Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial.

BACKGROUND: In patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma. METHODS: NORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing. FINDINGS: Between Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49-71) in the neoadjuvant FOLFIRINOX group versus 73% (62-84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2-34·9) versus 38·5 months (27·6-not reached; hazard ratio [HR] 1·52 [95% CI 1·00-2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46-67) in the neoadjuvant FOLFIRINOX group versus 70% (55-83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2-34·9) versus 34·4 months (19·4-not reached; HR 1·46 [95% CI 0·99-2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event. INTERPRETATION: This phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven. FUNDING: Norwegian Cancer Society, South Eastern Norwegian Health Authority, The Sjöberg Foundation, and Helsinki University Hospital Research Grants.

Severe hypercalcemia caused by parathyroid hormone in a rectal cancer metastasis: a case report.

BACKGROUND: Hypercalcemia of malignancy is relatively common in several cancers. However, in colorectal cancer, paraneoplastic phenomena that cause hypercalcemia is uncommon. In the few cases that are reported, secretion of parathyroid hormone-related peptide mediates the effect. We describe the first case of severe hypercalcemia mediated by intact parathyroid hormone secretion from a bone metastasis of colorectal origin. This was a diagnostic and therapeutic challenge. CASE PRESENTATION: A 68-year-old male treated for rectal adenocarcinoma 10 years earlier developed a bone metastasis. After initial treatment of the metastasis with surgery and irradiation, he developed a relapse with severe hypercalcemia and corresponding elevated parathyroid hormone levels. The workup showed no signs of parathyroid adenomas, but the metastasis produced intact parathyroid hormone. The hypercalcemia was successfully treated by irradiation and osteoclast inhibitor, and the patient received chemotherapy. Survival was 24 months from the onset of hypercalcemia. CONCLUSIONS: Proper diagnosis of the uncommon endocrine disturbance allowed targeted therapy and avoidance of neck exploration for wrongly suspecting primary hyperparathyroidism. Intact parathyroid hormone should be measured in cases of malignant hypercalcemia.

Transcription factor PAX6 as a novel prognostic factor and putative tumour suppressor in non-small cell lung cancer.

Lung cancer is the leading cause of cancer deaths. Novel predictive biomarkers are needed to improve treatment selection and more accurate prognostication. PAX6 is a transcription factor with a proposed tumour suppressor function. Immunohistochemical staining was performed on tissue microarrays from 335 non-small cell lung cancer (NSCLC) patients for PAX6. Multivariate analyses of clinico-pathological variables and disease-specific survival (DSS) was carried out, and phenotypic changes of two NSCLC cell lines with knockdown of PAX6 were characterized. While PAX6 expression was only associated with a trend of better disease-specific survival (DSS) (p = 0.10), the pN+ subgroup (N = 103) showed significant correlation between high PAX6 expression and longer DSS (p = 0.022). Median survival for pN + patients with high PAX6 expression was 127.4 months, versus 22.9 months for patients with low PAX6 expression. In NCI-H661 cells, knockdown of PAX6 strongly activated serum-stimulated migration. In NCI-H460 cells, PAX6 knockdown activated anchorage-independent growth. We did not observe any significant effect of PAX6 on proliferation in either of cell lines. Our findings strongly support the proposition of PAX6 as a valid and positive prognostic marker in NSCLC in node-positive patients. There is a need for further studies, which should provide mechanistical explanation for the role of PAX6 in NSCLC.

Monocarboxylate transporters 1-4 in NSCLC: MCT1 is an independent prognostic marker for survival.

INTRODUCTION: Monocarboxylate transporters (MCTs) 1-4 are lactate transporters crucial for cancers cells adaption to upregulated glycolysis. Herein, we aimed to explore their prognostic impact on disease-specific survival (DSS) in both cancer and tumor stromal cells in NSCLC. METHODS: Tissue micro arrays (TMAs) were constructed, representing both cancer and stromal tumor tissue from 335 unselected patients diagnosed with stage I-IIIA NSCLC. Immunohistochemistry was used to evaluate the expression of MCT1-4. RESULTS: In univariate analyses; ↓ MCT1 (P = 0.021) and ↑ MCT4 (P = 0.027) expression in cancer cells, and ↑ MCT1 (P = 0.003), ↓ MCT2 (P = 0.006), ↓ MCT3 (P = 0.020) expression in stromal cells correlated significantly with a poor DSS. In multivariate analyses; ↓ MCT1 expression in cancer cells (HR: 1.9, CI 95%: 1.3-2.8, P = 0.001), ↓ MCT2 (HR: 2.4, CI 95%: 1.5-3.9, P<0.001), ↓ MCT3 (HR: 1.9, CI 95%: 1.1-3.5, P = 0.031) and ↑ MCT1 expression in stromal cells (HR: 1.7, CI 95%: 1.1-2.7, P = 0.016) were significant independent poor prognostic markers for DSS. CONCLUSIONS: We provide novel information of MCT1 as a candidate marker for prognostic stratification in NSCLC. Interestingly, MCT1 shows diverging, independent prognostic impact in the cancer cell and stromal cell compartments.

Stage and tissue-specific prognostic impact of miR-182 in NSCLC.

BACKGROUND: MicroRNA (miR)-182 is frequently upregulated in cancers, has generally been viewed as an oncogene and is possibly connected to angiogenesis. We aimed to explore what impact miR-182 has in non-small cell lung cancer (NSCLC), and more explicitly its correlation with angiogenic markers. METHODS: From 335 unselected stage I to IIIA NSCLC carcinomas, duplicate tumor and tumor-associated stromal cores were collected in tissue microarray blocks (TMAs). In situ hybridization (ISH) was used to detect the expression of miR-182 in tumor cells, and immunohistochemistry (IHC) was used to detect the expression of angiogenesis related protein markers. RESULTS: In univariate analyses, high tumor cell expression of miR-182 was a positive prognostic factor for patients with squamous cell carcinoma (SCC, P = 0.042) and stage II patients (P = 0.003). Also in the multivariate analysis, high tumor cell miR-182 expression was associated with a good prognosis in the same groups (SCC: HR 0.57, CI 95% 0.33-0.99, P = 0.048; stage II: HR 0.50, CI 95% 0.28-0.90, P = 0.020). We found significant correlations between miR-182 and the angiogenesis related markers FGF2, HIF2α and MMP-7. CONCLUSION: In patients with SCC and in stage II patients, high tumor cell miR-182 expression is an independent positive prognostic factor.

High tumor cell expression of microRNA-21 in node positive non-small cell lung cancer predicts a favorable clinical outcome.

BACKGROUND: MicroRNA (miR)-21 has been revealed as an oncogene in cancer development, and is one of the miRNAs closely connected to angiogenesis. We aimed to explore the impact of miR-21 expression in both tumor and stromal compartments of non-small cell lung cancer (NSCLC), and correlations between miR-21 and angiogenic protein markers. METHODS: From 335 unselected stage I to IIIA NSCLC carcinomas, duplicate tumor and tumor-associated stromal cores were collected in tissue microarrays (TMAs). In situ hybridization (ISH) was used to detect the expression of miR-21 separately in tumor cells and stromal cells of the tumor, and immunohistochemistry (IHC) was used to detect the expression of the protein markers protein kinase B (Akt), phosphatidylinositol-3-kinase (PI3K), hypoxia induced factor 1 (HIF1α) and vascular endothelial growth factor-A (VEGF-A). RESULTS: In univariate analyses, high tumor cell expression of miR-21 in patients with lymph node metastasis was a positive prognostic factor (P = 0.024). High stromal miR-21 expression had a negative prognostic impact (P = 0.022). In the multivariate analysis, low tumor mir-21 expression in node positive patients was an independent adverse prognostic factor (HR 2.03, CI 95% 1.09-3.78, P = 0.027). CONCLUSIONS: In patients with lymph node metastasis, miR-21 expression in tumor cells is an independent positive prognostic factor. High stromal miR-21 expression is a negative prognostic factor.

Positive prognostic impact of miR-210 in non-small cell lung cancer.

OBJECTIVES: miR-210 is an important regulator of the cellular response to hypoxia. Therefore, we aimed to explore the prognostic significance of miR-210 in non-small cell lung cancer (NSCLC) patients with stage I-IIIA disease. MATERIALS AND METHODS: In addition to clinicopathological and demograpic information, tumor tissues were collected and tissue micro arrays (TMAs) were constructed from 335 patients with stage I-IIIA NSCLC. Expression of miR-210 in cancer cells and stromal cells of the tumor was assessed by in situ hybridization. RESULTS: In univariate analyses, high cancer cell (p=0.039) and high stromal cell expression (p=0.008) of miR-210 were both significantly associated with an improved disease-spesific survival (DSS). High co-expression of miR-210 in cancer and stromal cells was also a positive prognostic factor for DSS (p=0.010). In multivariate analysis, miR-210 in stromal cells (p=0.011), and miR-210 co-expressed in cancer and stromal cells was an independent prognosticator for DSS (p=0.011). CONCLUSIONS: We show that miR-210 in stromal cells, and co-expressed in cancer cells and stromal cells mediates an independent prognostic impact. It is a candidate marker for prognostic stratification in NSCLC.

CD4/CD8 co-expression shows independent prognostic impact in resected non-small cell lung cancer patients treated with adjuvant radiotherapy.

BACKGROUND: Though traditionally regarded as immunosuppressive, radiotherapy may also stimulate immune cells and facilitate an anti-tumor immune response. We therefore aimed to explore the prognostic significance of immune cell markers in non-small cell lung cancer (NSCLC) patients treated with postoperative radiotherapy (PORT). METHODS: In addition to demographic and clinicopathological information, tumor tissue samples were collected and tissue microarrays (TMAs) were constructed from 55 patients with stage I-IIIA NSCLC who received PORT. Tumor and stromal expression of CD1a+, CD3+, CD4+, CD8+, CD20+, CD56+, CD68+, CD117+ and CD138+ cells, as well as M-CSF and CSF-1R, was assessed by immunohistochemistry. RESULTS: In univariate analysis, high co-expression of CD4+ and CD8+ T lymphocytes as well as high expression of CD1a+ dendritic cells in the tumor stroma correlated with improved disease-specific survival (DSS). In multivariate analysis patients with stromal ↓CD4/↓CD8 expression had a hazard ratio of 21.1 (CI95% 3.9-115.6, P<0.001) when compared to those with ↑CD4/↑CD8 expression. CONCLUSIONS: Stromal ↓CD4/↓CD8 expression was an independent negative prognostic factor for survival in NSCLC patients receiving PORT, indicating a highly detrimental prognosis.

MicroRNA signatures in tumor tissue related to angiogenesis in non-small cell lung cancer.

BACKGROUND: Angiogenesis is regarded as a hallmark in cancer development, and anti-angiogenic treatment is presently used in non-small cell lung cancer (NSCLC) patients. MicroRNAs (miRs) are small non-coding, endogenous, single stranded RNAs that regulate gene expression. In this study we aimed to identify significantly altered miRs related to angiogenesis in NSCLC. METHODS: From a large cohort of 335 NSCLC patients, paraffin-embedded samples from 10 patients with a short disease specific survival (DSS), 10 with a long DSS and 10 normal controls were analyzed. The miRs were quantified by microarray hybridization and selected miRs were validated by real-time qPCR. The impacts of different pathways, including angiogenesis, were evaluated by Gene Set Enrichment Analysis (GSEA) derived from Protein ANalysis THrough Evolutionary Relationship (PANTHER). One of the most interesting candidate markers, miR-155, was validated by in situ hybridization (ISH) in the total cohort (n = 335) and correlation analyses with several well-known angiogenic markers were done. RESULTS: 128 miRs were significantly up- or down-regulated; normal versus long DSS (n = 68) and/or normal versus short DSS (n = 63) and/or long versus short DSS (n = 37). The pathway analysis indicates angiogenesis-related miRs to be involved in NSCLC. There were strong significant correlations between the array hybridization and qPCR validation data. The significantly altered angiogenesis-related miRs of high interest were miR-21, miR-106a, miR-126, miR-155, miR-182, miR-210 and miR-424. miR-155 correlated significantly with fibroblast growth factor 2 (FGF2) in the total cohort (r = 0.17, P = 0.002), though most prominent in the subgroup with nodal metastasis (r = 0.34, P<0.001). CONCLUSIONS: Several angiogenesis-related miRs are significantly altered in NSCLC. Further studies to understand their biological functions and explore their clinical relevance are warranted.

Overexpression of matrix metalloproteinase-7 and -9 in NSCLC tumor and stromal cells: correlation with a favorable clinical outcome.

BACKGROUND: Matrix metalloproteinases (MMPs) are considered important players in angiogenesis and cancer progression. Several drugs developed for targeting MMPs have until now been without clinical efficacy. As both malignant cells and cells of the surrounding stroma contribute to tumor growth, we have explored the impact of MMP-2, -7 and -9 expression in both the tumor and stromal compartment of non-small-cell lung cancers (NSCLC). PATIENTS AND METHODS: From 335 unselected stage I to IIIA NSCLC carcinomas, duplicate tumor and tumor-associated stromal cores were collected in tissue microarrays (TMAs). Immunohistochemistry was used to detect the expression of MMP-2, -7 and -9 in tumor and stromal cells. RESULTS: In univariate analyses, high tumor cell MMP-7 expression (P=0.029) and high stromal MMP-9 expression (P=0.001) were positive prognostic factors. In the multivariate analysis, high tumor cell MMP-7 expression (HR 1.58, CI 1.08-2.32, P=0.020) and high stromal MMP-9 expression (HR 1.92, CI 1.25-2.96, P=0.003) were independent positive prognostic factors for disease-specific survival. CONCLUSION: High levels of MMP-7 in tumor cells and high levels of MMP-9 in tumor associated stroma were independent positive prognostic factors in NSCLC patients.

Overexpression of the HIF hydroxylases PHD1, PHD2, PHD3 and FIH are individually and collectively unfavorable prognosticators for NSCLC survival.

INTRODUCTION: Hypoxia induced factors (HIFs) are at the heart of the adaptive mechanisms cancer cells must implement for survival. HIFs are regulated by four hydroxylases; Prolyl hydroxylase (PHD)-1,-2,-3 and factor inhibiting HIF (FIH). We aimed to investigate the prognostic impact of these oxygen sensors in NSCLC. METHODS: Tumor tissue samples from 335 resected stages I to IIIA NSCLC patients was obtained and tissue microarrays (TMAs) were constructed. Hydroxylase expression was evaluated by immunohistochemistry. PRINCIPAL FINDINGS: There was scorable expression for all HIF hydroxylases in tumor cells, but not in stroma. In univariate analyses, high tumor cell expression of all the HIF hydroxylases were unfavorable prognosticators for disease-specific survival (DSS); PHD1 (P = 0.023), PHD2 (P = 0.013), PHD3 (P = 0.018) and FIH (P = 0.033). In the multivariate analyses we found high tumor cell expression of PHD2 (HR = 2.03, CI 95% 1.20-3.42, P = 0.008) and PHD1 (HR = 1.45, CI 95% 1.01-2.10, P = 0.047) to be significant independent prognosticators for DSS. Besides, there was an additive prognostic effect by the increasing number of highly expressed HIF hydroxylases. Provided none high expression HIF hydroxylases, the 5-year survival was 80% vs. 23% if all four were highly expressed (HR = 6.48, CI 95% 2.23-18.8, P = 0.001). CONCLUSIONS: HIF hydroxylases are, in general, poor prognosticators for NSCLC survival. PHD1 and PHD2 are independent negative prognostic factors in NSCLC. Moreover, there is an additive poor prognostic impact by an increasing number of highly expressed HIF hydroxylases.

Correlation and coexpression of HIFs and NOTCH markers in NSCLC.

BACKGROUND: NOTCH and hypoxia pathways are both known to be highly involved in cancer. Because of the close interplay between both of these pathways, we investigated correlation and co-expression of molecules in these pathways. MATERIALS AND METHODS: In 335 unselected stage I-IIIA NSCLC patients, protein expressions of hypoxia inducible factor 1α (HIF1α), hypoxia inducible factor 2α (HIF2α), glucose transporter 1 (GLUT1), lactate dehydrogenase 5 (LDH5), carbonic anhydrase IX (CAIX), delta like 4 (DLL4), JAGGED1, NOTCH1 and NOTCH4, evaluated by immunohistochemistry, were correlated and co-expressions tested in tumor and stromal cells. RESULTS: HIF2α and LDH5 correlated moderately with DLL4, JAGGED1 and NOTCH4 in both tumor and stromal compartments (Spearman's r=0.16-0.33). The coexpression of HIF1α and NOTCH1 in tumor was significantly indicative of poor prognosis in univariate analysis. Hypoxia and NOTCH ligands and receptors were moderately correlated. CONCLUSION: The lack of appealing coexpression findings for HIF1α and NOTCH1 may be due to the way HIF1α directly influences NOTCH signalling without depending on an elevated NOTCH expression.

Prognostic impacts of angiopoietins in NSCLC tumor cells and stroma: VEGF-A impact is strongly associated with Ang-2.

INTRODUCTION: Angiopoietins and their receptor Tie-2 are, in concert with VEGF-A, key mediators in angiogenesis. This study evaluates the prognostic impact of all known human angiopoietins (Ang-1, Ang-2 and Ang-4) and their receptor Tie-2, as well as their relation to the prognostic expression of VEGF-A. METHODS: 335 unselected stage I-IIIA NSCLC-patients were included and tissue samples of respective tumor cells and stroma were collected in tissue microarrays (TMAs). Immunohistochemistry (IHC) was used to semiquantitatively evaluate the expression of markers in duplicate tumor and stroma cores. PRINCIPAL FINDINGS: In univariate analyses, low tumor cell expression of Ang-4 (P = 0.046) and low stromal expressions of Ang-4 (P = 0.009) and Ang-2 (P = 0.017) were individually associated with a poor survival. In the multivariate analysis, low stromal Ang-2 (HR 1.88; CI 95% 1.15-3.08) and Ang-4 (HR 1.47, CI 95% 1.02-2.11, P = 0.04) expressions were independently associated with a poor prognosis. In patients with high tumor cell expression of Ang-2, a concomitantly high tumor VEGF-A expression mediated a dramatic survival reduction (P<0.001). In the multivariate analysis of patients with high Ang-2 expression, high tumor VEGF-A expression appeared an independent poor prognosticator (HR 6.43; CI 95% 2.46-16.8; P<0.001). CONCLUSIONS: In tumor cells, only Ang-4 expression has prognostic impact in NSCLC. In tumor stroma, Ang-4 and Ang-2 are independently associated with survival. The prognostic impact of tumor cell VEGF-A in NSCLC appears strongly associated with a concomitantly high tumor cell expression of Ang-2.

Independent and tissue-specific prognostic impact of miR-126 in nonsmall cell lung cancer: coexpression with vascular endothelial growth factor-A predicts poor survival.

BACKGROUND: Angiogenesis is pivotal in tumor development. Vascular endothelial growth factor-A (VEGF-A) is considered one of the most important angiogenic factors, but lately several microRNAs (miRs) have been associated with vascular development. miR-126 has been related to tumor angiogenesis and in the regulation of VEGF-A. The authors aimed to investigate the prognostic impact of miR-126 and its co-expression with VEGF-A in nonsmall cell lung cancer (NSCLC) patients. METHODS: Tumor tissue samples from 335 resected stage I to IIIA NSCLC patients were obtained and tissue microarrays (TMAs) were constructed with 4 cores from each tumor specimen. VEGF-A expression was evaluated by immunohistochemistry, and in situ hybridization was used to evaluate the expression of miR-126. RESULTS: In the total material, miR-126 was a significant negative prognostic factor in both univariate (P = .005) and multivariate analyses (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.2-2.8, P = .01). Stratified by histology, miR-126 was only significant in squamous cell carcinomas (univariate: P < .001; multivariate: HR 3.1, CI 95% 1.7-5.6, P<.001). Stratified by lymph node status, miR-126 was significant only in the lymph node-positive subgroup (univariate: P<.001; multivariate: HR 4.1, CI 95% 2.0-8.4, P < .001). High miR-126 expression correlated significantly with high VEGF-A expression (P = .037). The co-expression of miR-126 and VEGF-A had a significant prognostic impact (P = .002), with 5-year survival rates of 68%, 51%, and 42% for low/low (n = 150), mixed combinations (n = 129), and high/high (n = 35) expression, respectively. CONCLUSIONS: miR-126 is a strong and independent negative prognostic factor in NSCLC, and its prognostic impact appears related primarily to histology and nodal status.

Prognostic impact of MiR-155 in non-small cell lung cancer evaluated by in situ hybridization.

BACKGROUND: In recent years, microRNAs (miRNAs) have been found to play an essential role in tumor development. In lung tumorigenesis, targets and pathways of miRNAs are being revealed, and further translational research in this field is warranted. MiR-155 is one of the miRNAs most consistently involved in various neoplastic diseases. We aimed to investigate the prognostic impact of the multifunctional miR-155 in non-small cell lung cancer (NSCLC) patients. METHODS: Tumor tissue samples from 335 resected stage I to IIIA NSCLC patients were obtained and tissue microarrays (TMAs) were constructed with four cores from each tumor specimen. In situ hybridization (ISH) was used to evaluate the expression of miR-155. RESULTS: There were 191 squamous cell carcinomas (SCCs), 95 adenocarcinomas (ACs), 31 large cell carcinomas and 18 bronchioalveolar carcinomas. MiR-155 expression did not have a significant prognostic impact in the total cohort (P = 0.43). In ACs, high miR-155 expression tended to a significant negative prognostic effect on survival in univariate analysis (P = 0.086) and was an independent prognostic factor in multivariate analysis (HR 1.87, CI 95% 1.01 - 3.48, P = 0.047). In SCC patients with lymph node metastasis, however, miR-155 had a positive prognostic impact on survival in univariate (P = 0.034) as well as in multivariate (HR 0.45, CI 95% 0.21-0.96, P = 0.039) analysis. CONCLUSIONS: The prognostic impact of miR-155 depends on histological subtype and nodal status in NSCLC.

The role of tumor-infiltrating immune cells and chronic inflammation at the tumor site on cancer development, progression, and prognosis: emphasis on non-small cell lung cancer.

In addition to malignant neoplastic cells, cancer tissues also include immune cells, fibroblasts, and endothelial cells, including an abundant collection of growth factors, proangiogenic mediators, cytokines, chemokines, and components of the extracellular matrix. The main physiological function of the immune cells is to monitor tissue homeostasis, to protect against invading pathogens, and to eliminate transformed or damaged cells. Between immune cells and malignant cells in the tumor stroma, there is in fact a complex interaction which has significant prognostic relevance as the immune system has both tumor-promoting and -inhibiting roles. In non-small cell lung cancer (NSCLC), there is a marked infiltration of different types of immune cells, and the distribution, tissue localization, and cell types are significantly associated with progression and survival. Cancer immunotherapy has seen a significant progress during the last decade. An increased understanding of the mechanisms by which lung cancer cells escape the immune system, and the recognition of the key tumor antigens and immune system components in tumor ignorance have led to the development of several lung cancer vaccines. As the NSCLC prognosis in general is dismal, one may hope that future immunotherapy may be an effective adjunct to standard therapy, reversing immunologic tolerance in the tumor microenvironment. This review reports on the tumor stroma and in particular tumor-suppressing and -promoting roles of the immune system. Furthermore, it presents recent literature on relevant immune cell-related research in NSCLC.

Management of women with epilepsy: Are guidelines being followed? Results from case-note reviews and a patient questionnaire.

PURPOSE: Several international guidelines for the management of women with epilepsy (WWE) have been developed since 1989. We aimed to determine whether guidelines for the management of WWE are followed and whether active implementation of such guidelines makes a difference to clinical practice. METHODS: The study covered a 2-year period of "passive dissemination" of guidelines followed by a 2-year period of "active implementation." Documentation reflecting adherence to the guidelines was abstracted retrospectively from electronic medical records on 215 WWE aged 16-42 years. Data abstracted from case notes included counselling on contraception and pregnancy-related issues; follow-up during pregnancy; advice on supplementation of folic acid, calcium, and vitamin D; and serum folate measurements. A questionnaire assessing the knowledge of WWE issues was completed by 112 (71%) of 157 patients. RESULTS: Documentation that WWE issues had been addressed was found in approximately one third of medical case records with no measurable effect of active implementation. Only the follow-up during pregnancy seemed to have improved. Serum folate measurements in 51 women treated with enzyme-inducing antiepileptic drugs (AEDs) revealed folate deficiency in 11 (22%). Respondents to the questionnaire recalled having received information from their neurologists on the interaction between AEDs and oral contraceptives (46%), need to plan pregnancy (63%), and folic acid requirement (56%). CONCLUSIONS: Judged by a review of documentation in case notes, active implementation of guidelines had no measurable effect on clinical practice. However, the follow-up during pregnancy seemed to have improved. Patients' knowledge of WWE issues compared favorably with published studies. Better strategies are needed to secure successful implementation of guidelines.