Immunotherapy for the prevention of high-risk oral disorders malignant transformation: the IMPEDE trial.

BACKGROUND: Oral Potentially Malignant Disorders (OPMD) have a non-negligible malignant transformation rate of up to 8%. Loss of heterozygosity (LOH) in critical chromosomal loci has proven to be the most effective marker in defining the risk of transformation and it is found in about 28% of OPMD and may therefore identify patients carrying higher risk. To date, clinical management of OPMD is limited to surgical excision and clinical surveillance, which however do not fully prevent oral cancer development. Immune system has been shown to play a key role in transformation surveillance mechanism and an immunosuppressive imbalance may be responsible for progression to cancer. Given all these considerations, we designed a clinical trial with the aim to prevent OPMD neoplastic transformation and revert the LOH status. METHODS: This is a phase II, open label, single arm, multicentric trial involving Italian referral centres and expected to enrol 80 patients out of a total of 175 screened. Patients who meet all inclusion criteria and test positive for LOH after an incisional biopsy of the OPMD will undergo a short course of immunotherapy with 4 administration of avelumab. After 6 months since treatment start, resection of the entire OPMD will be performed and LOH assessment will be repeated. The follow-up for malignant transformation and safety assessment will last 30 months from the end of treatment, for a total planned study duration of approximately 5.5 years. DISCUSSION: Restoring the activity of immune system through checkpoint inhibitor may play a crucial role against malignant transformation of OPMD by reverting the balance in favour of immune control and preventing cancer occurrence. TRIAL REGISTRATION: This trial was prospectively registered in ClinicalTrials.gov as NCT04504552 on 7th August 2020.

Prognostic implications of the coexisting precursor lesion types in invasive gallbladder cancer.

Invasive gallbladder carcinoma (GBC) is preceded by two main types of precursor lesions: intracholecystic papillary-tubular neoplasms (ICPNs) and biliary intraepithelial neoplasias (BilINs). Invasive GBCs with an ICPN component have more favorable prognoses than those without an ICPN component. Some BilINs show a relatively exophytic papillary pattern but do not meet the ICPN criteria; at our institution, we call these papillary neoplasias. To clarify the clinical significance of papillary neoplasia, we herein examined 80 invasive GBCs and classified them into three groups based on the type of preinvasive lesions: those with ICPN (ICPN group, n = 35), those with papillary neoplasia (pap-neoplasia group, n = 13), and those without ICPN/papillary neoplasia (group without ICPN/pap-neoplasia, n = 32). We then compared the prognostic differences and characterized the tumors of each group by determining the immunohistochemical expressions of various biomarkers. The overall survival periods of the ICPN and pap-neoplasia groups were significantly longer than that of the group without ICPN/pap-neoplasia (P < 0.0001, P = 0.0036, respectively). Multivariate analysis revealed that lacking ICPN/papillary neoplasia was independently associated with poor prognosis (P = 0.0007), as were poor differentiation (P = 0.0395), presence of preoperative symptoms (P = 0.0488), and advanced stage (P = 0.0234). Invasive components of the ICPN and pap-neoplasia groups were characterized by higher expressions of p16 and p53 compared with those of the group without ICPN/pap-neoplasia. The prognoses of the invasive GBCs with either papillary neoplasia or ICPN were thus more favorable than those of the invasive GBCs without ICPN/pap-neoplasia. Invasive GBCs with exophytic papillary preinvasive lesions (ICPN and papillary neoplasia) may be biologically different from those without such lesions.

TLM Outcomes in Elderly Patients with Glottic Pre-Malignancy and Early Malignancy; A 12-Year Retrospective Study.

INTRODUCTION: UK population ageing and associated cancer risk predicts an increase in the prevalence of laryngeal cancer in elderly patients. Whilst trans-oral laser microsurgery (TLM) has been demonstrated to achieve excellent control of early disease with few complications, data specifically related to its safety and efficacy in older patients is lacking. We report the largest series to date. OBJECTIVES: To assess the safety and efficacy of TLM in elderly patients with glottic pre-malignancy and early malignancy. METHODS: A retrospective review and statistical analysis of the clinical records of patients aged 70 or over undergoing TLM for early and premalignant glottic disease. RESULTS: The records of 106 patients over the age of 70 were identified. Thirteen records were excluded, 4 due to failure to meet the inclusion criteria (stage I/II disease, primary site of lesion in the glottis) and 9 due to incomplete follow up data capture. Most surgeries (>70%) were performed as a day case or overnight admission, with only 2 admissions >2 days. One patient required hospital readmission with dysphagia, resulting in an altered diet. No patients required tracheostomy or tube feeding. No treatment related deaths or intensive care admissions were observed. Ten patients had recurrent disease within 5 years; 1 received radiotherapy, 1 underwent salvage laryngectomy, the remainder had further TLM without complication. Five-year disease specific survival rates were >90%. CONCLUSION: Our results demonstrate that TLM is safe and effective for elderly patients, with outcomes comparable to those reported in large, non-age selected cohorts. Although our patients underwent more conservative cordectomy types (I-III) than those with similar disease stages reported elsewhere, our recurrence rates were not higher. This supports the oncological effectiveness of surgery whilst reducing the risk of associated functional compromise.

Precancerous Lesions and Liver Atrophy as Risk Factors for Hepatolithiasis-Related Death after Liver Resection for Hepatolithiasis.

BACKGROUND: Cholangiocarcinoma and secondary biliary cirrhosis can develop after liver resection for hepatolithiasis and are causes of hepatolithiasis-related death. We determined potential risk factors for hepatolithiasis-related death and subsequent cholangiocarcinoma, including precancerous lesions such as biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct, in patients undergoing liver resection for hepatolithiasis. METHODS: The study cohort included 62 patients who underwent liver resection for hepatolithiasis without concomitant cholangiocarcinoma and had surgical specimens available for pathological examination. Univariate and multivariate analyses were conducted to examine risk factors associated with subsequent cholangiocarcinoma after hepatolithiasis and hepatolithiasis-related death. In 28 patients with BilIN lesions, the specimens were immunohistochemically stained for γ-H2AX and S100P. RESULTS: In the study cohort, the causes of death were subsequent cholangiocarcinoma, biliary cirrhosis, and other diseases in 5, 3, and 7 patients, respectively. Liver atrophy, precancerous lesions, postoperative repeated cholangitis, and jaundice for ≥1 week during the follow-up period were risk factors for hepatolithiasis-related death. Multivariate analysis showed that liver atrophy and precancerous lesions were independent risk factors for hepatolithiasis-related death. Liver atrophy or precancerous lesions were also risk factors for subsequent cholangiocarcinoma by univariate analysis. The positive expression of γ-H2AX and S100P was observed in 18 and 14 of the 28 BilIN lesions, respectively. CONCLUSIONS: Liver atrophy and precancerous lesions with malignant transformation were risk factors not only for subsequent cholangiocarcinoma but also hepatolithiasis-related death after liver resection for hepatolithiasis, indicating that long-term follow-up is necessary even after liver resection in patients harboring these risk factors.
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Gene Expression Clustering and Selected Head and Neck Cancer Gene Signatures Highlight Risk Probability Differences in Oral Premalignant Lesions.

BACKGROUND: Oral premalignant lesions (OPLs) represent the most common oral precancerous conditions. One of the major challenges in this field is the identification of OPLs at higher risk for oral squamous cell cancer (OSCC) development, by discovering molecular pathways deregulated in the early steps of malignant transformation. Analysis of deregulated levels of single genes and pathways has been successfully applied to head and neck squamous cell cancers (HNSCC) and OSCC with prognostic/predictive implications. Exploiting the availability of gene expression profile and clinical follow-up information of a well-characterized cohort of OPL patients, we aim to dissect tissue OPL gene expression to identify molecular clusters/signatures associated with oral cancer free survival (OCFS). MATERIALS AND METHODS: The gene expression data of 86 OPL patients were challenged with: an HNSCC specific 6 molecular subtypes model (Immune related: HPV related, Defense Response and Immunoreactive; Mesenchymal, Hypoxia and Classical); one OSCC-specific signature (13 genes); two metabolism-related signatures (3 genes and signatures raised from 6 metabolic pathways associated with prognosis in HNSCC and OSCC, respectively); a hypoxia gene signature. The molecular stratification and high versus low expression of the signatures were correlated with OCFS by Kaplan-Meier analyses. The association of gene expression profiles among the tested biological models and clinical covariates was tested through variance partition analysis. RESULTS: Patients with Mesenchymal, Hypoxia and Classical clusters showed an higher risk of malignant transformation in comparison with immune-related ones (log-rank test, p = 0.0052) and they expressed four enriched hallmarks: "TGF beta signaling" "angiogenesis", "unfolded protein response", "apical junction". Overall, 54 cases entered in the immune related clusters, while the remaining 32 cases belonged to the other clusters. No other signatures showed association with OCFS. Our variance partition analysis proved that clinical and molecular features are able to explain only 21% of gene expression data variability, while the remaining 79% refers to residuals independent of known parameters. CONCLUSIONS: Applying the existing signatures derived from HNSCC to OPL, we identified only a protective effect for immune-related signatures. Other gene expression profiles derived from overt cancers were not able to identify the risk of malignant transformation, possibly because they are linked to later stages of cancer progression. The availability of a new well-characterized set of OPL patients and further research is needed to improve the identification of adequate prognosticators in OPLs.

Quantitative proteomics identified 3 oxidative phosphorylation genes with clinical prognostic significance in gastric cancer.

The aim of the present study was to explore the underlying mechanisms involved in gastric cancer (GC) formation using data-independent acquisition (DIA) quantitative proteomics analysis. We identified the differences in protein expression and related functions involved in biological metabolic processes in GC. Totally, 745 differentially expressed proteins (DEPs) were found in GC tissues vs. gastric normal tissues. Despite enormous complexity in the details of the underlying regulatory network, we find that clusters of proteins from the DEPs were mainly involved in 38 pathways. All of the identified DEPs involved in oxidative phosphorylation were down-regulated. Moreover, GC possesses significantly altered biological metabolic processes, such as NADH dehydrogenase complex assembly and tricarboxylic acid cycle, which is mostly consistent with that in KEGG analysis. Furthermore the higher expression of UQCRQ, NDUFB7 and UQCRC2 were positively correlated with a better prognosis, implicating these proteins may as novel candidate diagnostic and prognostic biomarkers.

Dissecting expression profiles of gastric precancerous lesions and early gastric cancer to explore crucial molecules in intestinal-type gastric cancer tumorigenesis.

Intestinal-type gastric cancer (IGC) has a clear and multistep histological evolution. No studies have comprehensively explored gastric tumorigenesis from inflammation through low-grade intraepithelial neoplasia (LGIN) and high-grade intraepithelial neoplasia (HGIN) to early gastric cancer (EGC). We sought to investigate the characteristics participating in IGC tumorigenesis and identify related prognostic information within the process. RNA expression profiles of 94 gastroscopic biopsies from 47 patients, including gastric precancerous lesions (GPL: LGIN and HGIN), EGC, and paired controls, were detected by Agilent Microarray. During IGC tumorigenesis from LGIN through HGIN to EGC, the number of activity-changed tumor hallmarks increased. LGIN and HGIN had similar expression profiles when compared to EGC. We observed an increase in the stemness of gastric epithelial cells in LGIN, HGIN, and EGC, and we found 27 consistent genes that might contribute to dedifferentiation, including five driver genes. Remarkably, we perceived that the immune microenvironment was more active in EGC than in GPL, especially in the infiltration of lymphocytes and macrophages. We identified a five-gene signature from the gastric tumorigenesis process that could independently predict the overall survival and disease-free survival of GC patients (log-rank test: p < 0.0001), and the robustness was verified in an independent cohort (n > 300) and by comparing with two established prognostic signatures in GC. In conclusion, during IGC tumorigenesis, cancer-like changes occur in LGIN and accumulate in HGIN and EGC. The immune microenvironment is more active in EGC than in LGIN and HGIN. The identified signature from the tumorigenesis process has robust prognostic significance for GC patients. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Augmented fluoroscopic bronchoscopy (AFB) versus percutaneous computed tomography-guided dye localization for thoracoscopic resection of small lung nodules: a propensity-matched study.

BACKGROUND: Dye localization is a useful method for the resection of unidentifiable small pulmonary lesions. This study compares the transbronchial route with augmented fluoroscopic bronchoscopy (AFB) and conventional transthoracic CT-guided methods for preoperative dye localization in thoracoscopic surgery. METHODS: Between April 2015 and March 2019, a total of 231 patients with small pulmonary lesions who received preoperative dye localization via AFB or percutaneous CT-guided technique were enrolled in the study. A propensity-matched analysis, incorporating preoperative variables, was used to compare localization and surgical outcomes between the two groups. RESULTS: After matching, a total of 90 patients in the AFB group (N = 30) and CT-guided group (N = 60) were selected for analysis. No significant difference was noted in the demographic data between both the groups. Dye localization was successfully performed in 29 patients (96.7%) and 57 patients (95%) with AFB and CT-guided method, respectively. The localization duration (24.1 ± 8.3 vs. 21.4 ± 12.5 min, p = 0.297) and equivalent dose of radiation exposure (3.1 ± 1.5 vs. 2.5 ± 2.0 mSv, p = 0.130) were comparable in both the groups. No major procedure-related complications occurred in either group; however, a higher rate of pneumothorax (0 vs. 16.7%, p = 0.029) and focal intrapulmonary hemorrhage (3.3 vs. 26.7%, p = 0.008) was noted in the CT-guided group. CONCLUSION: AFB dye marking is an effective alternative for the preoperative localization of small pulmonary lesions, with a lower risk of procedure-related complications than the conventional CT-guided method.

Clinicopathologic analysis of verrucous hyperplasia, verrucous carcinoma and squamous cell carcinoma as part of the clinicopathologic spectrum of oral proliferative verrucous leukoplakia: A literature review and analysis.

OBJECTIVE: Proliferative verrucous leukoplakia is classified as a potentially malignant disorder because of its high rate of malignant transformation. PVL progresses in a series of clinical stages where the early stage represents multiple, multifocal leukoplakias with a high recurrence rate. The intermediate and late stages are clinically exophytic lesion, diagnosed microscopically as verrucous hyperplasia that often progresses into verrucous carcinoma and/or squamous cell carcinoma. There is no single histologic definition and the diagnosis is retrospective following observed progression of the disorder. The goal of the current study was to conduct a literature review and analysis of PVL in the later stages to gain further knowledge on their clinicopathologic features. DATA SOURCES: Medline's PubMed and Google Scholar were searched for adequately documented cases from 1985 to 2018. References of published articles were searched for additional cases. REVIEW METHODS: Overall, 57 manuscripts were analyzed. 35/57 manuscripts provided adequate data on the clinicopathologic features in the premalignant and malignant stages. RESULTS: Malignant transformation rate was 50% (average of 57 months). Gingiva, palate and buccal mucosa were the most common locations. Clinicopathologic features included; well differentiated carcinoma (78%), perineural invasion (3%), lymph node metastasis (4%); distant metastasis (0%), average duration of illness (65 months), DOD-dead of disease (44%). Moderate dysplasia, severe dysplasia and carcinoma in situ were exceptionally uncommon in the premalignant stages (0.8%). CONCLUSION: Prognostic factors such as perineural invasion, lymph node metastasis and distant metastasis were uncommon occurrences which may have practical implications on treatment. Further studies are needed to substantiate our findings.

Modern Outcomes Following Treatment of Hepatocellular Carcinoma in Hereditary Hemochromatosis: A Matched Cohort Study.

OBJECTIVE: Hepatocellular carcinoma (HCC) is a complication of the common genetic condition hereditary hemochromatosis (HH). It is unknown whether HH as an etiology of liver disease impacts the outcome. We compared the results of liver transplantation (LT), surgical resection and locoregional therapies in a matched cohort study and investigated whether HH as an etiology has an impact on survival. MATERIALS AND METHODS: Consecutive patients with HH and HCC (2000 to 2015) were compared with age, sex and Barcelona Clinic Liver Cancer (BCLC) stage-matched non-HH HCC cases. Patients were offered curative or noncurative treatment according to BCLC stage and Milan criteria. The primary endpoint was all-cause mortality. RESULTS: A total of 102 patients (52 HH; total cohort median age: 67 [44 to 78] y, 97% male, Model for End-stage Liver Disease: 9 [5 to 31]) were studied with a median follow-up of 22 (3 to 126) months. Of the HH cases, the median serum ferritin at diagnosis of HCC was 326 (27 to 5718) µg/L and α-fetoprotein 33 (2 to 197,926) kIU/L. Five-year survival for HH patients receiving curative therapy was 77% (80% for LT, 67% for resection/radiofrequency ablation), and 15% (23% for transarterial chemoembolization) for those undergoing noncurative therapy. Survival for HH patients compared with controls was similar (hazard ratio=0.949; P=0.839). On multivariate Cox regression survival analysis, BCLC stage, and diagnosis of ischemic heart disease (but not HH diagnosis) were independently associated with reduced survival. CONCLUSIONS: Patients with HCC and HH can achieve comparable survival rates following curative or LRT modalities to other liver diseases. The BCLC staging system accurately stratifies survival and excellent 5-year survival is possible following LT in selected patients.

Joint detection of claudin-1 and junctional adhesion molecule-A as a therapeutic target in oral epithelial dysplasia and oral squamous cell carcinoma.

Abnormal expression of claudin-1 (CLDN-1) and junctional adhesion molecule-A (JAM-A) has been described in certain malignancies but their clinical relevance is poorly understood. The present study aims to elucidate the role of CLDN-1 and JAM-A in oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC). Changes in the expression of these proteins were identified immunohistochemically on tissue sections from patients with OED and OSCC and compared with control. A correlation between the expression level of proteins and clinicopathological features was analyzed by Pearson's correlation χ2 test. The survival curve of the follow-up data was estimated by the Kaplan-Meier method followed by the log-rank test. CLDN-1 and JAM-A were highly expressed in OED and OSCC tissues when compared to control. Also, delocalization of CLDN-1 from the membrane to the cytoplasm to the nucleus was observed as the cell proceeds from normal to malignancy. Increased expression of CLDN-1 and JAM-A in both OED and OSCC were concomitant with histological grades. In addition, increased JAM-A was associated with perineural invasion of cancer cells. A positive correlation between the expression level of proteins was observed in OED (r = 0.733) and OSCC (r = 0.577). Kaplan-Meier analysis in patients with OSCC showed that the survival rate was lower in patients with high CLDN-1 and high JAM-A expression compared to low expressed patients. To conclude, the elevated level and delocalization of CLDN-1 and JAM-A suggest their use as tumor markers. A positive correlation between CLDN-1 and JAM-A suggests joint detection of these proteins as a future diagnostic tool in oral precancerous and cancerous conditions.

Immunohistochemistry of YAP and dNp63 and survival analysis of patients bearing precancerous lesion and oral squamous cell carcinoma.

Background: Yes-associated protein (YAP) is a candidate oncogene in various human cancers, and recently, it has been reported that YAP expression and its activity was enhanced by ΔNp63. However, the role of YAP and ΔNp63 expression in carcinogenesis and progression of oral squamous cell carcinoma (OSCC) has been unknown. Therefore, we investigated how YAP and ΔNp63 influence carcinogenesis and progression of OSCC. Methods: We performed immunohistochemical analyses in whole tissue samples to investigate YAP and ΔNp63 expression in normal oral mucosa, epithelial hyperplasia, oral epithelial dysplasia (OED; low/high grade), carcinoma in situ (CIS), and OSCC. Furthermore, in OSCC, we analyzed clinical significance by using Kaplan-Meier survival analysis. Results: In normal oral mucosa and epithelial hyperplasia, YAP expression was primarily confined to the basal and parabasal layers, but YAP expression was elevated in OED, CIS, and OSCC. In OED, YAP and ΔNp63 expression levels were markedly higher in high grade than in low grade. In OSCC groups, YAP and ΔNp63 expression patterns tended to differ according to histopathological differentiation of OSCC. Furthermore, the YAP high expression group, which showed YAP staining in >50% positive cells with strong cytoplasmic staining or >10% positive cells with nuclear reactivity, showed a tendency to have a poor survival rate. Conclusion: YAP and ΔNp63 expression levels correlated with grade of oral OED. Additionally, YAP expression was associated with OSCC survival rate. Our results suggested that YAP and ΔNp63 expression might serve as predictive markers to distinguish OSCC development and progression.

Uterine Papillary Serous Carcinoma Arising in a Polyp: A Multicenter Retrospective Analysis on 75 Patients.

OBJECTIVES: The objectives of this study were to evaluate whether the international recommendations on the management of uterine papillary serous carcinoma arising in a polyp are uniformly followed in Italian Oncologic Centers and whether the strategy adopted is effective. MATERIALS AND METHODS: Patients with uterine papillary serous carcinoma arising in a polyp and who had undergone a hysterectomy were identified in the 2003-2013 database of 7 Italian Gynecologic Oncology Centers. Clinical and pathologic characteristics and outcomes were compared between staging procedure types. Survival curves of the women were plotted using the Kaplan-Meier method and analyzed using Cox regression hazard model and the log-rank test. Associations between clinical parameters and the incidence of recurrence were assessed by generalized linear models and the Fisher test. RESULTS: A total of 75 patients met the inclusion criteria. Recurrence-free survival was affected positively by type of surgical staging and negatively by preoperative diagnosis of hypertension. The association between surgical staging and recurrence-free survival resulted significant at univariate survival analysis (P=0.048 and 0.045) and maintained a trend of significance (P=0.070) in multivariate analysis, whereas hypertension was demonstrated to be the principal influencing factor. CONCLUSIONS: The international recommendations on the management of uterine papillary serous carcinoma are not uniformly followed in daily practice, although the extension of the surgery seems to be associated with lower recurrence rates also when uterine papillary serous carcinoma is confined to a polyp or endometrial surface.

Early Detection of Pancreatic Cancer: Opportunities and Challenges.

Most patients with pancreatic ductal adenocarcinoma (PDAC) present with symptomatic, surgically unresectable disease. Although the goal of early detection of PDAC is laudable and likely to result in significant improvement in overall survival, the relatively low prevalence of PDAC renders general population screening infeasible. The challenges of early detection include identification of at-risk individuals in the general population who would benefit from longitudinal surveillance programs and appropriate biomarker and imaging-based modalities used for PDAC surveillance in such cohorts. In recent years, various subgroups at higher-than-average risk for PDAC have been identified, including those with familial risk due to germline mutations, a history of pancreatitis, patients with mucinous pancreatic cysts, and elderly patients with new-onset diabetes. The last 2 categories are discussed at length in terms of the opportunities and challenges they present for PDAC early detection. We also discuss current and emerging imaging modalities that are critical to identifying early, potentially curable PDAC in high-risk cohorts on surveillance.

Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors.

BACKGROUND: Persistent infection with high-risk human papillomaviruses (hrHPV) types is causally linked with the development of cervical precancer and cancer. HPV types 16 and 18 cause approximately 70% of cervical cancers worldwide. OBJECTIVES: To evaluate the harms and protection of prophylactic human papillomaviruses (HPV) vaccines against cervical precancer and HPV16/18 infection in adolescent girls and women. SEARCH METHODS: We searched MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase (June 2017) for reports on effects from trials. We searched trial registries and company results' registers to identify unpublished data for mortality and serious adverse events. SELECTION CRITERIA: Randomised controlled trials comparing efficacy and safety in females offered HPV vaccines with placebo (vaccine adjuvants or another control vaccine). DATA COLLECTION AND ANALYSIS: We used Cochrane methodology and GRADE to rate the certainty of evidence for protection against cervical precancer (cervical intraepithelial neoplasia grade 2 and above [CIN2+], CIN grade 3 and above [CIN3+], and adenocarcinoma-in-situ [AIS]), and for harms. We distinguished between the effects of vaccines by participants' baseline HPV DNA status. The outcomes were precancer associated with vaccine HPV types and precancer irrespective of HPV type. Results are presented as risks in control and vaccination groups and risk ratios (RR) with 95% confidence intervals in brackets. MAIN RESULTS: We included 26 trials (73,428 participants). Ten trials, with follow-up of 1.3 to 8 years, addressed protection against CIN/AIS. Vaccine safety was evaluated over a period of 6 months to 7 years in 23 studies. Studies were not large enough or of sufficient duration to evaluate cervical cancer outcomes. All but one of the trials was funded by the vaccine manufacturers. We judged most included trials to be at low risk of bias. Studies involved monovalent (N = 1), bivalent (N = 18), and quadrivalent vaccines (N = 7). Most women were under 26 years of age. Three trials recruited women aged 25 and over. We summarize the effects of vaccines in participants who had at least one immunisation.Efficacy endpoints by initial HPV DNA statushrHPV negativeHPV vaccines reduce CIN2+, CIN3+, AIS associated with HPV16/18 compared with placebo in adolescent girls and women aged 15 to 26. There is high-certainty evidence that vaccines lower CIN2+ from 164 to 2/10,000 (RR 0.01 (0 to 0.05)) and CIN3+ from 70 to 0/10,000 (RR 0.01 (0.00 to 0.10). There is moderate-certainty evidence that vaccines reduce the risk of AIS from 9 to 0/10,000 (RR 0.10 (0.01 to 0.82).HPV vaccines reduce the risk of any CIN2+ from 287 to 106/10,000 (RR 0.37 (0.25 to 0.55), high certainty) and probably reduce any AIS lesions from 10 to 0/10,000 (RR 0.1 (0.01 to 0.76), moderate certainty). The size of reduction in CIN3+ with vaccines differed between bivalent and quadrivalent vaccines (bivalent: RR 0.08 (0.03 to 0.23), high certainty; quadrivalent: RR 0.54 (0.36 to 0.82), moderate certainty). Data in older women were not available for this comparison.HPV16/18 negativeIn those aged 15 to 26 years, vaccines reduce CIN2+ associated with HPV16/18 from 113 to 6 /10,000 (RR 0.05 (0.03 to 0.10). In women 24 years or older the absolute and relative reduction in the risk of these lesions is smaller (from 45 to 14/10,000, (RR 0.30 (0.11 to 0.81), moderate certainty). HPV vaccines reduce the risk of CIN3+ and AIS associated with HPV16/18 in younger women (RR 0.05 (0.02 to 0.14), high certainty and RR 0.09 (0.01 to 0.72), moderate certainty, respectively). No trials in older women have measured these outcomes.Vaccines reduce any CIN2+ from 231 to 95/10,000, (RR 0.41 (0.32 to 0.52)) in younger women. No data are reported for more severe lesions.Regardless of HPV DNA statusIn younger women HPV vaccines reduce the risk of CIN2+ associated with HPV16/18 from 341 to 157/10,000 (RR 0.46 (0.37 to 0.57), high certainty). Similar reductions in risk were observed for CIN3+ associated with HPV16/18 (high certainty). The number of women with AIS associated with HPV16/18 is reduced from 14 to 5/10,000 with HPV vaccines (high certainty).HPV vaccines reduce any CIN2+ from 559 to 391/10,000 (RR 0.70 (0.58 to 0.85, high certainty) and any AIS from 17 to 5/10,000 (RR 0.32 (0.15 to 0.67), high certainty). The reduction in any CIN3+ differed by vaccine type (bivalent vaccine: RR 0.55 (0.43 to 0.71) and quadrivalent vaccine: RR 0.81 (0.69 to 0.96)).In women vaccinated at 24 to 45 years of age, there is moderate-certainty evidence that the risks of CIN2+ associated with HPV16/18 and any CIN2+ are similar between vaccinated and unvaccinated women (RR 0.74 (0.52 to 1.05) and RR 1.04 (0.83 to 1.30) respectively). No data are reported in this age group for CIN3+ or AIS.Adverse effectsThe risk of serious adverse events is similar between control and HPV vaccines in women of all ages (669 versus 656/10,000, RR 0.98 (0.92 to 1.05), high certainty). Mortality was 11/10,000 in control groups compared with 14/10,000 (9 to 22) with HPV vaccine (RR 1.29 [0.85 to 1.98]; low certainty). The number of deaths was low overall but there is a higher number of deaths in older women. No pattern in the cause or timing of death has been established.Pregnancy outcomesAmong those who became pregnant during the studies, we did not find an increased risk of miscarriage (1618 versus 1424/10,000, RR 0.88 (0.68 to 1.14), high certainty) or termination (931 versus 838/10,000 RR 0.90 (0.80 to 1.02), high certainty). The effects on congenital abnormalities and stillbirths are uncertain (RR 1.22 (0.88 to 1.69), moderate certainty and (RR 1.12 (0.68 to 1.83), moderate certainty, respectively). AUTHORS' CONCLUSIONS: There is high-certainty evidence that HPV vaccines protect against cervical precancer in adolescent girls and young women aged 15 to 26. The effect is higher for lesions associated with HPV16/18 than for lesions irrespective of HPV type. The effect is greater in those who are negative for hrHPV or HPV16/18 DNA at enrolment than those unselected for HPV DNA status. There is moderate-certainty evidence that HPV vaccines reduce CIN2+ in older women who are HPV16/18 negative, but not when they are unselected by HPV DNA status.We did not find an increased risk of serious adverse effects. Although the number of deaths is low overall, there were more deaths among women older than 25 years who received the vaccine. The deaths reported in the studies have been judged not to be related to the vaccine. Increased risk of adverse pregnancy outcomes after HPV vaccination cannot be excluded, although the risk of miscarriage and termination are similar between trial arms. Long-term of follow-up is needed to monitor the impact on cervical cancer, occurrence of rare harms and pregnancy outcomes.

[Surgical Treatment of Pseudotumours of the Lung]. / Chirurgische Therapie von Pseudotumoren der Lunge.

INTRODUCTION: Pseudotumour of the lung is a collective term for various subentities. Some subgroups are considered to be intermediary malignant tumours. A pseudotumour is a rare condition, which makes it difficult to estimate its incidence and prevalence. METHODS: Retrospective analysis of all surgically treated patients between 2008 and 2015 diagnosed with a pseudotumour of the lung. The primary endpoint of this study was to estimate the rates of local recurrence and metastasis. Secondary endpoints were to determine the nomenclature, medical history, treatment, and the perioperative course. RESULTS: Out of 27 patients (10 females and 17 males) with a median age of 58 years, 19 patients (70%) had an inflammatory pseudotumour (IPT), and four patients (15%) had an inflammatory myofibroblastoma (IMT). Two patients had a pneumocytoma/histiocytoma. A preoperative pulmonary infection was present in 12 (44%) patients. The average tumour size was 2.1 cm (0.8 - 5.3 cm), with the lower pulmonary lobes being mostly affected (52%). One enucleation, 20 atypical wedge resections and six anatomical resections were performed. This was done in a minimally invasive procedure (VATS) in 48% of cases (13/27). R0 resection was achieved in 93% of cases (25/27). Complications occurred in seven (26%) patients. The difference between the duration of hospital stay (mean duration 8 days) after open resection and VATS was minimal (8.8 vs. 7.2 days). Patients were followed up over a period of 4 years, during which time only one patient developed a tumour recurrence, which led to the patient's death, although she had had a R0 resection of an IMT. CONCLUSIONS: The treatment of choice for pseudotumours of the lung is R0 resection, preferably with VATS. Most patients have a benign course of disease, although relapses are possible in some cases, especially in IMT. Follow-up monitoring is necessary for IMT. The application of a uniform nomenclature and classification would be a sensible approach.

Impact of surgery and surveillance in the management of branch duct intraductal papillary mucinous neoplasms of the pancreas according to Fukuoka guidelines: the Bologna experience.

The objective of the study was to evaluate the Fukuoka guidelines in indicating the proper management for recognising the risk factors of malignancy. Data of patients with branch duct intraductal papillary mucinous neoplasms who underwent pancreatic resection or surveillance according to the Fukuoka risk parameters were collected in a prospective database. The clinical outcome (development of pancreatic cancer, overall and disease-specific survival) and pathological results were evaluated in all patients and in resected cases, respectively. The data of 197 patients were collected: 23 primarily resected and 174 primarily followed. Of the latter, 16 were secondarily resected. Among the patients resected, 21 (53.9%) showed diagnosis of in situ or invasive carcinoma and only contrast-enhancing mural nodules were significantly related to malignancy (P = 0.002), with a DOR of 3.3 and an LH+ of 2.2. Development of pancreatic cancer was shown in ten (5.7%) of the patients primarily followed. The overall survival and disease-specific survival were similar between patients primarily followed and primarily resected. It seems reasonable to suggest that a branch duct intraductal papillary mucinous neoplasm should be treated as a benign and indolent disease that is rarely malignant. Enhancing mural nodules represent the best indicator for surgery.

[Outcome after surgical resection for rectal cancer and its precursors in Landspitali University Hospital 2008-2012].

BACKGROUND: Rectal cancer makes up 2-3% of all cancers in Iceland and surgery is the mainstay of its treatment. Information regarding those who undergo resection of the rectum because of rectal cancer or its precursors in Iceland today is lacking. The aim of this study was to evaluate what kind of surgical treatment rectal cancer patients receive at Landspitali University Hospital along with peri-operative and long-term outcomes. METHODS: The study was retrospective. All patients undergoing total or partial resection of the rectum for rectal cancer or its precursor from 2008-2012 in Landspitali University hospital were included. Information regarding age, sex, surgery, neoadjuvant and adjuvant treatment along with reoperations and survival were gathered. RESULTS: The total number of patients included were 144. Mean age was 66 years (33-89). Neoadjuvant treatment was used in 65 (45%) cases. Most of the patients (65%) underwent anterior resection of the rectum, 21% abdominoperineal resection, 11% Hartmann´s procedure and 3% other surgery. Majority of the patients had a cancer diagnoses (88%) but 12% had dysplastic adenomas. An anastomosis was made in 67% of cases, others (33%) got a permanent stoma. Reoperation rate within 30 days was 12%. Thirty day and 1 year mortality were 0.7% and 6.2% respectively. Average follow up time was 56 months (1-98). Local recurrence rate was 7,1%, five year survival rate was 77%. CONCLUSION: The surgical treatment for rectal cancer in Landspitali is up to international standard. Perioperative and long-term outcomes are similar to what other authors have reported.

[Cystic pancreatic tumors: diagnostics and new biomarkers]. / Zystische Pankreastumoren: Diagnostik und neue Biomarker.

Mortality due to pancreatic ductal adenocarcinoma (PDAC) will increase in the near future. The only curative treatment for PDAC is radical resection; however, even small carcinomas exhibit micrometastases leading to early relapse. Accordingly, detection of premalignant precursor lesions is important. In essence, PDAC develops from three precursor lesions: pancreatic intraepithelial lesions (PanIN), intraductal papillary-mucinous neoplasia (IPMN) and mucinous-cystic neoplasia (MCN). Together with serous cystic neoplasia (SCN) and solid pseudopapillary neoplasia (SPN), these cystic lesions constitute the most common cystic neoplasms in the pancreas. In the case of IPMN, main and branch duct IPMN have to be differentiated because of a markedly different malignancy potential. While main duct IPMN and MCN have a high malignancy transformation rate, branch duct IPMNs are more variable with respect to malignant transformation. This shows that differential diagnosis of cystic lesions is important; however, this is often very difficult to accomplish using conventional imaging. Novel biomarkers and diagnostic tools based on the molecular differences of cystic pancreatic lesions could be helpful to differentiate these lesions and facilitate early diagnosis. The aim is to distinguish the premalignant cysts from strictly benign cystic lesions and a timely detection of malignant transformation. This article provides an overview on the molecular characteristics of cystic pancreatic lesions as a basis for improved diagnostics and the development of new biomarkers.