Impact of HPV mRNA types 16, 18, 45 detection on the risk of CIN3+ in young women with normal cervical cytology.

BACKGROUND: Despite a well-established cervical cancer (CC) screening program in Norway, the incidence of CC in young women is increasing, peaking at 35 years of age. 25 percent of all women diagnosed with CC had normal cytology within 3 years prior to cancer diagnosis, addressing the need to improve the screening programme to further reduce cancer incidences missed by cytology. OBJECTIVE: We wanted to investigate the detection rate of CIN3+ in women 25-39 years with normal cytology by using a 3-type HPV mRNA test as a targeted quality assurance measure. The control group is women with normal cytology. METHODS: During 2014-2017, samples from 13,021 women 25-39 years of age attending cervical cancer screening were analysed at Nordlandssykehuset, Bodø, Norway, including 1,896 women with normal cytology and HPV mRNA test (intervention group), and 11,125 women with cytology only (control group). The HPV mRNA testing was performed using a 3-type HPV E6/E7 mRNA test (PreTect SEE; direct genotyping 16, 18 and 45). The women were followed-up according to national guidelines throughout December 2021. RESULTS: Of the 13,021 women, 429 women (3.3%) had CIN3+ confirmed by biopsy in the follow-up, including 13 cases of invasive cervical cancer. Of the 1,896 women with normal cytology and HPV mRNA test (intervention group), 49 women (2.6%) had a positive test. The risks of CIN3+ among women with either a positive or negative HPV mRNA test were 28.6% (14/49) and 0.8% (14/1847). None of the women in the intervention group developed cervical cancer during follow-up. Of the 11,125 women with cytology only (control group), 712 women (6.4%) had abnormal cytology (ASC-US+). The risks of CIN3+ among women with abnormal and normal cytology were 17.7% (126/712) and 2.6% (275/10,413). CONCLUSION: By testing women 25-39 years of age with a normal cytology result using a specific 3-type HPV mRNA test, an increase in screening programme sensitivity can be achieved without an excessive additional workload. Women with normal cytology and a negative HPV mRNA test have a very low risk of cervical cancer.

Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway.

BACKGROUND: Matching treatment based on tumour molecular characteristics has revolutionized the treatment of some cancers and has given hope to many patients. Although personalized cancer care is an old concept, renewed attention has arisen due to recent advancements in cancer diagnostics including access to high-throughput sequencing of tumour tissue. Targeted therapies interfering with cancer specific pathways have been developed and approved for subgroups of patients. These drugs might just as well be efficient in other diagnostic subgroups, not investigated in pharma-led clinical studies, but their potential use on new indications is never explored due to limited number of patients. METHODS: In this national, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled in multiple parallel cohorts. Each cohort is defined by the patient's tumour type, molecular profile of the tumour, and study drug. Treatment outcome in each cohort is monitored by using a Simon two-stage-like 'admissible' monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Molecular diagnostics are funded by the public health care system. DISCUSSION: Precision oncology means to stratify treatment based on specific patient characteristics and the molecular profile of the tumor. Use of targeted drugs is currently restricted to specific biomarker-defined subgroups of patients according to their market authorization. However, other cancer patients might also benefit of treatment with these drugs if the same biomarker is present. The emerging technologies in molecular diagnostics are now being implemented in Norway and it is publicly reimbursed, thus more cancer patients will have a more comprehensive genomic profiling of their tumour. Patients with actionable genomic alterations in their tumour may have the possibility to try precision cancer drugs through IMPRESS-Norway, if standard treatment is no longer an option, and the drugs are available in the study. This might benefit some patients. In addition, it is a good example of a public-private collaboration to establish a national infrastructure for precision oncology. Trial registrations EudraCT: 2020-004414-35, registered 02/19/2021; ClinicalTrial.gov: NCT04817956, registered 03/26/2021.

Differential expression of the miR-17-92 cluster and miR-17 family in breast cancer according to tumor type; results from the Norwegian Women and Cancer (NOWAC) study.

BACKGROUND: MicroRNAs (miRNAs) are promising biomarkers due to their structural stability and distinct expression profile in various cancers. We wanted to explore the miRNA expression in benign breast tissue and breast cancer subgroups in the Norwegian Women and Cancer study. METHODS: Specimens and histopathological data from study participants in Northern Norway diagnosed with breast cancer, and benign tissue from breast reduction surgery were collected. Main molecular subtypes were based on surrogate markers; luminal A (ER+ and/or PR+, HER2- and Ki67 ≤ 30%), luminal B (ER+ and/or PR+, HER2- and Ki67 > 30% or ER+ and/or PR+ and HER2+), HER2 positive (ER- and PR- and HER2+) and triple-negative (ER-, PR- and HER2-). RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue, and miRNAs were successfully analyzed in 102 cancers and 36 benign controls using the 7th generation miRCURY LNA microarray containing probes targeting all human miRNAs as annotated in miRBASE version 19.0. Validation with RT-qPCR was performed. RESULTS: On average, 450 miRNAs were detected in each sample, and 304 miRNAs were significantly different between malignant and benign tissue. Subgroup analyses of cancer cases revealed 23 miRNAs significantly different between ER+ and ER- tumors, and 47 miRNAs different between tumors stratified according to grade. Significantly higher levels were found in high grade tumors for miR-17-5p (p = 0.006), miR-20a-5p (p = 0.007), miR-106b-5p (p = 0.007), miR-93-5p (p = 0.007) and miR-25-3p (p = 0.015) from the paralogous clusters miR-17-92 and miR-106b-25. Expression of miR-17-5p (p = 0.0029), miR-20a-5p (p = 0.0021), miR-92a-3p (p = 0.011) and miR-106b-5p (p = 0.021) was significantly higher in triple-negative tumors compared to the rest, and miR-17-5p and miR-20a-5p were significantly lower in luminal A tumors. CONCLUSIONS: miRNA expression profiles were significantly different between malignant and benign tissue and between cancer subgroups according to ER- status, grade and molecular subtype. miRNAs in the miR-17-92 cluster and miR-17 family were overexpressed in high grade and triple-negative tumors associated with aggressive behavior. The expression and functional role of these miRNAs should be further studied in breast cancer to explore their potential as biomarkers in diagnostic pathology and clinical oncology.

Pembrolizumab as second-line therapy in non-small cell lung cancer in northern Norway: budget impact and expected gain-a model-based analysis.

BACKGROUND: Pembrolizumab is a new drug approved in several countries for second-line therapy in non-small cell lung cancer (NSCLC) being programmed cell death ligand (PD-L1) positive. This drug has a high cost, and the cost-effectiveness ratio has been debated. PATIENTS AND METHODS: The budget impact to the Northern Norwegian Regional Health Authority trust of implementing pembrolizumab in second-line therapy in patients with PD-L1-positive NSCLC was calculated. A model was developed employing data from the Cancer Registry of Norway, the KEYNOTE-010 study, the price list from The Hospital Pharmacy of North Norway, the cost of analysing PD-L1 expression and the cost of travelling. Today's cost of second-line therapy was compared with the new standard employing pembrolizumab. The sale price of pembrolizumab in Norway was not published due to price confidentiality. Norwegian krone (NKr) was converted into Euros (€) at a rate of 1€=Nkr 8.8138. (Bank of Norway, 21 February 2017). RESULTS: 105 new patients were identified available for pembrolizumab per year. The annual cost of pembrolizumab was €5.2 million, hospital pharmacy administration costs €0.1 million, PD-L1 testing €0.3 million, oncologist/pulmonologist/nurses €0.2 million, radiology €0.06 million and transportation €0.4 million. Savings due to avoided present second-line therapy was calculated €0.4 million. Consequently, the cost of implementing pembrolizumab was €5.5 million and the annual budget impact was €5.0 million. A mean gain of at least 9 months per patient treated was necessary to make pembrolizumab cost-effective. CONCLUSIONS: The net budget impact of pembrolizumab was €5.0 million. The expenditure could not be indicated cost-effective. Price confidentiality is a growing problem in health economics and it has become a 'menu without prices' setting.

Accuracy of cervical cytology: comparison of diagnoses of 100 Pap smears read by four pathologists at three hospitals in Norway.

BACKGROUND: Cervical cancer can be prevented by early detection and treatment for precancerous lesions. Since 1995, there has been a national cervical cancer screening program in Norway, where women aged 25-69 years are recommended to take Pap smears every three years. There are 17 cytology laboratories covering a population of 5 million people. The detection rate of cervical abnormalities varies from laboratory to laboratory. We wanted to investigate the accuracy of cytology diagnoses by four different pathologists at three different hospitals in Norway. METHODS: One hundred Pap smears (20 Normal, 20 ASC-US, 20 LSIL, 20 ASC-H and 20 HSIL) screened at UNN in 2015 were evaluated by four pathologists at three hospitals in Norway. All patients were followed up through December 2016. Histologically confirmed high-grade dysplasia (CIN2+) was considered as study endpoint. RESULTS: The number of Pap smears evaluated as abnormal (ASC-US+) by the four pathologists varied from 61 to 85. The number of high-grade cytology (ASC-H+) varied from 26 to 50. There was moderate agreement (weighted kappa 0.45-0.58) between the observers. There were 32 women with high-grade histology (CIN2+) in the follow-up, including 19 CIN2, 12 CIN3 and one squamous cell carcinoma (SCC). Using high-grade cytology (ASC-H+) as cut-off, the sensitivity for CIN2+ varied from 68.8% to 93.8% (mean 77.4%) and specificity from 70.6% to 95.6% (mean 81.3%). The pathologist with the highest sensitivity for CIN2+ had the highest false positive rate and the lowest specificity (p<0.05). The accuracy for CIN2+ varied from 74.1% to 83.8% (mean 79.4%). The Pap smear from the woman with cervical cancer was diagnosed as high-grade (ASC-H+) by one of the four pathologists. CONCLUSIONS: Cervical cancer screening based on cytology has limited accuracy. The study revealed a moderate agreement between the observers, along with a trade-off between sensitivity and specificity. This might indicate that hospitals with high detection rates of cervical cytology have higher sensitivity for CIN2+ but lower specificity.

The presence of intraepithelial CD45RO+ cells in resected lymph nodes with metastases from NSCLC patients is an independent predictor of disease-specific survival.

BACKGROUND: Operable non-small cell lung cancer (NSCLC) patients whose tumours have spread to regional or central lymph nodes at the time of diagnosis have dismal prognoses compared with those who have limited disease. The current TNM staging system for NSCLC poorly distinguishes patients with lymph-node metastases who will succumb to, and those who will eventually be cured from, their disease. This novel study: (1) evaluates the presence of different subsets of intraepithelial tumour-infiltrating lymphocytes (TILs) in lymph nodes with metastases from NSCLC patients; (2) explores the impact of intraepithelial TILs in lymph nodes on survival; (3) correlates their presence with both intraepithelial and stromal TILs in their corresponding primary tumours. METHODS: Metastatic lymph-node tissue from 143N+ NSCLC patients was collected and tissue microarrays were constructed. Immunohistochemistry was used to evaluate the presence of intraepithelial CD3+, CD4+, CD8+, CD20+ and CD45RO+ TILs and their impact on survival. RESULTS: A high level of intraepithelial CD45RO+ TILs in lymph-node metastases from N+ NSCLC patients was an independent positive prognostic factor for disease-specific survival in all patients (HR=0.58, P=0.029) and in squamous cell carcinoma (HR=0.31, P=0.006), but not in adenocarcinoma patients. CONCLUSIONS: The presence of intraepithelial CD45RO+ cells in lymph-node metastases from N+ NSCLC patients predicts favourable disease-specific survival and outperforms the established TNM staging system in the SCC subgroup.

CD45RO(+) Memory T Lymphocytes--a Candidate Marker for TNM-Immunoscore in Squamous Non-Small Cell Lung Cancer.

Tumor-infiltrating lymphocytes (TILs) are vital in limiting cancer progression and may supplement the TNM classification. CD45RO(+) memory TILs show major prognostic impact in various malignancies but have not been extensively explored in non-small cell lung cancer (NSCLC). In this study, we aimed to evaluate their potential in a NSCLC TNM-Immunoscore. Tissue microarrays were constructed from tumor tissue samples from two cohorts including in total 536 patients (University Hospital of North Norway, n = 285; Nordland Hospital, n = 251) with primary resected stage I to IIIA NSCLC. The density of CD45RO(+) and CD8(+) TILs in tumor epithelial and stromal compartments of the tumors was evaluated by immunohistochemistry. In univariate analyses, intraepithelial CD45RO(+) TIL density (T-CD45RO) was a significant prognostic factor for disease-specific survival (P = .007), limited to the squamous cell carcinoma (SCC) histology subgroup (P < .001), where it was significant in both cohorts (University Hospital of North Norway, P = .003; Nordland Hospital, P = .022). Combining T-CD45RO and stromal CD8(+) TIL density (S-CD8) increased the prognostic impact in SCC (P < .001) and showed a significant impact within all pathological stages (I, P = .025; II, P < .001; III, P = .001). In the multivariate analysis, T-CD45RO was an independent positive prognostic factor for SCC (hazard ratio 2.65, 95% confidence interval 1.64-4.28, P < .001), and in combination with S-CD8, the prognostic impact increased vastly (high + high versus low + low: hazard ratio 6.50, 95% confidence interval 3.54-11.91, P < .001). In conclusion, T-CD45RO was an independent prognostic factor for SCC NSCLC. When combined with S-CD8, the prognostic impact increased and was significant within each pathological stage. We propose CD45RO as a candidate marker for TNM-Immunoscore in SCC NSCLC.

Nontargeted Effect after Radiotherapy in a Patient with Non-Small Cell Lung Cancer and Bullous Pemphigoid.

Purpose. To describe tumor shrinkage of nonirradiated lung metastases in a patient with non-small cell lung cancer. Case Report. The patient had a concurrent autoimmune condition, bullous pemphigoid, which was clinically exacerbated during radiotherapy of mediastinal and axillary lymph node metastases. He also developed a series of infections during and after irradiation, and we hypothesize that the immunological events during this phase might have influenced the size of the nonirradiated metastases. Conclusion. Ionizing radiation generates inflammatory signals and, in principle, could provide both tumor-specific antigens from dying cells and maturation stimuli that are necessary for dendritic cells' activation of tumor-specific T cells. Even if the detailed mechanisms causing nontargeted immune modulatory effects in individual patients are poorly understood, clinical development of radioimmunotherapy is underway.

Prognostic impact of CXCL16 and CXCR6 in non-small cell lung cancer: combined high CXCL16 expression in tumor stroma and cancer cells yields improved survival.

BACKGROUND: The chemokine CXCL16 and its receptor CXCR6 are expressed by a variety of immune cells and have been shown to influence angiogenesis. The expression of CXCR6 and CXCL16 has been examined in numerous human cancers; however no studies have yet investigated their influence on prognosis in non-small cell lung cancer (NSCLC). We aimed to explore their prognostic significance in NSCLC, in addition to examining associations with previously investigated markers. METHODS: Resected tumor tissue from 335 consecutive unselected stage I-IIIA NSCLC patients (1990-2005) were collected. Immunohistochemistry was used to evaluate the expression of CXCR6 and CXCL16 on tissue microarrays. In vitro, NSCLC cells (NCI-H460, A549 cells) were transfected with CXCL16 siRNA to examine effects on proliferation. RESULTS: In univariate analysis, ↑ stromal cell CXCL16 expression was a significant positive prognostic factor (P = 0.016). CXCR6 was expressed in cancer cells, but did not show any prognostic impact. In the multivariate analysis, combined ↑cancer, and ↑stromal cell CXCL16 expression was an independent positive prognostic factor when compared to ↓stromal and ↓cancer cell expression (HR: 0.42; 95 % CI: 0.20-0.88; P = 0.022). Knockdown of CXCL16 by siRNA resulted in accelerated proliferation of NSCLC cell lines. CONCLUSION: We have shown that combined ↑cancer and ↑stromal cell CXCL16 expression is an independent positive prognostic factor in NSCLC. Further studies are warranted to elucidate the biological mechanism underlying this finding.

Stromal CD8+ T-cell Density­A Promising Supplement to TNM Staging in Non-Small Cell Lung Cancer.

PURPOSE: Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates, which appears to be superior to the tumor-node-metastasis (TNM) classification in colorectal cancer. In non-small cell lung cancer (NSCLC), no immunoscore has been established, but in situ tumor immunology is recognized as highly important. We have previously evaluated the prognostic impact of several immunological markers in NSCLC, yielding the density of stromal CD8(+) tumor-infiltrating lymphocytes (TIL) as the most promising candidate. Hence, we validate the impact of stromal CD8(+) TIL density as an immunoscore in NSCLC. EXPERIMENTAL DESIGN: The prognostic impact of stromal CD8(+) TILs was evaluated in four different cohorts from Norway and Denmark consisting of 797 stage I-IIIA NSCLC patients. The Tromso cohort (n = 155) was used as training set, and the results were further validated in the cohorts from Bodo (n = 169), Oslo (n = 295), and Denmark (n = 178). Tissue microarrays and clinical routine CD8 staining were used for all cohorts. RESULTS: Stromal CD8(+) TIL density was an independent prognostic factor in the total material (n = 797) regardless of the endpoint: disease-free survival (P < 0.001), disease-specific survival (P < 0.001), or overall survival (P < 0.001). Subgroup analyses revealed significant prognostic impact of stromal CD8(+) TIL density within each pathologic stage (pStage). In multivariate analysis, stromal CD8(+) TIL density and pStage were independent prognostic variables. CONCLUSIONS: Stromal CD8(+) TIL density has independent prognostic impact in resected NSCLC, adds prognostic impact within each pStage, and is a good candidate marker for establishing a TNM-Immunoscore.

The prognostic role of progesterone receptor expression in non-small cell lung cancer patients: Gender-related impacts and correlation with disease-specific survival.

PURPOSE: Progesterone has been shown to impact the development of hormone-sensitive cancers, such as breast and ovarian cancers. Emerging evidence has revealed a possible role of progesterone in the tumorigenesis of other cancers, including lung cancer. Herein, we aimed to elucidate the prevalence and prognostic significance of progesterone receptor (PR) expression in non-small cell lung cancer (NSCLC) tissue. EXPERIMENTAL: Tumor tissue samples were collected from our patient cohort consisting of 335 NSCLC patients with stage I-IIIA disease. Tissue microarrays (TMAs) were constructed, and immunohistochemical (IHC) analyses were performed to evaluate the PR expression in the tumor epithelial and stromal compartments. RESULTS: In a univariate analysis, positive PR expression in the stromal tumor compartment (P=0.005) was significantly and independently associated with a favorable outcome for both genders. Furthermore, positive PR expression in tumor epithelial cells (P=0.003) correlated with a poor prognosis for female patients. In a multivariate analysis, positive PR expression in the tumor stroma (P=0.007) was an independent prognostic factor for improved disease-specific survival (DSS). Positive PR expression in tumor epithelial cells emerged as an independent prognostic factor in female patients (P=0.001) for poor DSS. CONCLUSIONS: We show that PR expression in tumor-surrounding stromal cells is associated with improved DSS for both male and female patients. Additionally, we reveal that positive PR expression in tumor epithelial cells is an independent, unfavorable prognosticator for DSS in female patients, making PR expression a potential marker for prognostic stratification 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.

Disease-specific outcomes of radical prostatectomies in Northern Norway; a case for the impact of perineural infiltration and postoperative PSA-doubling time.

BACKGROUND: Prostate cancer is the most common male malignancy and a mayor cause of mortality in the western world. The impact of clinicopathological variables on disease related outcomes have mainly been reported from a few large US series, most of them not reporting on perineural infiltration. We therefore wanted to investigate relevant cancer outcomes in patients undergoing radical prostatectomy in two Norwegian health regions with an emphasis on the impact of perineural infiltration (PNI) and prostate specific antigen- doubling time (PSA-DT). METHODS: We conducted a retrospective analysis of 535 prostatectomy patients at three hospitals between 1995 and 2005 estimating biochemical failure- (BFFS), clinical failure- (CFFS) and prostate cancer death-free survival (PCDFS) with the Kaplan-Meier method. We investigated clinicopathological factors influencing risk of events using cox proportional hazard regression. RESULTS: After a median follow-up of 89 months, 170 patients (32%) experienced biochemical failure (BF), 36 (7%) experienced clinical failure and 15 (3%) had died of prostate cancer. pT-Stage (p = 0.001), preoperative PSA (p = 0.047), Gleason Score (p = 0.032), non-apical positive surgical margins (PSM) (p = 0.003) and apical PSM (p = 0.031) were all independently associated to BFFS. Gleason score (p = 0.019), PNI (p = 0.012) and non-apical PSM (p = 0.002) were all independently associated to CFFS while only PNI (P = 0.047) and subgroups of Gleason score were independently associated to PCDFS. After BF, patients with a shorter PSA-DT had independent and significant worse event-free survivals than patients with PSA-DT > 15 months (PSA-DT = 3-9 months, CFFS HR = 6.44, p < 0.001, PCDFS HR = 13.7, p = 0.020; PSA-DT < 3 months, CFFS HR = 11.2, p < 0.001, PCDFS HR = 27.5, p = 0.006). CONCLUSIONS: After prostatectomy, CFFS and PCDFS are variable, but both are strongly associated to Gleason score and PNI. In patients with BF, PSA-DT was most strongly associated to CF and PCD. Our study adds weight to the importance of PSA-DT and re-launches PNI as a strong prognosticator for clinically relevant endpoints.

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.

Prognostic impact of Skp2, ER and PGR in male and female patients with soft tissue sarcomas.

BACKGROUND: S-phase kinase-associated protein 2 (Skp2) is a member of mammalian F-box proteins. The purpose of this study is to clarify the prognostic significance of expression of Skp2 related to gender, estrogen receptor (ER) and progesterone receptor (PGR) in soft tissue sarcomas (STS). Skp2 has been demonstrated to display an oncogenic function since its overexpression has been observed in many human cancers. Optimized treatment of STS requires better identification of high-risk patients who will benefit from adjuvant therapy. The prognostic significance of Skp2 related to ER and PGR in STS has not been sufficiently investigated. METHODS: Tissue microarrays from 193 STS patients were constructed from duplicate cores of viable and representative neoplastic tumor areas. Immunohistochemistry was used to evaluate the expression of Skp2, ER and PGR. RESULTS: In univariate analyses, high tumor expression of Skp2 correlated (p = 0.050) with reduced disease-specific survival (DSS). In subgroup analyses expression of PGR in males (p = 0.010) and in patients older than 60 years (p = 0.043) were negative prognostic factors for DSS. Expression of ER in females was a positive prognostic factor for DSS (p = 0.041). In co-expression analyses in the whole cohort, low expression of Skp2 in combination with low expression of ER was positive for DSS (p = 0.049). In females high expression of Skp2 in combination with low expression of ER was a negative prognosticator (p = 0.021). In the multivariate analyses, age (p = 0.012), malignancy grade (p < 0.001), wide resection margins (P = 0.010), ER negative / PGR positive co-expression profile (p = 0.002) and ER positive / PGR negative co-expression profile (p = 0.015) were independent negative prognostic factors for DSS. In females expression of Skp2 (p = 0.006) was associated with shorter DSS. CONCLUSIONS: We found diverse prognostic impacts of expression of Skp2, ER, PGR and DSS in male and female patients with STS. In men, but not women, ER positive / PGR negative co-expression profile was an independent negative prognostic factor for DSS. In women, but not men, high expression of Skp2 was associated with reduced DSS.

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.

Prognostic impact of Jab1, p16, p21, p62, Ki67 and Skp2 in soft tissue sarcomas.

PURPOSE: The purpose of this study is to clarify the prognostic significance of expression of Jab1, p16, p21, p62, Ki67 and Skp2 in soft tissue sarcomas (STS). Optimised treatment of STS requires better identification of high risk patients who will benefit from adjuvant therapy. The prognostic significance of Jab1, p16, p21, p62, Ki67 and Skp2 in STS has not been sufficiently investigated. EXPERIMENTAL DESIGN: Tissue microarrays from 193 STS patients were constructed from duplicate cores of viable and representative neoplastic tumor areas. Immunohistochemistry was used to evaluate the expression of Jab1, p16, p21, p62, Ki67 and Skp2. RESULTS: In univariate analyses, high tumor expression of Ki67 (P = 0.007) and Skp2 (P = 0.050) correlated with shorter disease-specific survival (DSS). In subgroup analysis, a correlation between Skp2 and DSS was seen in patients with malignancy grade 1 or 2 (P = 0.027), tumor size >5 cm (P = 0.018), no radiotherapy given (P = 0.029) and no chemotherapy given (P = 0.017). No such relationship was apparent for Jab1, p16, p21 and p62; but p62 showed a positive correlation to malignancy grade (P = 0.019). Ki67 was strongly positively correlated to malignancy grade (P = 0.001). In multivariate analyses, Skp2 was an independent negative prognostic factor for DSS in women (P = 0.009) and in patients without administered chemotherapy or radiotherapy (P = 0.026). CONCLUSIONS: Increased expression of Skp2 in patients with soft tissue sarcomas is an independent negative prognostic factor for disease-specific survival in women and in patients not administered chemotherapy or radiotherapy. Besides, further studies are warranted to explore if adjuvant chemotherapy or radiotherapy improve the poor prognosis of STS with high Skp2 expression.

High expression of CD20+ lymphocytes in soft tissue sarcomas is a positive prognostic indicator.

The immune status is important in cancer patients. Tissue microarrays from 249 patients with soft tissue sarcomas were constructed. Immunohistochemistry was used to evaluate the CD3+, CD4+, CD8+, CD20+ and CD45+ lymphocytes in tumors. High density of CD20+ lymphocytes is an independent positive prognostic indicator for these patients.