receptor (AR). PIK3CA mutations were analyzed by Sanger sequencing (exon 20) and qPCR (exon 9) (Sanger/qPCR mutations). In 610 cases, next generation sequencing (NGS) PIK3CA mutation data were also available. PIK3CA mutations and PTEN protein expression (IHC) were analyzed in luminal tumors (ER and/or PgR positive), molecular apocrine carcinomas (MAC; ER/PgR negative / AR positive) and hormone receptor (ER/PgR/AR) negative tumors. Results PIK3CA mutations were detected in 235/1008 tumors (23%) with Sanger/qPCR and in 149/610 tumors (24%) with NGS. Concordance between the two methods was good with a Kappa coefficient of 0.76 (95% CI 0.69-0.82). Lobular histology, low tumor grade and luminal A tumors were associated with helical domain mutations (PIK3CAhel), while luminal B with kinase domain mutations (PIK3CAkin). The overall incidence of PIK3CA mutations was higher in luminal as compared to MAC and hormone receptor negative tumors (p = 0.004). Disease-free and overall survival did not significantly differ with respect to PIK3CA mutation presence and type. However, a statistically significant interaction between PIK3CA mutation status and PTEN low protein expression with regard to prognosis was identified. Conclusions The present study did not show any prognostic significance of specific PIK3CA mutations in a large group of predominantly lymph-node positive breast cancer women treated with adjuvant chemotherapy. Further analyses in larger cohorts are warranted to investigate possible differential effect of distinct PIK3CA mutations in small subgroups of patients.

Currently, randomized phase III trials have demonstrated that docetaxel is an effective strategy in the adjuvant treatment of breast cancer. However, previous attempts to incorporate docetaxel with an anthracycline in a dose-dense regimen have been unsuccessful. Therefore, new schedules containing both drugs should be explored. Forty-four patients with high-risk operable breast cancer entered this feasibility study. They were treated with three cycles of epirubicin 110 mg/m2 every 2 wk with G-CSF followed by three cycles of "intensified" CMF (840 mg/m2 cyclophosphamide; 57 mg/m2 methotrexate; 840 mg/m2 fluorouracil) every 2 wk with G-CSF followed 3 wk later by nine weekly cycles of 35 mg/m2 docetaxel (E-CMF-doc). Totally, 39 patients (89%) received all cycles of chemotherapy. The vast majority (92%) of cycles were administered at full dose. Therefore, dose intensity was sufficiently maintained for all drugs. Toxicity was generally mild to moderate. Most frequently recorded side effects apart from alopecia were neutropenia (54%) and nausea/vomiting (89%). Infection developed in nine patients. Two cases of febrile neutropenia were reported. The E-CMF-doc regimen, as used in this study, is feasible and well tolerated. Its impact on survival should be evaluated in phase III trials.

We report a case of malignant fibrous histiocytoma (MFH) metastatic to the spine. A 41-yr-old male was admitted to our hospital for radiation treatment of MFH of the spine. He began to show signs suggestive of partial small bowel obstruction. Computed tomography demonstrated jejuno-jejunal intussusception. The patient was taken to the operating room, where the diagnosis was confirmed. Partial jejunal resection was performed. The lead point of the intussusception was histologically diagnosed to be a high-grade malignant fibrous histiocytoma. We believe that the spinal lesion was the metastatic lesion and that metastasis occurred via the vessels of Adamciewicz. To our knowledge this is the first case thus reported.

In the treatment of papillary thyroid carcinoma (PTC), supplementary lymph node dissection (LND) is not well standardized. The purpose of this study was to evaluate the significance of the cervical compartments in the lymphatic spread of PTC and the impact of modified radical neck dissection (MRND) as an additional surgical procedure to thyroid resection. From 1999 to 2002, LND of the central compartment (compartment A) was performed in 39 patients. Among this group, additional MRND of the ipsilateral compartment (compartment B) and the contralateral compartment (compartment C) was performed in 29 and 15 patients respectively, who met the selection criteria. The mean number of nodes resected was 11 (5-22) in compartment A, 23 (8-37) in compartment B, and 22 (10-31) in compartment C. Histopathologic findings revealed node invasion of compartment A in 25 patients (64.1%), of A and B in 20 patients (51,2%) and of A, B, and C in 13 patients (33.3%). From the 25 patients with metastases in compartment A, 80% (20 patients) already had metastases in compartment B and 52% (13 patients) had metastases in all three compartments. All patients free of metastasis (M0) in compartment A were also metastasis free in both lateral compartments. Postoperative whole-body scanning I(131) in M0 patients showed no uptake at all. Mapping of the cervical anatomy in compartments seems to be a useful taxonomy for clarifying the lymphatic spread of PTC. Patients having PTC without metastasis in compartment A are almost certainly disease free at the time of operation. Lymph node metastasis in the central compartment appears to be a valuable indicator of lymphatic invasion of the lateral compartment and a strong indication for performance of a unilateral or bilateral MRND to complete the surgical removal of tumor.

Anaplastic lymphoma kinase (ALK) break-apart fluorescent in situ hybridization (FISH) is currently used in diagnostics for the selection of non-small cell lung cancer (NSCLC) patients to receive crizotinib. We evaluated ALK status in NSCLC with a novel ALK mRNA test based on the break-apart FISH concept, which we called break-apart transcript (BAT) test. ALK5' and ALK3' transcript patterns were established with qPCR for ALK-expressing controls including fusion-negative neuroblastomas, as well as fusion-positive anaplastic large cell lymphomas and NSCLC. The BAT test was evaluated on 271 RNA samples from routinely processed paraffin NSCLC tissues. Test results were compared with ALK FISH (n=121), immunohistochemical (IHC) analysis (n=86), and automated quantitative analysis (AQUA, n=83). On the basis of the nonoverlapping ALK BAT patterns in ALK-expressing controls (P0.0001), 8/174 adenocarcinomas (4.6%) among 259 informative NSCLC were predicted as fusion positive. Overall concordance for paired method results was high (94.1% to 98.8%) but mainly concerned negative prediction because of the limited availability of positive-matched cases. Tumors with 100% cytoplasmic IHC staining of any intensity (n=3) were positive for AQUA, FISH, and BAT test; tumors with lower IHC positivity and different staining patterns were AQUA-negative. Upon multiple reevaluations, ALK gene status was considered as originally misinterpreted by FISH in 3/121 cases (2.5%). Tumors with4 ALK gene copies were associated with longer overall survival upon first-line chemotherapy. In conclusion, application of the ALK BAT test on routinely processed NSCLC tissues yields the same fusion partner independent information as ALK break-apart FISH but is more robust and cost-effective. The BAT concept may be considered for the development of further drug-predictive translocation tests.

There are scarce data available on the prognostic/predictive value of p-Akt and p-mTOR protein expression in patients with high-risk early breast cancer. Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 997 patients participating in two adjuvant phase III trials were assessed for EGFR, PTEN, p-Akt, p-mTOR protein expression, and PIK3CA mutational status. These markers were evaluated for associations with each other and with selected patient and tumor characteristics, immunohistochemical subtypes, disease-free survival (DFS), and overall survival (OS). p-mTOR protein expression was negatively associated with EGFR and positively associated with PTEN, with p-Akt473, and with the presence of PIK3CA mutations. EGFR expression was positively associated with p-Akt473, p-Akt308, and PIK3CA wild-type tumors. Finally, p-Akt308 was positively associated with p-Akt473 expression. In univariate analysis, EGFR (p = 0.016) and the coexpression of EGFR and p-mTOR (p = 0.015) were associated with poor OS. Among patients with p-Akt308-negative or low-expressing tumors, those treated with hormonal therapy were associated with decreased risk for both relapse and death (p = 0.013 and p

Management of skin avulsion injuries of the upper extremity may require coverage with large flaps or skin autografts. Cutaneous grafting is frequently combined with artificial skin to optimize the final functional and cosmetic result. The conventional use of bilaminated dermal substitutes consists of a two-stage procedure and requires long immobilization of the operated area. The purpose of this retrospective study is to evaluate the impact of a dermal regeneration template immediately covered by skin grafts in a one-step procedure for reconstructing skin avulsion injuries of the hand and forearm.We performed this technique in eight patients who presented with extended skin defects of the hand and forearm following skin avulsion injuries. Dimensions of the defects ranged from 160 to 1,250 cm(2). After debridement, Integra(®) Single Layer was applied and covered with unmeshed thin skin autografts; compressive dressings were used for 1 week and mobilization started by the second postoperative week. Histological examination of the grafted areas was performed 2 weeks after surgery. Functional and cosmetic outcome was assessed 12 months postoperatively.The overall take rate of the dermal substitute and skin graft was 95-98 %. Histological results showed complete incorporation and vascular proliferation of the template, which allowed the neo-vascularization of the overlying autograft. The mean grip strength of the operated hands was at the 83 % of the normal contralateral hands. Pliability and overall appearance of the reconstructed areas was satisfactory (mean Vancouver Scar Scale Score 1.875).The use of Integra(®) Single Layer dermal substitute and immediate skin overgrafting consists an alternative reconstructive option for managing extended skin avulsion injuries of the upper extremity; it reduces postoperative immobilization, minimizes donor site morbidity and provides good functional and esthetic results in a single surgical procedure.