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Cancer Statistics
Population in 2012: 5.4m
People newly diagnosed with cancer (excluding NMSC) / yr: 28,400
Age-standardised rate, incidence per 100,000 people/yr: 256.8
Risk of getting cancer before age 75:25.9%
People dying from cancer /yr: 11,400
Data from IARC GlobalCan (2012)
Finland Cancer Organisations and Resources
Latest Research Publications Related to Finland

Finland Cancer Organisations and Resources (7 links)

Latest Research Publications Related to Finland

Vallius T, Hynninen J, Auranen A, et al.
Postoperative human epididymis protein 4 predicts primary therapy outcome in advanced epithelial ovarian cancer.
Tumour Biol. 2017; 39(2):1010428317691189 [PubMed] Related Publications
Primary chemotherapy treatment response monitoring in advanced epithelial ovarian cancer (EOC) is currently based on CT-imaging and serum CA125 values. Serum HE4 profile during first line chemotherapy has not been previously studied. We evaluated the HE4 profile during first line chemotherapy after primary (PDS) and interval debulking surgery (IDS). In total, 49 FIGO stage III/IV EOC patients were included in the study. 22 patients underwent PDS and 27 patients neoadjuvant chemotherapy (NACT) followed by IDS. Serial HE4 and CA125 serum samples were taken during first line chemotherapy. The association of postoperative tumor markers to surgery outcome, primary therapy outcome and progression free survival (PFS) were determined. The lowest HE4 and CA125 values during chemotherapy were compared to primary therapy outcome and PFS. The postoperative HE4 was associated to residual tumor after surgery (p = 0.0001), primary therapy outcome (p = 0.004) and PFS (p = 0.03) in all patients (n = 40). The postoperative CA125 was associated to PFS after IDS (n = 26, p = 0.006), but not after PDS. In multivariate analysis with FIGO stage (III/IV), residual tumor (0/>0) and postoperative CA125, the postoperative HE4 was the only statistically significant prognostic variable predicting PFS. Both HE4 and CA125 nadir corresponded to primary therapy outcome (HE4 p < 0.0001, CA125 p < 0.0001) and PFS (HE4 p = 0.009, CA125 p < 0.0001). HE4 is a promising candidate for EOC response monitoring. In our study, the performance of HE4 in response monitoring of first line chemotherapy was comparable to that of CA125. Of the postoperative values, only HE4 was statistically significantly associated to primary therapy outcome.

Ghanbari R, Rezasoltani S, Hashemi J, et al.
Expression Analysis of Previously Verified Fecal and Plasma Dow-regulated MicroRNAs (miR-4478, 1295-3p, 142-3p and 26a-5p), in FFPE Tissue Samples of CRC Patients.
Arch Iran Med. 2017; 20(2):92-95 [PubMed] Related Publications
BACKGROUND: Colorectal cancer (CRC) is one of the most common causes of cancer-related mortality worldwide. Early diagnosis of this neoplasm is critical and may reduce patients' mortality. MicroRNAs are small non-coding RNA molecules whose expression pattern can be altered in various diseases such as CRC.
METHODS: In this study, we evaluated the expression levels of miR-142-3p, miR-26a-5p (their reduced expression in plasma samples of CRC patients was previously confirmed), miR-4478 and miR-1295-3p (their reduced expression in stool samples of CRC patients was previously confirmed) in tissue samples of CRC patients in comparison to healthy subjects. To achieve this purpose, total RNA including small RNA was extracted from 53 CRC and 35 normal subjects' Formalin-fixed, Paraffin-embedded (FFPE) tissue samples using the miRNeasy FFPE Mini Kit. The expression levels of these four selected miRNAs were measured using quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR).
RESULTS: We found that the expression levels of miR-4478 and miR-1295b-3p (two previously down-regulated fecal miRNAs) were significantly decreased in FFPE samples of CRC patients compared to healthy controls. On the other hand, no significant differences were seen in expression levels of miR-142-3p and miR-26a-5p (two previously down-regulated circulating miRNAs) in FFPE samples between these two groups.
CONCLUSION: Regarding current findings, it may be concluded that to diagnose CRC patients based on the miRNAs approach, stool samples are more likely preferable to plasma samples; nevertheless, additional studies with more samples are needed to confirm the results.

Laitinen MK, Parry MC, Albergo JI, et al.
Is computer navigation when used in the surgery of iliosacral pelvic bone tumours safer for the patient?
Bone Joint J. 2017; 99-B(2):261-266 [PubMed] Related Publications
AIMS: Due to the complex anatomy of the pelvis, limb-sparing resections of pelvic tumours achieving adequate surgical margins, can often be difficult. The advent of computer navigation has improved the precision of resection of these lesions, though there is little evidence comparing resection with or without the assistance of navigation. Our aim was to evaluate the efficacy of navigation-assisted surgery for the resection of pelvic bone tumours involving the posterior ilium and sacrum.
PATIENTS AND METHODS: Using our prospectively updated institutional database, we conducted a retrospective case control study of 21 patients who underwent resection of the posterior ilium and sacrum, for the treatment of a primary sarcoma of bone, between 1987 and 2015. The resection was performed with the assistance of navigation in nine patients and without navigation in 12. We assessed the accuracy of navigation-assisted surgery, as defined by the surgical margin and how this affects the rate of local recurrence, the disease-free survival and the effects on peri-and post-operative morbidity.
RESULTS: The mean age of the patients was 36.4 years (15 to 66). The mean size of the tumour was 10.9 cm. In the navigation-assisted group, the margin was wide in two patients (16.7%), marginal in six (66.7%) and wide-contaminated in one (11.1%) with no intralesional margin. In the non-navigated-assisted group; the margin was wide in two patients (16.7%), marginal in five (41.7%), intralesional in three (25.0%) and wide-contaminated in two (16.7%). Local recurrence occurred in two patients in the navigation-assisted group (22.2%) and six in the non-navigation-assisted group (50.0%). The disease-free survival was significantly better when operated with navigation-assistance (p = 0.048). The blood loss and operating time were less in the navigated-assisted group, as was the risk of a foot drop post-operatively.
CONCLUSION: The introduction of navigation-assisted surgery for the resection of tumours of the posterior ilium and sacrum has increased the safety for the patients and allows for a better oncological outcome. Cite this article: Bone Joint J 2017;99-B:261-6.

Andritsch E, Beishon M, Bielack S, et al.
ECCO Essential Requirements for Quality Cancer Care: Soft Tissue Sarcoma in Adults and Bone Sarcoma. A critical review.
Crit Rev Oncol Hematol. 2017; 110:94-105 [PubMed] Related Publications
BACKGROUND: ECCO essential requirements for quality cancer care (ERQCC) are checklists and explanations of organisation and actions that are necessary to give high-quality care to patients who have a specific tumour type. They are written by European experts representing all disciplines involved in cancer care. ERQCC papers give oncology teams, patients, policymakers and managers an overview of the elements needed in any healthcare system to provide high quality of care throughout the patient journey. References are made to clinical guidelines and other resources where appropriate, and the focus is on care in Europe. Sarcoma: essential requirements for quality care • Sarcomas - which can be classified into soft tissue and bone sarcomas - are rare, but all rare cancers make up more than 20% of cancers in Europe, and there are substantial inequalities in access to high-quality care. Sarcomas, of which there are many subtypes, comprise a particularly complex and demanding challenge for healthcare systems and providers. This paper presents essential requirements for quality cancer care of soft tissue sarcomas in adults and bone sarcomas. • High-quality care must only be carried out in specialised sarcoma centres (including paediatric cancer centres) which have both a core multidisciplinary team and an extended team of allied professionals, and which are subject to quality and audit procedures. Access to such units is far from universal in all European countries. • It is essential that, to meet European aspirations for high-quality comprehensive cancer control, healthcare organisations implement the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis and follow-up, to treatment, to improve survival and quality of life for patients.
CONCLUSION: Taken together, the information presented in this paper provides a comprehensive description of the essential requirements for establishing a high-quality service for soft tissue sarcomas in adults and bone sarcomas. The ECCO expert group is aware that it is not possible to propose a 'one size fits all' system for all countries, but urges that access to multidisciplinary teams is guaranteed to all patients with sarcoma.

Beets G, Sebag-Montefiore D, Andritsch E, et al.
ECCO Essential Requirements for Quality Cancer Care: Colorectal Cancer. A critical review.
Crit Rev Oncol Hematol. 2017; 110:81-93 [PubMed] Related Publications
BACKGROUND: ECCO essential requirements for quality cancer care (ERQCC) are checklists and explanations of organisation and actions that are necessary to give high-quality care to patients who have a specific tumour type. They are written by European experts representing all disciplines involved in cancer care. ERQCC papers give oncology teams, patients, policymakers and managers an overview of the elements needed in any healthcare system to provide high quality of care throughout the patient journey. References are made to clinical guidelines and other resources where appropriate, and the focus is on care in Europe. Colorectal cancer: essential requirements for quality care CONCLUSION: Taken together, the information presented in this paper provides a comprehensive description of the essential requirements for establishing a high-quality CRC service. The ECCO expert group is aware that it is not possible to propose a 'one size fits all' system for all countries, but urges that access to multidisciplinary units or centres must be guaranteed for all those with CRC.

Strien L, Joensuu K, Heikkilä P, Leidenius MH
Different Expression Patterns of CXCR4, CCR7, Maspin and FOXP3 in Luminal Breast Cancers and Their Sentinel Node Metastases.
Anticancer Res. 2017; 37(1):175-182 [PubMed] Related Publications
AIM: Luminal A breast cancers (BC) represent low-risk tumors conferring better outcome than luminal B and human epidermal growth factor 2 (HER2)-positive or triple-negative tumors. One reason for the heterogeneous outcome among patients with luminal BC is the variation in cell proliferation. As chemokine receptors and tumor suppressors show potential for estimation of infiltration to regional lymph nodes, we aimed to compare differently sized sentinel node metastases with their primary tumors (PT).
MATERIALS AND METHODS: We compared 29 BCs of luminal subtype A and 23 of subtype B (Ki-67 cut off at 14%) by immunohistochemistry for the chemokine receptors C-X-C chemokine receptor 4 (CXCR4), C-C-chemokine receptor 7 (CCR7), the tumor suppressor Maspin and the regulatory T-cell immunosuppressor forkhead box protein 3 (FOXP3) between PTs and their metastases of different size.
RESULTS: Expression of CXCR4 was low in luminal A type tumors, and CCR7 and FOXP3 expression were high in luminal B type cancer. CXCR4 expression significantly positively correlated with CCR7 both in PTs and metastases. Most Maspin-positive PTs became negative in the metastases. The PTs for all Maspin-positive metastases were luminal B type.
CONCLUSION: High CXCR4 expression in PTs was found to be associated with luminal A type tumor, suggesting more favorable outcome. In contrast, CCR7 and FOXP3 expressions in PTs represented luminal B tumors, pointing to more aggressive tumor behavior. Maspin expression did not differ between luminal types.

Ritvonen E, Pitkänen E, Karppinen A, et al.
Impact of AIP and inhibitory G protein alpha 2 proteins on clinical features of sporadic GH-secreting pituitary adenomas.
Eur J Endocrinol. 2017; 176(2):243-252 [PubMed] Related Publications
INTRODUCTION: In sporadic acromegaly, downregulation of AIP protein of the adenomas associates with invasive tumor features and reduced responsiveness to somatostatin analogues. AIP is a regulator of Gai signaling, but it is not known how the biological function of the Gai pathway is controlled.
AIM: To study GNAS and AIP mutation status, AIP and Gai-2 protein expressions, Ki-67 proliferation indices and clinical parameters in patients having primary surgery because of acromegaly at a single center between years 2000 and 2010.
RESULTS: Sixty patients (F/M, 31/29), mean age 49 (median 50), mean follow-up 7.7 years (range 0.6-14.0) underwent primary surgery. Four adenoma specimens (6.8%) harbored an AIP and 21 (35.6%) an activating GNAS (Gsp+) mutation. Altogether 13/56 (23%) adenomas had low AIP protein levels, and 14/56 (25%) low Gai-2 staining. In regression modeling, AIP expression associated with Gai-2 (P = 2.33 × 10(-9)) and lower Ki-67 (P = 0.04). In pairwise comparison, low AIP protein predicted high GH at last follow-up (mean 7.7 years after surgery, q = 0.045). Extent of treatments given for acromegaly associated with higher preoperative GH (P = 7.94 × 10(-4)), KNOSP (P = 0.003) and preoperative hypopituitarism (P = 0.03) and remission at last follow-up with change in 3-month postoperative IGF1 (P = 2.07 × 10(-7)).
CONCLUSIONS: We demonstrate, for the first time, that AIP protein expression associates with Gai-2 protein intensities in sporadic somatotropinomas, suggesting a joint regulation on somatostatin signaling. Low AIP level associates with higher proliferative activity and predicts high GH concentrations after long-term follow-up. The AIP mutation rate of 6.8% is fairly high, reflecting the genetic composition of the Finnish population.

Prabhakar N, Zhang J, Desai D, et al.
Stimuli-responsive hybrid nanocarriers developed by controllable integration of hyperbranched PEI with mesoporous silica nanoparticles for sustained intracellular siRNA delivery.
Int J Nanomedicine. 2016; 11:6591-6608 [PubMed] Free Access to Full Article Related Publications
Small interfering RNA (siRNA) is a highly potent drug in gene-based therapy with the challenge being to deliver it in a sustained manner. The combination of mesoporous silica nanoparticles (MSNs) and polycations in the confined pore space allows for incorporation and controlled release of therapeutic siRNA payloads. We hereby constructed MSNs with expanded mesopores and pore-surface-hyperbranched poly(ethyleneimine) (PEI) tethered with redox-cleavable linkers that could carry a high payload of siRNA (120 mg·g(-1)). The developed nanocarriers were efficiently taken up by cancer cells and were subsequently able to escape to the cytoplasm from the endosomes, most likely owing to the integrated PEI. Triggered by the intracellular redox conditions, the siRNA was sustainably released inside the cells over a period of several days. Functionality of siRNAs was demonstrated by using cell-killing siRNA as cargo. Despite not being the aim of the developed system, in vitro experiments using cell-killing siRNAs showed that the efficacy of siRNA transfection was comparable to the commercial in vitro transfection agent Lipofectamine. Consequently, the developed MSN-based delivery system offers a potential approach to hybrid nanocarriers for more efficient and long-term siRNA delivery and, in a longer perspective, in vivo gene silencing for RNA interference (RNAi) therapy.

Santala S, Talvensaari-Mattila A, Soini Y, et al.
Cyclins A, B, E and p27 in Endometrial Endometrioid Adenocarcinoma.
Anticancer Res. 2016; 36(12):6467-6473 [PubMed] Related Publications
BACKGROUND/AIM: We have previously shown that cyclin A, B and E hold prognostic significance in endometrial endometrioid adenocarcinoma. The aim of this study was to investigate the impact of cyclin-dependent kinase inhibitor p27 on cancer-specific survival and other clinicopathological variables, as well as further analyze the relationship between p27 and cyclins A, B and E and their combined relation to prognosis in the disease.
PATIENTS AND METHODS: The study comprised of 211 patients surgically treated for endometrial endometrioid adenocarcinoma at the Oulu University Hospital between 1992 and 2000. Tissue samples were immunohistochemically stained for cyclins A, B and E, as well as p27. Clinicopathological data were retrospectively retrieved from the patients' records.
RESULTS: In this study, universally low cyclin expression was found to be an independent, favorable prognostic factor in endometrial endometrioid adenocarcinoma. A strong correlation was found between cyclin A and cyclin B expression and weaker correlations between other cyclin and p27 pairs. Nuclear p27 expression correlated with stage and produced near-significant results in univariate survival analysis.
CONCLUSION: Combining the expression level of different cyclins may be useful in determining the prognosis in endometrial cancer. Unfortunately, it remains unclear whether high p27 expression is a poor or a favorable prognostic factor. Further large-scale studies are required to assess the effects of cyclins and p27 in endometrial cancer.

Joensuu T, Joensuu G, Kairemo K, et al.
Multimodal Primary Treatment of Metastatic Prostate Cancer with Androgen Deprivation and Radiation.
Anticancer Res. 2016; 36(12):6439-6447 [PubMed] Related Publications
AIM: We combined anti-androgen therapy with radiotherapy in a first-line setting for metastatic prostate cancer aiming to cause maximal cancer-cell death to delay the emergence of castration-resistant disease.
MATERIALS AND METHODS: In this non-randomized retrospective series of 46 patients, the initial median prostate-specific antigen (PSA) was 98.5 μg/l (range=6.7-15,500), median Gleason score 9 and most men had at least T3N1M1 disease. All patients received luteinizing hormone releasing hormone analog or degarelix with bicalutamide. If PSA remained above 1 μg/l, docetaxel was initiated. At PSA nadir, all patients received radical radiotherapy of the prostate.
RESULTS: The median follow-up time was 4.38 years (range=0.36-11.24). Most radiotherapy-related adverse events were grade 1 and transient. There were no grade 4 events. Overall survival (OS) at 5 years was 81.3%.
CONCLUSION: The feasibility and safety of aggressive multimodality treatment were good resulting in an excellent median OS of 8.35 years.

Tiainen L, Tanner M, Lahdenperä O, et al.
Bevacizumab Combined with Docetaxel or Paclitaxel as First-line Treatment of HER2-negative Metastatic Breast Cancer.
Anticancer Res. 2016; 36(12):6431-6438 [PubMed] Related Publications
AIM: The study evaluated the efficacy of bevacizumab combined with a taxane-based treatment for advanced breast cancer.
PATIENTS AND METHODS: In this non-randomized phase II study 65 patients received 10 mg/kg bevacizumab i.v. (days 1 and 15, q4w) plus either 50 mg/m(2) docetaxel (days 1 and 15, q4w) or 90 mg/m(2) paclitaxel (days 1,8 and 15, q4w) i.v. until disease progression, maximal response, unacceptable toxicity or the withdrawal of consent. Patients without progression continued bevacizumab at 15 mg/kg i.v. (q3w) alone, or with endocrine therapy. (NCT00979641).
RESULTS: Progression-free survival was 11.3 months (95% confidence interval=9.7-16.0 months) and overall survival was 35.1 months (95% confidence interval=22.2-50.3 months). More than half of the patients (62%) responded at least partially. Bevacizumab-related serious adverse events occurred in 10.8% patients and one patient died because of gastrointestinal perforation.
CONCLUSION: Treating advanced breast cancer with a bevacizumab-containing regimen as the first-line cytotoxic treatment resulted in excellent response rates and long survival.

Fogliata A, Seppälä J, Reggiori G, et al.
Dosimetric trade-offs in breast treatment with VMAT technique.
Br J Radiol. 2017; 90(1070):20160701 [PubMed] Related Publications
OBJECTIVE: Breast planning with volumetric modulated arc therapy (VMAT) has been explored, especially for left-sided breast treatments, with the primary intent of lowering the heart dose and improving target dose homogeneity. As a trade-off, larger healthy tissue volumes would receive low dose levels, with the potential risk of increasing late toxicities and secondary cancer induction, although no clinical data are available today to confirm the risk level. The scope of this work is to explore the dosimetric trade-offs using two different VMAT plans.
METHODS: Two planning strategies for dual-partial-arc VMAT, RA_avoid and RA_full, with and without avoidance sectors, were explored in a cohort of 20 patients, for whole left breast irradiation for 40.05 Gy to the mean target dose in 15 fractions. Common dose objectives included a stringent dose homogeneity, mean dose to the heart <5 Gy, ipsilateral lung (Ilung) <8 Gy, contralateral lung (Clung) <2 Gy and contralateral breast (Cbreast) <3 Gy.
RESULTS: RA_full showed a better dose conformity, lower high-dose spillage in the healthy tissue and lower skin dose. RA_avoid presented a reduction of the mean doses for all critical structures: 51% to the heart, 12% to the Ilung, 81% to the Clung and 73% to the Cbreast. All differences were significant with p < 0.0001.
CONCLUSION: The adaptation of VMAT options to planning objectives reduced significantly the healthy tissue dose levels at the price of some high-dose spillage. Evaluation of the trade-offs for application to the different critical structures should drive in improving the usage of the VMAT technique for breast cancer treatment. Advances in knowledge: Different planning strategies in the same VMAT technique could give significant variations in dose distributions. The choice of the trade-offs would affect the possible future late toxicity and secondary cancer induction risk.

Lundberg M, Munsterhjelm B, Mäkitie A, Leivo I
Immunohistochemical Staining of Histological Fragments Derived from Salivary Gland Tumour Fine-Needle Biopsy Aspirates.
Acta Cytol. 2017; 61(1):17-20 [PubMed] Related Publications
OBJECTIVES: The aim of this study was to describe a method for analysing histological fragments derived from fine- needle aspirate biopsy (FNAB) of salivary gland tumours (SGTs), and to evaluate the use of immunohistochemistry (IHC) on them.
STUDY DESIGN: We reviewed all 509 FNAB pathology reports taken from SGTs at Helsinki University Hospital, Finland, between 1999 and 2009. In 51% of the cases (n = 209) "histo-fragments" had been obtained and 31 had been further analysed by IHC. Of these, 25 (81%) were available for review. We evaluated the benefit of IHC by relating its added value to the preoperative cytological diagnosis and its accuracy compared with the postoperative histological diagnosis.
RESULTS: Most of the samples analysed by IHC were assigned a malignant diagnosis, with 12 different types of malignancy represented. IHC was advantageous in 76% of the cases. In the 108 studies using IHC in this series, antibodies to 36 different antigens were used.
CONCLUSION: Analysis of histo-fragments in FNABs using IHC can be valuable in specific differential diagnostics and raises diagnostic accuracy in SGTs.

Plato N, Martinsen JI, Sparén P, et al.
Occupation and mesothelioma in Sweden: updated incidence in men and women in the 27 years after the asbestos ban.
Epidemiol Health. 2016; 38:e2016039 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: We updated the Swedish component of the Nordic Occupational Cancer (NOCCA) Study through 2009 in order to investigate the incidence of mesothelioma of the peritoneum and pleura in both genders, and explored occupational exposures that may be associated with mesothelioma.
METHODS: The Swedish component of the NOCCA Study includes 6.78 million individuals. Data from this cohort were linked to the population-based Swedish Cancer Registry and Swedish Total Population Registry for three periods between 1961 and 2009, and then further linked to the Swedish NOCCA job-exposure matrix, which includes 25 carcinogenic substances and the corresponding exposure levels for 280 occupations. Multivariate analysis was used to calculate standardized incidence ratios (SIRs) for mesothelioma of the peritoneum and pleura by gender, occupational category, carcinogenic substance, and for multiple occupational exposures simultaneously.
RESULTS: A total of 3,716 incident mesotheliomas were recorded (21.1% in women). We found a significantly increased risk of mesothelioma in 24 occupations, as well as clear differences between the genders. Among men, increased risks of mesothelioma of the pleura were observed in male-dominated occupations, with the greatest elevation of risk among plumbers (SIR, 4.99; 95% confidence interval, 4.20 to 5.90). Among women, increased risks were observed in sewing workers, canning workers, packers, cleaners, and postal workers. In multivariate analysis controlling for multiple occupational exposures, significant associations were only observed between asbestos exposure and mesothelioma.
CONCLUSIONS: Asbestos exposure was associated with mesothelioma incidence in our study. The asbestos ban of 1982 has yet to show any clear effect on the occurrence of mesothelioma in this cohort. Among women, the occupations of canning workers and cleaners showed increased risks of mesothelioma of the pleura without evidence of asbestos exposure.

Joensuu H
Escalating and de-escalating treatment in HER2-positive early breast cancer.
Cancer Treat Rev. 2017; 52:1-11 [PubMed] Related Publications
The current standard adjuvant systemic treatment of early HER2-positive breast cancer consists of chemotherapy plus 12months of trastuzumab, with or without endocrine therapy. Several trials have investigated modifications of the standard treatment that are shorter and less resource-demanding (de-escalation) or regimens that aim at dual HER2 inhibition or include longer than 12months of HER2-targeted treatment (escalation). Seven randomized trials investigate shorter than 12months of trastuzumab treatment duration. The shorter durations were not statistically inferior to the 1-year duration in the 3 trials with survival results available, but 2 of the trials were small and 1 had a relatively short follow-up time of the patients at the time of reporting. The pathological complete response (pCR) rates were numerically higher in all 9 randomized trials that compared chemotherapy plus dual HER2 inhibition consisting of trastuzumab plus either lapatinib, neratinib, or pertuzumab with chemotherapy plus trastuzumab as neoadjuvant treatments, but the superiority of chemotherapy plus dual HER2-inhibition over chemotherapy plus trastuzumab remains to be demonstrated in the adjuvant setting. One year of adjuvant trastuzumab was as effective as 2years of trastuzumab in the HERA trial, and was associated with fewer side-effects. Extending 1-year adjuvant trastuzumab treatment with 1year of neratinib improved disease-free survival in the ExteNET trial, but the patient follow-up times are still short, and no overall survival benefit was reported. Several important trials are expected to report results in the near future and may modify the current standard.

Virtanen E, Kalliala I, Dyba T, et al.
Performance of mRNA- and DNA-based high-risk human papillomavirus assays in detection of high-grade cervical lesions.
Acta Obstet Gynecol Scand. 2017; 96(1):61-68 [PubMed] Related Publications
INTRODUCTION: The aim was to assess the performance of two commercial assays for the detection of high-risk human papillomavirus (hrHPV): Aptima HPV Assay (Hologic, Inc., Marlborough, MA, USA) which detects mRNA of 14 different hrHPV types, and Hybrid Capture 2 HPV DNA test (HC2; Qiagen, Gaithersburg, MD, USA), which detects the DNA of 13 different hrHPV types. Test performance was compared in the settings of a standard colposcopy clinic, among the regular patient flow.
MATERIAL AND METHODS: Two separate cervical cell samples for Aptima and HC2 testing were collected from women referred to colposcopy or a cervical follow-up visit. Altogether, 481 paired samples were analyzed and all positive samples were also tested using the Aptima HPV 16 18/45 Genotype Assay. Results from the two assays were compared directly and with stratification by histology and cytology from the same sampling visit.
RESULTS: The overall agreement between HC2 and Aptima assays was 92.9% (Kappa coefficient of 0.855). The sensitivity and specificity of the assays in detecting CIN2(+) were 92.5 and 58.2% for HC2, and 94.0 and 59.3% for Aptima, respectively. No significant differences between the assays were found (p-values >0.5). Both assays detected all CIN3 (n = 30) and carcinoma (n = 2) cases.
CONCLUSIONS: The mRNA-based Aptima assay and the extensively studied DNA-based HC2 test performed equally well in detecting high-grade cervical lesions. Our data contribute to the growing evidence base indicating that the mRNA-based Aptima assay could be used for the triage of patients with HPV-associated cervical disease.

Park BY, Grisham RN, den Hollander B, et al.
Tumor Inhibition by Enzalutamide in a Xenograft Model of Ovarian Cancer.
Cancer Invest. 2016; 34(10):517-520 [PubMed] Related Publications
OBJECTIVES: To investigate the tumor-suppressive properties of enzalutamide in androgen-driven ovarian cancer.
METHODS: Mice were implanted subcutaneously with OVCAR-3 cells and treated with dihydrotestosterone in combination with enzalutamide or vehicle control. Tumor volumes were measured twice weekly until day 56.
RESULTS: Dihydrotestosterone exposure led to a significant increase in tumor growth, while concomitant treatment with enzalutamide led to significant reductions in tumor volume compared to the androgen-exposed groups.
CONCLUSIONS: We present the first evidence that the second-generation anti-androgen enzalutamide may possess efficacy in the treatment of ovarian cancer, paving the way for the future clinical trials.

Kekki H, Peltola M, van Vliet S, et al.
Improved cancer specificity in PSA assay using Aleuria aurantia lectin coated Eu-nanoparticles for detection.
Clin Biochem. 2017; 50(1-2):54-61 [PubMed] Related Publications
OBJECTIVES: The objective was to study the differences in PSA fucosylation obtained from LNCaP and PC-3 prostate cancer cell lines, seminal plasma PSA and recombinant precursor form of PSA expressed in baculovirus, using Aleuria aurantia lectin (AAL). The aim was to assess whether differences in fucosylation (Fucα1-6/3GlcNAc carbohydrates) of PSA either in urine, blood or tissue enable the discrimination of patients with prostate cancer (PCa) from benign prostatic hyperplasia (BPH) and young males.
DESIGN AND METHODS: Two novel lectin-immunoassays were developed for the analysis of fucosylation of PSA by measuring the time-resolved fluorescence of europium chelate. The lectin-immunoassays utilize free PSA-specific Fab-fragments for capturing the analyte and either europium-labeled AAL or AAL coupled to Eu(III)-chelate-dyed nanoparticles for the detection of Fucα1-6/3GlcNAc carbohydrates on PSA.
RESULTS: Using the novel lectin-immunoassays, we showed higher levels of Fucα1-6/3GlcNAc on PSA derived from LNCaP and PC-3 cells compared to seminal plasma PSA. With the more sensitive nanoparticle-based lectin-immunoassay we detected a statistically significant increase in the PSA fucosylation in PCa tissue compared to benign tissue (p=0.001) and in urine from PCa patients compared to BPH patients (p=0.030), and an even greater discrimination (p=0.010) when comparing BPH patients to PCa patients with Gleason score≥7.
CONCLUSIONS: AAL coupled to Eu(III)-chelate-dyed nanoparticles improved the sensitivity of immunoassay for the detection of Fucα1-6/3GlcNAc structures on PSA. The preliminary findings show an increased fucosylation in PCa compared to benign conditions. Further validation is required to assess the true clinical utility of AAL in PCa diagnosis.

Elzagheid A, Emaetig F, Elsaghayer W, et al.
Neurofibromin Expression is Associated with Aggressive Disease and Poor Outcome in Colorectal Carcinoma.
Anticancer Res. 2016; 36(10):5301-5306 [PubMed] Related Publications
AIM: To assess the predictive and prognostic value of neurofibromin (NF) expression in colorectal carcinoma (CRC).
MATERIALS AND METHODS: The present series consists of archival samples from 191 patients with stage I, II, III, or IV CRC treated between 1981 and 1990 at the Turku University Hospital (Finland). Tumor biopsies as microarray blocks were analyzed for expression of NF by immunohistochemistry. Different grading systems were tested for NF expression.
RESULTS: A significant correlation between NF expression and tumor localization was found, with tumors arising in the colon showing intense NF expression more often than those arising in the rectum (p=0.014). Higher expression of NF was more common in tumors not responding to treatment (p=0.004). Tumors with multiple metastases showed higher expression of NF than those with single metastasis only (p=0.025). Furthermore, NF expression showed a borderline (p=0.068) correlation with gender; tumors of women showed higher NF expression that those of males. On the other hand, NF expression was not significantly associated with tumor recurrence, age, lymph node involvement, tumor grade and tumor stage or disease outcome.
CONCLUSION: Positive NF expression in CRC is a sign of aggressive disease and poor outcome.

Ylivinkka I, Keski-Oja J, Hyytiäinen M
Netrin-1: A regulator of cancer cell motility?
Eur J Cell Biol. 2016; 95(11):513-520 [PubMed] Related Publications
Netrins form a family of secreted and membrane-associated proteins, netrin-1 being the prototype and most investigated member of the family. The major physiological functions of netrin-1 lie in the regulation of axonal development as well as morphogenesis of different branched organs, by promoting the polarity of migratory/invasive front of the cell. On the other hand, netrin-1 acts as a factor preventing cell apoptosis. These events are mediated via a range of different receptors, including UNC5 and DCC-families. Cancer cells often employ developmental pathways to gain survival and motility advantage. Within recent years, there has been increasing number of observations of upregulation of netrin-1 expression in different forms of cancer, and the increased expression of netrin-1 has been linked to its functions as a survival and invasion promoting factor. We review here recent advances in the netrin-1 related developmental processes that may be of special interest in tumor biology, in addition to the known functions of netrin-1 in tumor biology with special focus on cancer cell migration.

Will OM, Purcz N, Chalaris A, et al.
Increased survival rate by local release of diclofenac in a murine model of recurrent oral carcinoma.
Int J Nanomedicine. 2016; 11:5311-5321 [PubMed] Free Access to Full Article Related Publications
Despite aggressive treatment with radiation and combination chemotherapy following tumor resection, the 5-year survival rate for patients with head and neck cancer is at best only 50%. In this study, we examined the therapeutic potential of localized release of diclofenac from electrospun nanofibers generated from poly(D,L-lactide-co-glycolide) polymer. Diclofenac was chosen since anti-inflammatory agents that inhibit cyclooxygenase have shown great potential in their ability to directly inhibit tumor growth as well as suppress inflammation-mediated tumor growth. A mouse resection model of oral carcinoma was developed by establishing tumor growth in the oral cavity by ultrasound-guided injection of 1 million SCC-9 cells in the floor of the mouth. Following resection, mice were allocated into four groups with the following treatment: 1) no treatment, 2) implanted scaffolds without diclofenac, 3) implanted scaffolds loaded with diclofenac, and 4) diclofenac given orally. Small animal ultrasound and magnetic resonance imaging were utilized for longitudinal determination of tumor recurrence. At the end of 7 weeks following tumor resection, 33% of mice with diclofenac-loaded scaffolds had a recurrent tumor, in comparison to 90%-100% of the mice in the other three groups. At this time point, mice with diclofenac-releasing scaffolds showed 89% survival rate, while the other groups showed survival rates of 10%-25%. Immunohistochemical staining of recurrent tumors revealed a near 10-fold decrease in the proliferation marker Ki-67 in the tumors derived from mice with diclofenac-releasing scaffolds. In summary, the local application of diclofenac in an orthotopic mouse tumor resection model of oral cancer reduced tumor recurrence with significant improvement in survival over a 7-week study period following tumor resection. Local drug release of anti-inflammatory agents should be investigated as a therapeutic option in the prevention of tumor recurrence in oral squamous carcinoma.

He T, Surdez D, Rantala JK, et al.
High-throughput RNAi screen in Ewing sarcoma cells identifies leucine rich repeats and WD repeat domain containing 1 (LRWD1) as a regulator of EWS-FLI1 driven cell viability.
Gene. 2017; 596:137-146 [PubMed] Related Publications
A translocation leading to the formation of an oncogenic EWS-ETS fusion protein defines Ewing sarcoma. The most frequent gene fusion, present in 85 percent of Ewing sarcomas, is EWS-FLI1. Here, a high-throughput RNA interference screen was performed to identify genes whose function is critical for EWS-FLI1 driven cell viability. In total, 6781 genes were targeted by siRNA molecules and the screen was performed both in presence and absence of doxycycline-inducible expression of the EWS-FLI1 shRNA in A673/TR/shEF Ewing sarcoma cells. The Leucine rich repeats and WD repeat Domain containing 1 (LRWD1) targeting siRNA pool was the strongest hit reducing cell viability only in EWS-FLI1 expressing Ewing sarcoma cells. LRWD1 had been previously described as a testis specific gene with only limited information on its function. Analysis of LRWD1 mRNA levels in patient samples indicated that high expression associated with poor overall survival in Ewing sarcoma. Gene ontology analysis of LRWD1 co-expressed genes in Ewing tumors revealed association with DNA replication and analysis of differentially expressed genes in LRWD1 depleted Ewing sarcoma cells indicated a role in connective tissue development and cellular morphogenesis. Moreover, EWS-FLI1 repressed genes with repressive H3K27me3 chromatin marks were highly enriched among LRWD1 target genes in A673/TR/shEF Ewing sarcoma cells, suggesting that LRWD1 contributes to EWS-FLI1 driven transcriptional regulation. Taken together, we have identified LRWD1 as a novel regulator of EWS-FLI1 driven cell viability in A673/TR/shEF Ewing sarcoma cells, shown association between high LRWD1 mRNA expression and aggressive disease and identified processes by which LRWD1 may promote oncogenesis in Ewing sarcoma.

Køstner AH, Kersten C, Löwenmark T, et al.
The prognostic role of systemic inflammation in patients undergoing resection of colorectal liver metastases: C-reactive protein (CRP) is a strong negative prognostic biomarker.
J Surg Oncol. 2016; 114(7):895-899 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Systemic inflammation has been associated with poor survival in several tumor types, but has been less extensively studied in resectable metastatic disease. The aim of the present study was to evaluate the prognostic role of CRP in colorectal cancer patients with liver metastases (CRLM) compared to conventional tumor- and patient-related clinicopathological features as well as other indicators of the systemic inflammatory response (SIR).
METHODS: A multinational retrospective study of 492 CRLM patients undergoing potentially curative resection of liver metastases between 1999 and 2009. Clinicopathological findings and the SIR markers CRP, hypoalbuminemia, and their combined Glasgow Prognostic Score (GPS) were analyzed.
RESULTS: Multivariate analysis showed that preoperative CRP >10 mg/L was a strong predictor of compromised survival (HR = 1.72, 95%CI 1.84-2.50, P < 0.01). Patients with CRP ≤10 mg/L had a median survival of 4.27 years compared to only 47 days in patients with CRP ≥30 mg/L (P < 0.01). Similarly, increased GPS was independently predictive of poor survival (HR 1.67, 95%CI 1.22-2.27, P < 0.01), but hypoalbuminemia alone did not have significant prognostic value.
CONCLUSIONS: CRP alone is a strong prognostic factor, following curative resection of colorectal liver metastases and should be taken into consideration when selecting treatment strategies in CRLM patients. J. Surg. Oncol. 2016;114:895-899. © 2016 2016 Wiley Periodicals, Inc.

Veskimäe K, Staff S, Grönholm A, et al.
Assessment of PARP protein expression in epithelial ovarian cancer by ELISA pharmacodynamic assay and immunohistochemistry.
Tumour Biol. 2016; 37(9):11991-11999 [PubMed] Related Publications
Targeting Poly (ADP-ribose) polymerase 1 (PARP-1) involved in base excision repair (BER) has been shown to be a clinically effective treatment strategy in epithelial ovarian cancer (EOC) defective in homologous recombination (HR). The aim of this study was to evaluate fresh EOC tumor tissue in regard to PAR (Poly (ADP-ribose)) concentration as a surrogate marker for PARP activity and PARP protein expression in archival samples by immunohistochemistry (IHC). The prospective study cohort consisted of 57 fresh tumor samples derived from patients undergoing primary (n = 38) or interval debulking surgery (n = 19) for EOC and parallel archival paraffin-embedded tumor samples. PARP activity in fresh frozen tumor tissue was assessed by an enzymatic chemiluminescence assay and PARP protein expression in paraffin-embedded tumor tissue by IHC. No correlation was detected between PARP enzyme activity and PARP staining by IHC (p = 0.82). High PARP activity was associated with platinum sensitivity both in the entire study cohort (p = 0.022) and in the high-grade subgroup (p = 0.017). High PARP activity was also associated with improved progression-free survival (PFS) (32 vs 14 months, log-rank p = 0.009). However, PARP immunostaining pattern was not predictive of patient survival. In conclusion, we present a novel finding of high PARP activity associated with platinum sensitivity and improved PFS in EOC. There was no association between PARP IHC and pharmacodynamic assay, and the correlation of PARP IHC with clinico-pathological characteristics and patient survival was poor. Pharmacodynamic assay rather than IHC seems to reflect better biologically significant PARP.

Färkkilä A, Zauli G, Haltia UM, et al.
Circulating levels of TNF-related apoptosis inducing-ligand are decreased in patients with large adult-type granulosa cell tumors-implications for therapeutic potential.
Tumour Biol. 2016; 37(9):11909-11916 [PubMed] Related Publications
Targeted treatments are needed for advanced adult-type granulosa cell tumors (AGCTs). We set out to assess tumor tissue and circulating levels of TNF-related apoptosis-inducing ligand (TRAIL), a promising anti-cancer cytokine, in patients affected by AGCT. We analyzed tissue expression of TRAIL in 127 AGCTs using immunohistochemistry or RT-PCR. Soluble TRAIL was measured by means of ELISA from 141 AGCT patient serum samples, as well as the conditioned media of 15 AGCT patient-derived primary cell cultures, and the KGN cell line. Tissue and serum TRAIL levels were analyzed in relationship with clinical parameters, and serum estradiol, FSH, and LH levels. We found that AGCT samples expressed TRAIL mRNA and protein at levels comparable to normal granulosa cells. AGCT cells did not release soluble TRAIL. TRAIL protein levels were decreased in tumors over 10 cm in diameter (p = 0.04). Consistently, circulating TRAIL levels correlated negatively to tumor dimension (p = 0.01). Circulating TRAIL levels negatively associated with serum estradiol levels. In multiple regression analysis, tumor size was an independent factor contributing to the decreased levels of soluble TRAIL in AGCT patients. AGCTs associate with significantly decreased tumor tissue and serum TRAIL levels in patients with a large tumor mass. These findings encourage further study of agonistic TRAIL treatments in patients with advanced or recurrent AGCT.

Veijalainen O, Kares S, Kujala P, et al.
Human papillomavirus test with cytology triage in organized screening for cervical cancer.
Acta Obstet Gynecol Scand. 2016; 95(11):1220-1227 [PubMed] Related Publications
INTRODUCTION: In randomized studies, testing for high-risk (HR) human papillomavirus (hrHPV) has been more sensitive than conventional cytology in detecting cervical intraepithelial neoplasia (CIN). The aim of this study was to evaluate the performance of HPV testing in the setting of an organized routine screening program.
MATERIAL AND METHODS: Since 2012, 35- to 60-year-old women living in the city of Tampere have been screened with the Abbott RealTime hrHPV test. HPV-negative women are referred to the next screening round in five years. HPV-positive women are triaged with conventional cytology, and women with at least low-grade squamous intraepithelial lesion (LSIL(+) ) are referred to colposcopy. The remaining HPV-positive women are referred for re-testing after 12 months, and then all HPV-positive women are referred to colposcopy. The data from the last cohort with cytological screening (screened in 2011) is presented for comparison.
RESULTS: A total 5637 (70%) women attended the first round of HPV screening, and 369 were HPV-positive. Of them, 54 women LSIL(+) were referred to colposcopy, resulting in 16 CIN2(+) lesions found. Of the remaining HPV-positive women, 66% were still positive one year later, and were referred to colposcopy, with 18 additional CIN2(+) lesions found. The attendance rate to the last round of cytological screening was 71% (5814 women). Sixty-four women with LSIL(+) cytology were referred to colposcopy, and 11 CIN2(+) lesions were found. Of the 777 women with borderline cytology and scheduled for reflex screening in the following year, 109 (19%) had ASC-US(+) , and 57 underwent colposcopy, resulting in six additional CIN2(+) lesions found. The total detection rate of CIN2(+) was significantly higher in the HPV-screened cohort (6.0/1000 vs. 2.9/1000, p = 0.015). However, the total colposcopy rate was 4% vs. 2%, respectively (p < 0.001).
CONCLUSION: Human papillomavirus testing also seems to be more sensitive than cytology in detecting CIN2(+) lesions in the setting of a routine organized screening program, besides in the context of randomized trials. The problem of an increased colposcopy rate needs to be addressed in the future.

Rice TW, Apperson-Hansen C, DiPaola LM, et al.
Worldwide Esophageal Cancer Collaboration: clinical staging data.
Dis Esophagus. 2016; 29(7):707-714 [PubMed] Related Publications
To address uncertainty of whether clinical stage groupings (cTNM) for esophageal cancer share prognostic implications with pathologic groupings after esophagectomy alone (pTNM), we report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for clinically staged patients from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted data using variables with standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 22,123 clinically staged patients, 8,156 had squamous cell carcinoma, 13,814 adenocarcinoma, 116 adenosquamous carcinoma, and 37 undifferentiated carcinoma. Patients were older (62 years) men (80%) with normal body mass index (18.5-25 mg/kg(2) , 47%), little weight loss (2.4 ± 7.8 kg), 0-1 ECOG performance status (67%), and history of smoking (67%). Cancers were cT1 (12%), cT2 (22%), cT3 (56%), cN0 (44%), cM0 (95%), and cG2-G3 (89%); most involved the distal esophagus (73%). Non-risk-adjusted survival for squamous cell carcinoma was not distinctive for early cT or cN; for adenocarcinoma, it was distinctive for early versus advanced cT and for cN0 versus cN+. Patients with early cancers had worse survival and those with advanced cancers better survival than expected from equivalent pathologic categories based on prior WECC pathologic data. Thus, clinical and pathologic categories do not share prognostic implications. This makes clinically based treatment decisions difficult and pre-treatment prognostication inaccurate. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient characteristics, cancer categories, and treatment characteristics and should direct 9th edition data collection.

Rice TW, Lerut TE, Orringer MB, et al.
Worldwide Esophageal Cancer Collaboration: neoadjuvant pathologic staging data.
Dis Esophagus. 2016; 29(7):715-723 [PubMed] Related Publications
To address uncertainty of whether pathologic stage groupings after neoadjuvant therapy (ypTNM) for esophageal cancer share prognostic implications with pathologic groupings after esophagectomy alone (pTNM), we report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for pathologically staged cancers after neoadjuvant therapy from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted data using variables with standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 7,773 pathologically staged neoadjuvant patients, 2,045 had squamous cell carcinoma, 5,686 adenocarcinoma, 31 adenosquamous carcinoma, and 11 undifferentiated carcinoma. Patients were older (61 years) men (83%) with normal (40%) or overweight (35%) body mass index, 0-1 Eastern Cooperative Oncology Group performance status (96%), and a history of smoking (69%). Cancers were ypT0 (20%), ypT1 (13%), ypT2 (18%), ypT3 (44%), ypN0 (55%), ypM0 (94%), and G2-G3 (72%); most involved the distal esophagus (80%). Non-risk-adjusted survival for yp categories was unequally depressed, more for earlier categories than later, compared with equivalent categories from prior WECC data for esophagectomy-alone patients. Thus, survival of patients with ypT0-2N0M0 cancers was intermediate and similar regardless of ypT; survival for ypN+ cancers was poor. Because prognoses for ypTNM and pTNM categories are dissimilar, prognostication should be based on separate ypTNM categories and groupings. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient, cancer, and treatment characteristics and should direct 9th edition data collection.

Rice TW, Chen LQ, Hofstetter WL, et al.
Worldwide Esophageal Cancer Collaboration: pathologic staging data.
Dis Esophagus. 2016; 29(7):724-733 [PubMed] Related Publications
We report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for patients with pathologically staged cancer of the esophagus and esophagogastric junction after resection or ablation with no preoperative therapy from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted de-identified data using standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 13,300 patients, 5,631 had squamous cell carcinoma, 7,558 adenocarcinoma, 85 adenosquamous carcinoma, and 26 undifferentiated carcinoma. Patients were older (62 years) men (80%) with normal body mass index (51%), little weight loss (1.8 kg), 0-2 ECOG performance status (83%), and a history of smoking (70%). Cancers were pT1 (24%), pT2 (15%), pT3 (50%), pN0 (52%), pM0 (93%), and pG2-G3 (78%); most involved distal esophagus (71%). Non-risk-adjusted survival for both squamous cell carcinoma and adenocarcinoma was monotonic and distinctive across pTNM. Survival was more distinctive for adenocarcinoma than squamous cell carcinoma when pT was ordered by pN. Survival for pTis-1 adenocarcinoma was better than for squamous cell carcinoma, although monotonic and distinctive for both. WECC pathologic staging data is improved over that of the 7th edition, with more patients studied and patient and cancer variables collected. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient, cancer, and treatment characteristics, and should direct 9th edition data collection. However, the role of pure pathologic staging as the principal point of reference for esophageal cancer staging is waning.

Syrjänen S, Rautava J
Vaccination Expectations in HNSCC.
Recent Results Cancer Res. 2017; 206:257-267 [PubMed] Related Publications
HPV-associated head and neck squamous cell carcinoma (HNSCC), more specifically the incidence of oropharyngeal cancer, is dramatically increasing in industrialized countries. According to what has been learned from anogenital vaccination programs, there are reasons to believe that current human papillomavirus (HPV) vaccinations may be potentially effective also against HNSCC. However, before specific results on HNSCC are available, one must keep in mind that carcinogenesis in the head and neck region may differ from that of the anogenital tract. Furthermore, the current evidence supports the view that HPV infection is much more complex than simply a sexually transmitted disease. HPV is present in the semen, placenta and in the newborns, and these infections of the newborns create cell-mediated immunity (CMI) against HPV, including the T memory cells. Acquisition of HPV infection in early life will rise new series of questions in the field of HPV vaccination.

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