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Background Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease that may lead to liver cirrhosis or cholangiocarcinoma. Liver histology and fibrosis stage are predictive markers of disease progression, and histological cirrhosis is defined as a significant endpoint. PSC-specific histological scoring methods are lacking at present. We aimed to develop a tailored classification system for PSC, the PSC histoscore, based on histological features associated with disease progression. Methods In total, 300 PSC patients diagnosed between 1988 and 2018 were enrolled; their data were collected from the PSC registry (Helsinki University Hospital), and liver specimens were obtained from the Biobank of Helsinki. Five histological features included in the adapted Nakanuma scoring system and three additional parameters typical for PSC histology were evaluated and compared with the clinical and laboratory data. A compound endpoint consisting of liver transplantation, development of cholangiocarcinoma, or death was used as outcome measurement. Results Stage (fibrosis, bile duct loss, ductular reaction, and chronic cholestasis) and grade (portal inflammation, portal edema, hepatitis activity, and cholangitis activity) parameters were found to be independent predictive risk factors for the compound endpoint (P < 0.001). High disease grade (2-6) and stage (2-4) better correlated with clinical endpoints when evaluated with the PSC histoscore system compared to the adapted Nakanuma classification. The risk for disease progression in sequential endoscopic retrograde cholangiography (ERC) examinations was increased with elevated total PSC histoscores. Conclusion The PSC histoscore is a novel histological classification system for PSC. Our findings support the applicability of liver histology as a marker for disease progression.

Background and Objective After whiplash injury, some patients develop chronic whiplash-associated disorders. The exact pathophysiology of this chronification is still unclear and more knowledge is needed regarding the different post-injury phases. Therefore, studies were searched that examined temporal changes in pain processing, measured by Quantitative Sensory Testing (QST). Databases and Data Treatment This systematic review searched three electronic databases (Medline, Web of Science and Embase) for articles meeting the eligibility requirements. Risk of bias was assessed according to a modified Newcastle-Ottawa Scale. Results The 12 included studies presented moderate to good methodological quality. These studies showed altered pain processing within the first month after injury and normalization within 3 months in 59%-78% of the patients. After 3 months, recovery stagnates during the following years. Thermal and widespread mechanical hyperalgesia occur already in the acute phase, but only in eventually non-recovered patients. Conclusions Differences in pain processing between recovering and non-recovering patients can be observed already in the acute phase. Early screening for signs of altered pain processing can identify patients with high risk for chronification. These insights in temporal changes show the importance of rehabilitation in the acute phase. Future research should target to develop a standardized (bed-site) QST protocol and collect normative data which could, in relation with self-reported pain parameters, allow clinicians to identify the risk for chronification. Significance Altered pain processing is present soon after whiplash injury, but usually recovers within 3 months. Non-recovering patients show little to no improvements in the following years. Differences between recovering and non-recovering patients can be observed by Quantitative Sensory Testing already in the acute phase. Therefore, it is considered a feasible and effective tool that can contribute to the identification of high-risk patients and the prevention of chronification.

Leukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing severe symptoms and high mortality through chronic inflammation, tissue destruction, and serious infections. Despite numerous genomic sequencing efforts, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analyses with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL. We detected copy number gains of loci containing the STAT3/5 oncogenes in 74% (n = 17/23) of L-CTCL, which correlated with the increased clonal T-cell count in the blood. Dual inhibition of STAT3/5 using small-molecule degraders and multi-kinase blockers abolished L-CTCL cell growth in vitro and ex vivo, whereby PAK kinase inhibition was specifically selective for L-CTCL patient cells carrying STAT3/5 gains. Importantly, the PAK inhibitor FRAx597 demonstrated encouraging anti-leukemic activity in vivo by inhibiting tumor growth and disease dissemination in intradermally xenografted mice. We conclude that STAT3/5 and PAK kinase interaction represents a new therapeutic node to be further explored in L-CTCL.

Objective The management of occult lymph node metastasis (LNM) in head and neck squamous cell carcinoma has been a matter of controversy for decades. The vascular density within the tumor microenvironment, as an indicator of ongoing angiogenesis, could constitute an attractive predictor of LNM. The use of the panvascular endothelial antibody CD31 as a marker of occult LNM has never been reported. The aim of this study was to assess the predictive value of CD31 microvascular density for the detection of occult LNM in squamous cell carcinoma of the oral cavity and oropharynx. Study Design Case series with chart review. Setting Tertiary university hospital. Subjects and Methods Intra- and peritumoral microvascular density values were determined in 56 cases of squamous cell carcinoma of the oral cavity (n = 50) and oropharynx (n = 6) with clinically negative necks using the CD31 marker. Statistical associations of CD31 microvascular densities with clinicopathologic data were then established. Results Peritumoral CD31 microvascular density was significantly associated with occult LNM in multivariate analysis (P < .01). Recursive partitioning analysis for this parameter found a cutoff of 19.33, which identified occult LNM with a sensitivity of 91%, a specificity of 65%, a positive predictive value of 40%, a negative predictive value of 97%, and an overall diagnostic accuracy of 71%. Conclusion Peritumoral CD31 microvascular density in primary squamous cell carcinoma of the oral cavity and oropharynx allows accurate prediction of occult LNM.

This study aimed to systematically review and meta-analyze the value of pretransplant FDG-PET in predicting outcome after autologous stem cell transplantation in aggressive non-Hodgkin lymphoma. MEDLINE was systematically searched; included studies were methodologically assessed and meta-analyzed, when possible. Overall methodological quality of included studies (n = 11) was poor, with moderate risk of bias in the domains of study participation (n = 7) and prognostic factor measurement (n = 7), and high risk of bias in the domains of outcome measurement (n = 10), and study confounding (n = 11). In all aggressive non-Hodgkin lymphomas, pooled sensitivity and specificity were 54.0% and 73.1% in predicting treatment failure, and 54.5% and 68.7% in predicting death. Because of interstudy heterogeneity, additional subgroup analyses were performed. In newly diagnosed aggressive non-Hodgkin lymphoma, pooled sensitivity and specificity were 20.0% and 70.0% in predicting treatment failure, and 8.3% % and 30.5% in predicting death. In refractory/relapsed aggressive non-Hodgkin lymphoma, pooled sensitivity and specificity were 68.1% and 72.1% in predicting treatment failure, and 77.3% and 69.6% in predicting death. At present, pretransplant FDG-PET cannot be recommended in aggressive non-Hodgkin lymphoma, because available studies suffer from major methodological flaws, and reported prognostic estimates are low (i.e., poor in newly diagnosed and moderate in refractory/relapsed aggressive non-Hodgkin lymphoma).

BackgroundGrade I or low-grade chondrosarcoma (LGCS) is a primary bone tumour with low malignant potential. Historically, it was treated by wide resection, since accurate pre-operative exclusion of more aggressive cancers can be challenging and under-treatment of a more aggressive cancer could negatively influence oncological outcomes. Intralesional surgery for LGCS has been advocated more often in the literature over the past few years. The potential advantages of less aggressive treatment are better functional outcome and lower complication rates although these need to be weighed against the potential for compromising survival outcomes.ObjectivesTo assess the benefits and harms of intralesional treatment by curettage compared to wide resection for central low-grade chondrosarcoma (LGCS) of the long bones.Search methodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 4), MEDLINE and Embase up to April 2018. We extended the search to include trials registries, reference lists of relevant articles and review articles. We also searched 'related articles' of included studies suggested by PubMed.Selection criteriaIn the absence of prospective randomised controlled trials (RCTs), we included retrospective comparative studies and case series that evaluated outcome of treatment of central LGCS of the long bones. The primary outcome was recurrence-free survival after a minimal follow-up of 24 months. Secondary outcomes were upgrading of tumour; functional outcome, as assessed by the Musculoskeletal Tumor Society (MSTS) score; and occurrence of complications.Data collection and analysisWe used standard methodological procedures recognised by Cochrane. We conducted a systematic literature search using several databases and contacted corresponding authors, appraised the evidence using the ROBINS-I risk of bias tool and GRADE, and performed a meta-analysis. If data extraction was not possible, we included studies in a narrative summary.Main resultsWe included 18 studies, although we were only able to extract participant data from 14 studies that included a total of 511 participants; 419 participants were managed by intralesional treatment and 92 underwent a wide resection. We were not able to extract participant data from four studies, including 270 participants, and so we included them as a narrative summary only. The evidence was at high risk of performance, detection and reporting bias.Meta-analysis of data from 238 participants across seven studies demonstrated little or no difference in recurrence-free survival after intralesional treatment versus wide resection for central LGCS in the long bones (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.92 to 1.04; very low-certainty evidence). MSTS scores were probably better after intralesional surgery (mean score 93%) versus resection (mean score 78%) with a mean difference of 12.69 (95% CI 2.82 to 22.55; P value Authors' conclusionsOnly evidence of low- and very low-certainty was available for this review according to the GRADE system. Included studies were all retrospective in nature and at high risk of selection and attrition bias. Therefore, we could not determine whether wide resection is superior to intralesional treatment in terms of event-free survival and recurrence rates. However, functional outcome and complication rates are probably better after intralesional surgery compared to wide resection, although this is low-certainty evidence, considering the large effect size. Nevertheless, recurrence-free survival was excellent in both groups and a prospective RCT comparing intralesional treatment versus wide resection may be challenging for both practical and ethical reasons. Future research could instead focus on less invasive treatment strategies for these tumours by identifying predictors that help to stratify participants for surgical intervention or close observation.

Lymph node (LN) metastasis is the most important prognostic factor in oral squamous cell carcinoma (OSCC) patients. However, in approximately one third of OSCC patients nodal metastases remain undetected, and thus are not adequately treated. Therefore, clinical assessment of LN metastasis needs to be improved. The purpose of this study was to identify DNA methylation biomarkers to predict LN metastases in OSCC. Genome wide methylation assessment was performed on six OSCC with (N+) and six without LN metastases (N0). Differentially methylated sequences were selected based on the likelihood of differential methylation and validated using an independent OSCC cohort as well as OSCC from The Cancer Genome Atlas (TCGA). Expression of WISP1 using immunohistochemistry was analyzed on a large OSCC cohort (n = 5204). MethylCap-Seq analysis revealed 268 differentially methylated markers. WISP1 was the highest ranking annotated gene that showed hypomethylation in the N+ group. Bisulfite pyrosequencing confirmed significant hypomethylation within the WISP1 promoter region in N+ OSCC (P = 0.03) and showed an association between WISP1 hypomethylation and high WISP1 expression (P = 0.01). Both these results were confirmed using 148 OSCC retrieved from the TCGA database. In a large OSCC cohort, high WISP1 expression was associated with LN metastasis (P = 0.05), disease-specific survival (P = 0.022), and regional disease-free survival (P = 0.027). These data suggest that WISP1 expression is regulated by methylation and WISP1 hypomethylation contributes to LN metastasis in OSCC. WISP1 is a potential biomarker to predict the presence of LN metastases. (c) 2015 Wiley Periodicals, Inc.

BACKGROUND: The purpose of this study was to reveal prognostic factors for surgical complications and survival in young and elderly patients with malignant salivary gland tumors.METHODS: Retrospective analysis of surgically treated patients with malignant major salivary gland tumors was performed. Of the 111 patients, 33 patients were 70 years or older and 78 patients were under 70. Comorbidity was recorded using the Adult Comorbidity Evaluation-27 index and complications using the Clavien-Dindo classification.RESULTS: Comorbidity and complications were significantly more frequent in elderly patients (p < .05). Age, comorbidity, and length of surgery were not significant independent predictors of complications. Stage was the only independent predictive factor for postoperative complications and disease-specific survival.CONCLUSION: Based on this retrospective analysis reviewing surgically treated patients, age alone should not be a reason to treat elderly patients differently, as it was not a predictor of either complications or disease-specific survival.

Extensive population-based studies are much needed to accurately establish epidemiology and disease course in patients with primary sclerosing cholangitis (PSC). We aimed to obtain population-based prevalence and incidence figures, insight in disease course with regard to survival, liver transplantation (LT), and occurrence of malignancies, as well as risk factors thereof. Four independent hospital databases were searched in 44 hospitals in a large geographically defined area of the Netherlands, comprising 50% of the population. In addition, all PSC patients in the three Dutch liver transplant centers and all inflammatory bowel disease (IBD) patients in the adherence area of a large district hospital were identified. All medical records were reviewed on-site, verifying diagnosis. Five hundred and ninety PSC patients were identified, resulting in an incidence of 0.5 and a point prevalence of 6.0 per 100,000. Median follow up was 92 months. Estimated median survival from diagnosis until LT or PSC-related death in the entire cohort was 21.3 years, as opposed to 13.2 years in the combined transplant centers cohort (n = 422; P

Smoking is a strong risk factor of bladder cancer (BC), but it is currently unclear whether smoking is also associated with severity of BC at diagnosis. We performed a large hospital-based case-comparison study, examining the relation between smoking and clinical characteristics of BC at diagnosis. A total of 1,544 cases from participating hospitals in the West Midlands were recruited between 19 December 2005 and 21 April 2011. Eligible cases were adult BC patients without a previous history of this disease. At time of diagnosis, semi-structured face-to-face interviews were conducted by trained research nurses to collect smoking information. Clinical characteristics were obtained from medical records. Linear mixed models were performed to calculate predicted means in clinical outcomes for a variety of smoking behaviours. A P

Although uncommon, cancer of an unknown primary (CUP) metastatic to cervical lymph nodes poses a range of dilemmas relating to optimal treatment. The ideal resolution would be a properly designed prospective randomized trial, but it is unlikely that this will ever be conducted in this group of patients. Accordingly, knowledge gained from retrospective studies and experience from treating patients with known head and neck primary tumors form the basis of therapeutic strategies in CUP. This review provides a critical appraisal of various treatment approaches described in the literature. Emerging treatment options for CUP with metastases to cervical lymph nodes are discussed in view of recent innovations in the field of head and neck oncology and suitable therapeutic strategies for particular clinical scenarios are presented. For pN1 or cN1 disease without extracapsular extension (ECE), selective neck dissection or radiotherapy offer high rates of regional control. For more advanced neck disease, intensive combined treatment is required, either a combination of neck dissection and radiotherapy, or initial (chemo) radiotherapy followed by neck dissection if a complete response is not recorded on imaging. Each of these approaches seems to be equally effective. Use of extensive bilateral neck/mucosal irradiation must be weighed against toxicity, availability of close follow-up with elective neck imaging and guided fine-needle aspiration biopsy (FNAB) when appropriate, the human papillomavirus (HPV) status of the tumor, and particularly against the distribution pattern (oropharynx in the majority of cases) and the emergence rate of hidden primary lesions (

Background and Objectives: Dose reduction and shortening of duration of perfusion in isolated limb perfusion with TNF-alpha and Melphalan (TMILP) are associated with less systemic toxicity and seem to be safe and effective on short-term. However, data on long-term patient outcome are scarce.Methods: From 1991 to 2008, 102 TM-ILPs were performed in 98 patients for a locally advanced soft tissue sarcoma of the extremity. Perfusions were categorized in three groups: (A) high dose and long duration (n = 59), (B) high dose and short duration (n 16), and (C) low dose and short duration (n = 27). Long-term local control rates and (limb)-survival were evaluated.Results: Limb salvage rates were in group A 76.3%, B 62.5%, and C 85.2% (P = 0.2). With a median follow up of 76 (range 4-203) months, 50 patients were still alive (51%). Disease-specific 5-year survival was not different between the three groups: A 55.4%, B 52.5%, and C 57.3% (P = 0.9). There was no difference in local recurrence-free 5-year survival (adjusted P = 0.1) and distant metastases-free survival (P = 0.9).Conclusions: Dose reduction and shorter duration of TM-ILP seem to be safe and effective regarding long-term patient outcome, as 5-year local control rates and (limb)-survival are not compromised. J. Surg. Oncol. 2011;103:648-655. (C) 2011 Wiley-Liss, Inc.

P>Hepatocellular carcinoma (HCC) arising in noncirrhotic and nonfibrotic liver (NC-HCC) is a rare type of malignancy frequently found in healthy young individuals. Partial liver resection is the treatment of choice with expected 5-year survival rates between 40% and 70%. As a result of absence of any symptom, a considerable number of patients are diagnosed when the malignancy has progressed to an advanced stage and the tumor has turned already unresectable. Some other patients suffer from intrahepatic recurrence after previous liver resection that cannot be re-resected or locally ablated. In these situations, liver transplantation (LT) may be the only potentially curative treatment. The indication for LT in NC-HCC patients, however, is not well established. The preliminary results of recent analysis of the European Liver Transplant Registry (ELTR) together with a literature review identified over 150 patients transplanted for NC-HCC during the last 15 years. In contrast to the historical data, these studies showed 5-year survival rates at 50-70% in well-selected patients. Important determinants of poor outcome are macrovascular invasion, lymph node involvement, and time interval of

Background. Extent of neck dissection is controversial in patients with palpable medullary thyroid cancer (MTC).Methods. We evaluated 64 MTC patients (19 hereditary, 45 sporadic) with palpable thyroid nodules (group 1, n = 35) or palpable lymph node metastases (group 2, In = 29). Standard surgery included total thyroidectomy, central compartment dissection, and additional neck dissection on indication.Results. In group 1, 40% of the patients were cured. Thirty-one percent of all patients had central, 23% ipsilateral, 14% contralateral, and 14% mediastinal, metastases. Fifty-one percent developed locoregional recurrence. Locoregional recurrence (p =.043) and reoperations (p =.020) were noted more often after a less than standard initial procedure, In group 2, no patients were cured, All had central, 93% ipsilateral, 45% contralateral, and 52% mediastinal metastases. Thirty-eight percent developed locoregional recurrence.Conclusions. Locoregional recurrence frequently occurs in palpable MTC, and tumor control may be improved by standard central, bilateral, and upper mediastinal neck dissection. (c) 2007 Wiley Periodicals, Inc.

Objective In medullary thyroid cancer (MTC) age is considered an important prognostic factor but survival has never been properly adjusted for baseline mortality in the general population. We aimed to identify prognostic factors by analysing patients with MTC regarding life expectancy.Design We described a retrospective cohort study with a median follow-up of 8 years (range 1-35 years).Patients We included 120 consecutive patients of whom 66 (55%) had sporadic MTC. Male/female ratio was 1 : 1; median age was 45 years (range 3-83 years).Measurements Measurements were overall and disease-specific survival and life expectancy expressed as survival adjusted for baseline mortality rate in the general population.Results Overall and disease-specific 10-year survival was 65% and 73%, respectively. After 10 years, 29% of patients were biochemically and 63% clinically cured. Median overall life expectancy was 0.58 (95%CI 0.37-0.80). Detectable recurrence occurred in 60 patients after a median of 36 months (range 5-518 months). On multivariate regression analysis only stage of disease and extrathyroidal extension predicted recurrence-free life expectancy. Extrathyroidal extension was the only independent predictor of overall life expectancy. Persistent biochemical MTC did not independently affect life expectancy but calcitonin doubling time of less than one year indicated worse prognosis. Patients without detectable recurrences after initial treatment had a life expectancy similar to the general population.Conclusions In MTC patients, extrathyroidal extension and stage at diagnosis are the only independent predictors of (recurrence-free) life expectancy. Patients diagnosed in an early stage of disease and patients without detectable recurrence have favourable life expectancy independently of biochemical cure.

Despite the fact that numerous studies have been performed on diffuse large B-cell lymphoma (DLBCL), only few have concerned extranodal lymphomas occurring in the testis. We performed a cytogenetic and molecular study of 17 testicular non-Hodgkin lymphomas, of which 14 were proven primary DLBCL of the testis. Cytogenetic analysis revealed in 8 out of 11 evaluable cases a structural abnormality of the long arm of chromosome 6, with deletion or addition of material of unknown origin, and with breakpoints spanning the region 6q12-6q23. The cytogenetic findings were confirmed by fluorescent in situ hybridization (FISH) with a chromosome 6 painting probe. Using array based-comparative genomic hybridization on 16 evaluable cases, including 5 cases not tested by cytogenetics or FISH, 14 (88%) showed chromosome 6q deletions. We identified two regions of minimal deletion (RMD), at 104-113 Mb (6q16.3-q21) and 137.5-138.8 Mb (6q23.3), respectively. In one case, we observed a 2.7 Mb homozygous deletion ranging from 135.3 to 138.0 Mb that partly overlapped with the RMD at 6q23.3. Our study indicates that 6q deletions play a major pathogenetic role in DLBCL of the testis and that many of these deletions are part of unbalanced translocations. (c) 2006 Wiley-Liss, Inc.

Since the 1950s, it has been recognized that a subgroup of multiple sclerosis (MS) patients exists that shows little or no progression in the severity of the disease over time. This group is referred to as 'benign' MS. Although a substantial amount of research in MS indicates a multifactorial background in disease severity, to date it is still difficult to predict whether the course will be benign at onset and it is difficult to find factors that influence the course of the disease over time. Maintaining or restoring neural conduction inside a central nervous system lesion seems to be the essence of staying 'benign'.