History of HPV in HPV-positive elderly women.

Background: The aim of this study was to examine the natural course of HPV infection in women of 60 years and older who were HPV positive at inclusion, and any association between HPV positivity in historical samples and dysplasia outcome. Methods: Eighty-nine women aged 60-82 years, who tested positive for HPV between 2012 and 2016 were included. Sampling for cytology and/or histology was also performed. HPV genotyping was carried out on archived material back to 1999. Results: Of the 89 HPV-positive women 16 had HSIL, 34 had LSIL and 39 were benign at inclusion. Of the women with HSIL, 50.0% had the same HPV type in the archive samples, 12.5% had another type, and 37.5% were HPV negative. Among the 34 women with LSIL, 47.1% had the same HPV type in archive samples, 5.8% had another type, and 47.1% were HPV negative. Of the 39 women without dysplasia at inclusion, 25.6% had the same HPV type in archive samples, 5.1% had another HPV type and 69.2% were HPV negative. Conclusion: Surprisingly few of the elderly women thus seem to have a history with the same or any HPV infection the years before being diagnosed with an HPV infection and dysplasia. The significance of an HPV infection for dysplasia development in elderly women is still not fully understood.

Full genotyping and FAM19A4/miR124-2 methylation analysis in high-risk human papillomavirus-positive samples from women over 30 years participating in cervical cancer screening in Örebro, Sweden.

Currently, cervical cancer prevention is undergoing comprehensive development regarding human papillomavirus (HPV) vaccination and cervical cancer screening. In Sweden and many other countries, high coverage vaccinated cohorts are entering screening within the next few years. This entails demands for baseline HPV genotype data across the screening age range for surveillance and a basis for screening program adjustment. In 2016, Örebro County, Sweden, changed to primary HPV screening using HPV mRNA testing followed by cytology triage. An alternative triage method to cytology could allow for a fully molecular screening algorithm and be implemented in a screening program where self-sampling is included. Hypermethylation analysis of the human genes FAM19A4/miR124-2 has been suggested as a promising triage method. HPV mRNA-positive screening samples (n = 529) were included and subjected to genotyping targeting a broad range of both low-risk and high-risk genotypes in addition to hypermethylation analysis of the two human genes FAM19A4/miR124-2. Data were connected to cytological and histological status and age. The most commonly detected genotypes were HPV31, 16, and 52. In addition, HPV18 was one of the most common genotypes in high-grade squamous intraepithelial lesions (HSILs) samples. In relation to available vaccines, 26% of the women with histological HSIL or cancer (≥HSIL) tested positive for only hrHPV included in the quadrivalent vaccine and 77% of the genotypes in the nonavalent vaccine. According to these figures, a relatively large proportion of the HSILs will probably remain, even after age cohorts vaccinated with the quadrivalent vaccine enter the screening program. Hypermethylation positivity was associated with increasing age, but no HPV-related independently predictive factors were found. Accordingly, age needs to be considered in development of future screening algorithms including triage with hypermethylation methodology.

Effectiveness and costs of an implemented primary HPV cervical screening programme in Sweden - A population based cohort study.

Swedish guidelines recommend cervical screening with primary HPV for women ≥ 30 years of age. The aim of this study was to compare an implemented HPV cervical screening programme in the Region of Örebro County from September 1, 2016, with the former cytology-based screening programme. The clinical effectiveness by means of number of high-grade squamous intraepithelial lesions (HSILs) and cervical cancer cases detected in histology within 12 months after the screening test, together with cost implications were the main outcomes. Data were retrieved from the Swedish National Cervical Screening Registry between the years 2014-2015 (cytology based screening) and 2017-2018(HPV based screening), including screening information such as invitations and cytology and histology diagnoses. The detection rate of HSIL + among women ≥ 30 years of age was 1.2 times higher with HPV screening, but data revealed an increase in direct colposcopy referral rate by 54% and a higher percentage of irrelevant findings (≤LSIL). Screening based on HPV for women ≥ 30 has increased yearly cost from 1 to 1.3 million EUR, while increasing the number of HSIL + identified. Two thirds of the total costs are from visits for screening samples in the programme. HPV screening detected more cases of HSIL + compared to cytology screening among women ≥ 30 although high colposcopy rate, high rate of clinical irrelevant findings and higher costs were shown in the HPV-based screening programme, which implies that alterations in the screening programme in the future are important to consider.

Evaluation of dyskerin expression and the Cajal body protein WRAP53ß as potential prognostic markers for patients with primary vaginal carcinoma.

Primary vaginal cancer (PVC) is a rare gynaecological malignancy, which, at present, lacks appropriate biomarkers for prognosis. The proteins dyskerin and WD repeat containing antisense to TP53 (WRAP53ß), both of which exert their functions in the telomerase holoenzyme complex, have been shown to be upregulated in different cancer types. These proteins have also been proposed as prognostic markers in some types of cancer. The aim of the present study was to examine the expression patterns of dyskerin and WRAP53ß in patients with PVC. Moreover, as part of a search for effective biomarkers to evaluate prognosis in PVC, the expression of these two proteins and their potential association with clinical variables and survival were also evaluated. The expression of dyskerin and WRAP53ß was assessed in PVC tumour samples from 68 patients using immunohistochemistry. The majority of tumour samples showed low and moderate expression levels of dyskerin. Upregulation of dyskerin in tumour samples was significantly associated with a shorter survival time and a poorer cancer-specific survival rate. WRAP53ß was also expressed in most of the cells but was not significantly associated with clinical variables or survival. This study demonstrates that upregulation of dyskerin is significantly associated with poor prognosis. Thus, dyskerin may serve as a promising prognostic marker and a potential putative therapeutic target in PVC.

Low level of interobserver concordance in assessing histological subtype and tumor grade in patients with penile cancer may impair patient care.

Differentiation between penile squamous cell carcinoma patients who can benefit from limited organ-sparing surgery and those at significant risk of lymph node metastasis is based on histopathological prognostic factors including histological grade and tumor histological subtype. We examined levels of interobserver and intraobserver agreement in assessment of histological subtype and grade in 207 patients with penile squamous cell carcinoma. The cases were assessed by seven pathologists from three hospitals located in Sweden and Italy. There was poor to moderate concordance in assessing both histological subtype and grade, with Fleiss kappas of 0.25 (range: 0.02-0.48) and 0.23 (range: 0.07-0.55), respectively. When choosing HPV-associated and non-HPV-associated subtypes, interobserver concordance ranged from poor to good, with a Fleiss kappa value of 0.36 (range: 0.02-0.79). A re-review of the slides by two of the pathologists showed very good intraobserver concordance in assessing histological grade and subtype, with Cohen's kappa values of 0.94 and 0.91 for grade and 0.95 and 0.84 for subtype. Low interobserver concordance could lead to undertreatment and overtreatment of many patients with penile cancer, and brings into question the utility of tumor histological subtype and tumor grade in determining patient treatment in pT1 tumors.

Detection of High- and Low-Risk HPV DNA in Archived Breast Carcinoma Tissues from Ethiopian Women.

BACKGROUND: Human papilloma virus (HPV) is involved in the development of cancer of the cervix, mouth and throat, anus, penis, vulva, or vagina, but it has not been much considered as a cause of breast cancer. Recently, a number of investigations have linked breast cancer to viral infections. High-risk HPV types, predominantly HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, are established as carcinogens in humans. In this study we aimed to detect 19 high-risk and 9 low-risk HPVs from archived breast tumor tissue among Ethiopian women. METHODS: In this study, 75 breast cancer patients from Tikur Anbassa Specialized Hospital in Addis Ababa (Ethiopia) were included. HPV detection and genotyping were done using the novel Anyplex™ II HPV28 Detection Assay at the Orebro University Hospital, Sweden. The Anyplex™ II PCR System detects 19 high-risk HPV types (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 69, 73, and 82) and 9 low-risk HPV types (6, 11, 40, 42, 43, 44, 54, 61, and 70). IHC for p16 was done using an automated system, the Dako Autostainer Link. RESULTS: Out of the 75 valid tests, two were found to be positive (2.7%) for HPV. One of the cases was positive for the high-risk HPV16 genotype while the other was positive both for the high-risk HPV39 and the low-risk HPV6. The cell cycle protein p16 was highly expressed in the case positive for the high-risk HPV16, but it was not expressed in the case positive for HPV39. CONCLUSION: The prevalence of HPV is low in Ethiopian breast cancer patients, but the role played by HPV in breast carcinogenesis among Ethiopian breast cancer patients cannot be commented based on these observations.

Presence of hyaluronan in lung alveoli in severe Covid-19: An opening for new treatment options?

Severe coronavirus disease 2019 (Covid-19) is characterized by inflammation of the lungs with increasing respiratory impairment. In fatal Covid-19, lungs at autopsy have been filled with a clear liquid jelly. However, the nature of this finding has not yet been determined. The aim of the study was to demonstrate whether the lungs of fatal Covid-19 contain hyaluronan, as it is associated with inflammation and acute respiratory distress syndrome (ARDS) and may have the appearance of liquid jelly. Lung tissue obtained at autopsy from three deceased Covid-19 patients was processed for hyaluronan histochemistry using a direct staining method and compared with staining in normal lung tissue. Stainings confirmed that hyaluronan is obstructing alveoli with presence in exudate and plugs, as well as in thickened perialveolar interstitium. In contrast, normal lungs only showed hyaluronan in intact alveolar walls and perivascular tissue. This is the first study to confirm prominent hyaluronan exudates in the alveolar spaces of Covid-19 lungs, supporting the notion that the macromolecule is involved in ARDS caused by SARS-CoV-2. The present finding may open up new treatment options in severe Covid-19, aiming at reducing the presence and production of hyaluronan in the lungs.

Distribution and characteristics of androgen receptor (AR) in breast cancer among women in Addis Ababa, Ethiopia: A cross sectional study.

Evaluation of the role of androgen receptor (AR) in the biology of breast cancer is an emerging area of research. There are compelling evidences that AR expression may be used to further refine breast cancer molecular subtyping with prognostic and therapeutic implications. Many studies indicated co-expression of AR with the hormonal receptors in breast cancer has a favorable prognosis. AR is also investigated by many researchers as a potential therapeutic target in treatment of breast cancer. Studies on the frequency and distribution of AR in breast cancer among Africans is barely available. Given the heightened interest to understand its role in breast cancer, we determined AR expression and assessed its association with clinicopathological parameters among Ethiopian women. In this study, 112 newly diagnosed patient with invasive breast cancer at Tikur Anbessa Specialized Hospital were enrolled. Immunohistochemical assessment of AR, ER, PR, Ki67 and HER2 were performed using tissue microarrays (TMA) constructed from their primary tumor block. Out of the 112 participants, 91 (81%) were positive for AR expression and the remaining 21 participants (19%) were negative for AR expression. Expression of AR in ER+, HER2+ and TNBC cases were 93%, 83% and 48% respectively. Our study reveals AR is expressed in a significant number of breast cancers patients and this may indicate that breast cancers cases in Ethiopia have favorable prognosis and could benefit from progresses in AR targeted treatments. Since AR expression has important consequences on the prognosis and treatment of breast cancer, further studies with an increased number of participants is necessary to confirm our reports.

Prevalence of HPV and pathological changes among women 70 years of age, 10 years after exclusion from the Swedish cervical cancer screening program.

PURPOSE: Örebro County introduced an updated screening program 2016 with primary HPV test for women over 30 years and prolonged screening, increasing the cut-off age from 56-60 to 64-70. The aim of this study was to investigate the prevalence of HPV genotypes and their correlation to histological changes in women, 10 years after exclusion from the screening program, due to an eventual implementation of a catch-up program including all women aged 60-70. METHODS: All women in Örebro County, born 1,946 (n = 1,968), were invited to a liquid-based cell sample with primary HPV screening. Samples were analyzed for hrHPV mRNA and positive samples were genotyped. hrHPV positive women were offered to do a conization. RESULTS: Out of 809 participants, 31 (3.8%) were hrHPV positive, of these 22 did a conization. Histologically, 5/22 (23%) had LSIL and 5/22 (23%) had HSIL. Normal histology was found in 12/22 (55%). The most prevalent genotypes were HPV 16, 33, 52, 56, and 68. Of the women with HSIL, one case of cervical cancer was confirmed in a recone biopsy after 4 months. CONCLUSION: The study showed considerable prevalence of hrHPV and histologically confirmed LSIL/HSIL. These data led to catch-up screening for women between 60 and 70 years when overlapping two screening strategies.

HPV-negative Tumors in a Swedish Cohort of Cervical Cancer.

Despite the common perception that the human papilloma virus (HPV) is a requirement for the development of cervical cancer (CC), a considerable number of CCs test HPV negative. Presently, many countries are shifting to HPV primary CC screening, and it is of importance to increase the knowledge about the group of CCs that test HPV negative. The aim of this study was to reinvestigate a proportion of cervical tumors with a primary negative or invalid test result. Reinvestigation with repeated genotyping (targeting L1) was followed by analysis with an alternative target method (targeting E6/E7) on existing or additional tumor material. Consistently negative tumors were histologically evaluated, and cases with low or lacking tumor cell content, consistent invalid test results, or with suspicion of other than cervical origin were excluded. HPV-negative cases were thereafter subjected to immunohistochemistry (Cytokeratin 5, pan cytokeratin, protein 63, P16, and P53). The HPV-negative proportion could after reinvestigation be reduced by one-half (14%-7%). Additional positive samples were often detected in late polymerase chain reaction cycles, with an alternative (E6/E7) or the same (L1) target, or with a method using shorter amplicon lengths. Confirmed HPV negativity was significantly associated with worse prognosis, high patient age, longer storage time, and adenocarcinoma histology. Some of the HPV-negative cases showed strong/diffuse p16 immunoreactivity, indicating some remaining false-negative cases. False HPV negativity in this cohort was mainly linked to methodological limitations in the analysis of stored CC material. The small proportion of presumably true HPV-negative adenocarcinomas is not a reason for hesitation in revision to CC screening with primary HPV testing.

HPV-based screening for cervical cancer among women 55-59 years of age.

AIM: Many cervical cancers occurs among women over 65 and prevalence of HPV genotypes in this age cohort is sparingly studied. One aim of this study was to study the prevalence and distribution of HPV genotypes in women 55-59 years, with normal cytology when exiting the screening program. Secondly, HPV clearance as well as the value of HPV genotyping and/or liquid based cytology as triage tests for identifying histological dysplasia among women with persistent HPV was studied. METHODS: Women that exited the screening program with normal cytology, between the years 2012-2014, in Örebro County, Sweden, were invited to this study. A total of 2946 samples were analyzed with a broad-spectrum assay to detect both hrHPV and lrHPV in order to investigate the distribution of genotypes. In the consent group, women with a positive hrHPV test were offered a follow-up test and a cone biopsy for histological confirmation, and a follow up sample 6 months post cone. RESULTS: The overall prevalence of hrHPV was 7.4% and 59% of them remained hrHPV positive in a follow-up test after 12 months. A total of 99 women had a cone biopsy done, where 19% showed histological dysplasia. HPV 53 was the most common genotype, and among women with histology confirmed LSIL or HSIL, HPV 31 was most common. A positive hrHPV result showed a PPV of 25% for LSIL+ and 12.5%for HSIL+. Using detection of HPV 16/18 genotypes as a triage test for hrHPV positive tests, indicated FNR for histological LSIL+ and HSIL+ of 94% and 87.5% respectively, whilst triage based on cervical cytology had a FNR of 69% for LSIL+ and 37.5% for HSIL+. CONCLUSION: The most common hrHPV genotypes among women 55-59 years of age were non HPV16/18 genotypes, and in this population, these genotypes represented most of the histological verified HSIL lesions. This result does not support the proposition of a HPV 16/18 triaging test after a positive hrHPV test as a marker of histological HSIL+ cervical lesions in women over 55 years of age. Similarly, cytological triage after a positive hrHPV showed no additional benefit in this population. Specific triaging tests should be validated to follow post-menopausal women with a positive hrHPV test.

HPV16 viral characteristics in primary, recurrent and metastatic vulvar carcinoma.

Vulvar carcinoma is the fourth most common gynecological malignancy. Two separate carcinogenic pathways are suggested, where one is associated with the human papillomavirus (HPV) and HPV16 the most common genotype. The aim of this study was to evaluate HPV-markers in a set of primary tumors, metastases and recurrent lesions of vulvar squamous cell carcinomas (VSCC). Ten HPV16-positive VSCC with metastatic regional lymph nodes, distant lymphoid/hematogenous metastases or local recurrent lesions were investigated for HPV genotype, HPV16 variant, HPV16 viral load, HPV16 integration and HPV16 E2BS3 and 4 methylation. In all 10 analyzed case series, the same HPV genotype (HPV16), HPV16 variant and level of viral load were detected in all lesions within a patient case. Primary tumors with a high E2/E6 ratio were found to have fewer vulvar recurrences and/or metastases after diagnosis and treatment. Also, a significantly lower viral load was evident in regional lymph nodes compared to primary tumors. The data presented strengthens the evidence for a clonal HPV-induced pathway for vulvar carcinoma.

Cytokine Measurements for Diagnosing and Characterizing Leukemoid Reactions and Immunohistochemical Validation of a Granulocyte Colony-Stimulating Factor and CXCL8-Producing Renal Cell Carcinoma.

BACKGROUND: Various paraneoplastic syndromes are encountered in renal cell carcinomas. This case report illustrates that a paraneoplastic leukemoid reaction may precede the diagnosis of renal cell carcinoma and be explained by cytokine production from the cancer cells. CASE PRESENTATIONS: A 64-year-old man was referred for hematology workup due to pronounced leukocytosis. While being evaluated for a possible hematologic malignancy as the cause, he was found to have a metastasized renal cell carcinoma, and hyperleukocytosis was classified as a leukemoid reaction. A multiplex panel for measurement of 25 serum cytokines/chemokines showed highly elevated levels of granulocyte colony-stimulating factor (G-CSF) and CXCL8 (C-X-C-motif chemokine ligand 8, previously known as interleukin [IL]-8). By immunohistochemistry it was shown that the renal carcinoma cells expressed both these cytokines. Two additional, consecutive patients with renal cell carcinoma with paraneoplastic leukocytosis also showed elevated serum levels of CXCL8, but not of G-CSF. Nonparametric statistical evaluation showed significantly higher serum concentrations of CXCL8, IL-6, IL-10, monocyte chemoattractant protein 1 (MCP-1), and tumor necrosis factor, but lower interferon gamma (IFN-γ) and IL-1α, for the 3 renal cell carcinoma cases compared with healthy blood donors. CONCLUSIONS: In suspected paraneoplastic leukocytosis, multiplex serum cytokine analyses may facilitate diagnosis and provide an understanding of the mechanisms for the reaction. In the index patient, combined G-CSF and CXCL8 protein expression by renal carcinoma cells was uniquely documented. A rapidly fatal course was detected in all 3 cases, congruent with the concept that autocrine/paracrine growth signaling in renal carcinoma cells may induce an aggressive tumor phenotype. Immune profiling studies could improve our understanding for possible targets when choosing therapies for patients with metastatic renal cell carcinoma.

Comparison between professional sampling and self-sampling for HPV-based cervical cancer screening among postmenopausal women.

OBJECTIVE: To investigate whether self-sampling is as reliable as professional sampling for HPV testing and genotype detection among postmenopausal women. METHODS: In the present prospective cross-sectional study, women in Örebro County, Sweden, who had high-risk HPV (hrHPV) and normal cytology results in exit screening tests conducted in between January 1, 2012, and December 31, 2014, were invited to follow-up screenings between February 24, 2015 and May 15, 2015, that included professional sampling and self-sampling. HPV genotypes were identified by a DNA-based assay that could detect 35 HPV genotypes. Findings between the different sampling methods were compared. RESULTS: Of 143 women who participated, 119 returned a self-sample. Completely concordant results were observed in 67 of these samples when both hrHPV and low-risk HPV genotypes were analyzed. Overall, 99 (83.2%) women had the same clinically relevant finding from both sampling methods. Twenty women had discordant hrHPV results (hrHPV detected in 10 self-samples vs 10 professionally collected samples; Cohen κ 0.66, 95% confidence interval 0.53-0.80). There was no significant difference between the two sampling methods for clinically significant infections (P>0.99) or extended genotyping (P=0.827). CONCLUSION: Postmenopausal women could be offered self-sampling devices to increase screening-program coverage while maintaining test quality.

Findings of multiple HPV genotypes in cervical carcinoma are associated with poor cancer-specific survival in a Swedish cohort of cervical cancer primarily treated with radiotherapy.

Cervical cancer (CC) is one of the most common cancers in women and virtually all cases of CC are a result of a persistent infection of human papillomavirus (HPV). For disease detected in early stages there is curing treatment but when diagnosed late with recurring disease and metastasis there are limited possibilities. Here we evaluate HPV impact on treatment resistance and metastatic disease progression. Prevalence and distribution of HPV genotypes and HPV16 variants in a Swedish CC patient cohort (n=209) was evaluated, as well as HPV influence on patient prognosis. Tumor samples suitable for analysis (n=204) were genotyped using two different real-time PCR methods. HPV16 variant analysis was made using pyrosequencing. Results showed that HPV prevalence in the total series was 93%. Of the HPV-positive samples, 13% contained multiple infections, typically with two high-risk HPV together. Primary cure rate for the complete series was 95%. Recurrence rate of the complete series was 28% and distant recurrences were most frequent (20%). Patients with tumors containing multiple HPV-strains and particularly HPV genotypes belonging to the alpha 7 and 9 species together had a significantly higher rate of distant tumor recurrences and worse cancer-specific survival rate.

Breast cancer in Ethiopia: evidence for geographic difference in the distribution of molecular subtypes in Africa.

BACKGROUND: Breast cancer is a heterogeneous disease with several morphological and molecular subtypes. Widely accepted molecular classification system uses assessment of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and proliferation marker Ki67. Few studies have been conducted on the incidence and molecular types of breast cancer in Sub-Saharan Africa. Previous studies mainly from Western and Central Africa, showed breast cancer to occur at younger ages and to present with aggressive features, such as high-grade, advanced stage and triple-negative phenotype (negative for ER, PR and HER2). Limited data from East Africa including Ethiopia however shows hormone receptor negative tumors to account for a lower proportion of all breast cancers than has been reported from elsewhere in Africa. METHODS: In this study from Tikur Anbessa Specialized Hospital, 114 breast cancer patients diagnosed between 2012 and 2015 were enrolled. ER, PR, Ki67 and HER2 receptor status were assessed using immunohistochemistry from tissue microarrays. FISH was used for assessment of gene amplification in all equivocal tumor samples and for confirmation in HER2-enriched cases. RESULTS: The distribution of molecular subtypes was: Luminal A: 40%; Luminal B: 26%; HER2-enriched: 10%; TNBC: 23%. ER were positive in 65% of all tumors and 43% the cases were positive for PR. There was statistically significant difference in median age at diagnosis between the molecular subtypes (P < 0.05). There was a bimodal distribution of molecular subtypes in different age ranges with Luminal B subtype being more common at younger ages (median = 36) and Luminal A subtype more prevalent at older ages (median = 42). There were no statistically significant differences in tumor grade, histology, and stage between the molecular subtypes of breast cancer. CONCLUSION: The present study detected Luminal A breast cancer to be the most common subtype and reveals a relatively low rate of hormone receptor negative and TNBC. Our findings and results from other East African studies suggest geographic variability in the distribution of the molecular subtypes of breast cancer in Africa and hence have important clinical and policy implications for breast cancer control and treatment in Ethiopia.

Expression of LRIG proteins as possible prognostic factors in primary vaginal carcinoma.

BACKGROUND: Primary vaginal carcinoma (PVC) is a rare malignancy. Established prognostic factors include tumour stage and age at diagnosis. The leucine-rich repeats and immunoglobuline-like domains (LRIG)-1 protein functions as a tumour suppressor, but less is known about the functions of LRIG2 and LRIG3. The present study aimed to evaluate the expression of LRIG proteins and analyse their possible associations with clinical characteristics and survival in a cohort of PVC patients. METHODS: We used immunohistochemistry to investigate LRIG1, LRIG2, and LRIG3 expression in tumour samples from a consecutive cohort of 70 PVC patients. The association between LRIG protein expression and clinical characteristics and cancer-specific survival was investigated using univariate and multivariate analyses. RESULTS: The majority of PVC patients (72%) had >50% LRIG1- and LRIG2-positive cells, and no or low LRIG3-positive cells. HPV status was significantly correlated with LRIG1 expression (p = 0.0047). Having high LRIG1 expression was significantly correlated with superior cancer-specific survival in univariate and multivariate analyses. LRIG2 and LRIG3 expression did not significantly correlate with clinical characteristics or survival. CONCLUSION: LRIG1 expression might be of interest as a prognostic marker in PVC patients, whereas the role of LRIG2 and LRIG3 expression remains to be clarified.

Does p53 codon 72 polymorphism have a prognostic value in carcinoma of the vulva and vagina?

Human papilloma virus (HPV) is considered to be responsible for a large part of vaginal and vulvar carcinomas, and the p53 codon 72 polymorphism has been implicated in susceptibility to cancer induced by this virus, but with contradicting results. In this study, we have investigated the prognostic value of the codon 72 polymorphism by real-time PCR (qPCR) in two cohorts of vaginal (n = 66) and vulvar (n = 123) carcinomas. In vaginal carcinoma, arginine homozygous patients were significantly associated with a higher primary cure rate (p = 0.023) but also associated with a higher recurrence rate (p = 0.073), significant at distant locations (p = 0.009). No significant differences were found in overall survival rate (p = 0.499) or cancer-specific survival rate (p = 0.222). A higher frequency of arginine homozygosity was noted in HPV-positive tumors (p = 0.190) in comparison with HPV-negative tumors. In vulvar carcinoma, the genotype homozygous for arginine was significantly associated with a larger tumor size at diagnosis in the entire cohort (p = 0.015) and a lower cancer-specific survival rate (p = 0.024) compared with heterozygous (arginine/proline) in HPV-negative tumors. Our results indicate that the relation between HPV and the p53 codon 72 polymorphism is complex and the significance and mechanisms responsible for this relationship need to be further elucidated.

Inconsistent results in the analysis of ALK rearrangements in non-small cell lung cancer.

BACKGROUND: Identification of targetable EML4-ALK fusion proteins has revolutionized the treatment of a minor subgroup of non-small cell lung cancer (NSCLC) patients. Although fluorescence in situ hybridization (FISH) is regarded as the gold standard for detection of ALK rearrangements, ALK immunohistochemistry (IHC) is often used as screening tool in clinical practice. In order to unbiasedly analyze the diagnostic impact of such a screening strategy, we compared ALK IHC with ALK FISH in three large representative Swedish NSCLC cohorts incorporating clinical parameters and gene expression data. METHODS: ALK rearrangements were detected using FISH on tissue microarrays (TMAs), including tissue from 851 NSCLC patients. In parallel, ALK protein expression was detected using IHC, applying the antibody clone D5F3 with two different protocols (the FDA approved Ventana CDx assay and our in house Dako IHC protocol). Gene expression microarray data (Affymetrix) was available for 194 patients. RESULTS: ALK rearrangements were detected in 1.7 % in the complete cohort and 2.0 % in the non-squamous cell carcinoma subgroup. ALK protein expression was observed in 1.8 and 1.4 % when applying the Ventana assay or the in house Dako protocol, respectively. The specificity and accuracy of IHC was high (> 98 %), while the sensitivity was between 69 % (Ventana) and 62 % (in house Dako protocol). Furthermore, only 67 % of the ALK IHC positive cases were positive with both IHC assays. Gene expression analysis revealed that 6/194 (3 %) tumors showed high ALK gene expression (≥ 6 AU) and of them only three were positive by either FISH or IHC. CONCLUSION: The overall frequency of ALK rearrangements based on FISH was lower than previously reported. The sensitivity of both IHC assays was low, and the concordance between the FISH and the IHC assays poor, questioning current strategies to screen with IHC prior to FISH or completely replace FISH by IHC.

Frequency and typing of Propionibacterium acnes in prostate tissue obtained from men with and without prostate cancer.

BACKGROUND: Prostate cancer is the most common cancer among men in Western countries but the exact pathogenic mechanism of the disease is still largely unknown. An infectious etiology and infection-induced inflammation has been suggested to play a role in prostate carcinogenesis and Propionibacterium acnes has been reported as the most prevalent microorganism in prostatic tissue. We investigated the frequency and types of P. acnes isolated from prostate tissue samples from men with prostate cancer and from control patients without the disease. METHODS: We included 100 cases and 50 controls in this study. Cases were men diagnosed with prostate cancer undergoing radical prostatectomy and controls were men undergoing surgery for bladder cancer without any histological findings of prostate cancer. Six biopsies taken from each patient's prostate gland at the time of surgery were used for cultivation and further characterization of P. acnes. RESULTS: The results revealed that P. acnes was more common in men with prostate carcinoma than in controls, with the bacteria cultured in 60 % of the cases vs. 26 % of the controls (p = 0.001). In multivariable analyses, men with P. acnes had a 4-fold increase in odds of a prostate cancer diagnosis after adjustment for age, calendar year of surgery and smoking status (OR: 4.46; 95 % CI: 1.93-11.26). To further support the biologic plausibility for a P. acnes infection as a contributing factor in prostate cancer development, we subsequently conducted cell-based experiments. P. acnes- isolates were co-cultured with the prostate cell line PNT1A. An increased cell proliferation and cytokine/chemokine secretion in infected cells was observed. CONCLUSION: The present study provides further evidence for a role of P. acnes in prostate cancer development.