Research autopsy programmes in oncology: shared experience from 14 centres across the world.

While there is a great clinical need to understand the biology of metastatic cancer in order to treat it more effectively, research is hampered by limited sample availability. Research autopsy programmes can crucially advance the field through synchronous, extensive, and high-volume sample collection. However, it remains an underused strategy in translational research. Via an extensive questionnaire, we collected information on the study design, enrolment strategy, study conduct, sample and data management, and challenges and opportunities of research autopsy programmes in oncology worldwide. Fourteen programmes participated in this study. Eight programmes operated 24 h/7 days, resulting in a lower median postmortem interval (time between death and start of the autopsy, 4 h) compared with those operating during working hours (9 h). Most programmes (n = 10) succeeded in collecting all samples within a median of 12 h after death. A large number of tumour sites were sampled during each autopsy (median 15.5 per patient). The median number of samples collected per patient was 58, including different processing methods for tumour samples but also non-tumour tissues and liquid biopsies. Unique biological insights derived from these samples included metastatic progression, treatment resistance, disease heterogeneity, tumour dormancy, interactions with the tumour micro-environment, and tumour representation in liquid biopsies. Tumour patient-derived xenograft (PDX) or organoid (PDO) models were additionally established, allowing for drug discovery and treatment sensitivity assays. Apart from the opportunities and achievements, we also present the challenges related with postmortem sample collections and strategies to overcome them, based on the shared experience of these 14 programmes. Through this work, we hope to increase the transparency of postmortem tissue donation, to encourage and aid the creation of new programmes, and to foster collaborations on these unique sample collections. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Extracellular vesicles promote migration despite BRAF inhibitor treatment in malignant melanoma cells.

Extracellular vesicles (EVs) constitute a vital component of intercellular communication, exerting significant influence on metastasis formation and drug resistance mechanisms. Malignant melanoma (MM) is one of the deadliest forms of skin cancers, because of its high metastatic potential and often acquired resistance to oncotherapies. The prevalence of BRAF mutations in MM underscores the importance of BRAF-targeted therapies, such as vemurafenib and dabrafenib, alone or in combination with the MEK inhibitor, trametinib. This study aimed to elucidate the involvement of EVs in MM progression and ascertain whether EV-mediated metastasis promotion persists during single agent BRAF (vemurafenib, dabrafenib), or MEK (trametinib) and combined BRAF/MEK (dabrafenib/trametinib) inhibition.Using five pairs of syngeneic melanoma cell lines, we assessed the impact of EVs - isolated from their respective supernatants - on melanoma cell proliferation and migration. Cell viability and spheroid growth assays were employed to evaluate proliferation, while migration was analyzed through mean squared displacement (MSD) and total traveled distance (TTD) measurements derived from video microscopy and single-cell tracking.Our results indicate that while EV treatments had remarkable promoting effect on cell migration, they exerted only a modest effect on cell proliferation and spheroid growth. Notably, EVs demonstrated the ability to mitigate the inhibitory effects of BRAF inhibitors, albeit they were ineffective against a MEK inhibitor and the combination of BRAF/MEK inhibitors. In summary, our findings contribute to the understanding of the intricate role played by EVs in tumor progression, metastasis, and drug resistance in MM.

Novel functional proteins coded by the human genome discovered in metastases of melanoma patients.

In the advanced stages, malignant melanoma (MM) has a very poor prognosis. Due to tremendous efforts in cancer research over the last 10 years, and the introduction of novel therapies such as targeted therapies and immunomodulators, the rather dark horizon of the median survival has dramatically changed from under 1 year to several years. With the advent of proteomics, deep-mining studies can reach low-abundant expression levels. The complexity of the proteome, however, still surpasses the dynamic range capabilities of current analytical techniques. Consequently, many predicted protein products with potential biological functions have not yet been verified in experimental proteomic data. This category of 'missing proteins' (MP) is comprised of all proteins that have been predicted but are currently unverified. As part of the initiative launched in 2016 in the USA, the European Cancer Moonshot Center has performed numerous deep proteomics analyses on samples from MM patients. In this study, nine MPs were clearly identified by mass spectrometry in MM metastases. Some MPs significantly correlated with proteins that possess identical PFAM structural domains; and other MPs were significantly associated with cancer-related proteins. This is the first study to our knowledge, where unknown and novel proteins have been annotated in metastatic melanoma tumour tissue.

Cancer heterogeneity determined by functional proteomics.

Current manuscript gives a synopsis of tumor heterogeneity related to patient samples analyzed by proteomics, protein expression analysis and imaging mass spectrometry. First, we discuss the pathophysiologocal background of cancer biology as a multifactorial and challenging diseases. Disease pathology forms the basis for protein target selection. Therefore, histopathological diagnostics and grading of tumors is highlighted. Pathology is the cornerstone of state-of-the-art diagnostics of tumors today both by establishing dignity and - when needed - describing molecular properties of the cancers. Drug development by the pharmaceutical industry utilizes proteomics studies to pinpoint the most relevant targets. Molecular studies profiling affinity-interactions of the protein(s) with targeted small drug molecules to reach efficacy and optimal patient safety are today requested by the FDA and other agencies for new drug development. An understading of basic mechanisms, controlling drug action and drug binding is central, as a new era of personalized medicine becomes an important milestone solution for the healthcare sector as well as the Pharma and Biotech industry. Development of further diagnostic, prognostic and predictive tests will aid current and future treatment of cancer patients. In the paper we present current status of Proteomics that we believe requires attention in order to collectively advance forward in the fight against cancer, addressing the burning opportunities and challenges.

Clinical protein science in translational medicine targeting malignant melanoma.

Melanoma of the skin is the sixth most common type of cancer in Europe and accounts for 3.4% of all diagnosed cancers. More alarming is the degree of recurrence that occurs with approximately 20% of patients lethally relapsing following treatment. Malignant melanoma is a highly aggressive skin cancer and metastases rapidly extend to the regional lymph nodes (stage 3) and to distal organs (stage 4). Targeted oncotherapy is one of the standard treatment for progressive stage 4 melanoma, and BRAF inhibitors (e.g. vemurafenib, dabrafenib) combined with MEK inhibitor (e.g. trametinib) can effectively counter BRAFV600E-mutated melanomas. Compared to conventional chemotherapy, targeted BRAFV600E inhibition achieves a significantly higher response rate. After a period of cancer control, however, most responsive patients develop resistance to the therapy and lethal progression. The many underlying factors potentially causing resistance to BRAF inhibitors have been extensively studied. Nevertheless, the remaining unsolved clinical questions necessitate alternative research approaches to address the molecular mechanisms underlying metastatic and treatment-resistant melanoma. In broader terms, proteomics can address clinical questions far beyond the reach of genomics, by measuring, i.e. the relative abundance of protein products, post-translational modifications (PTMs), protein localisation, turnover, protein interactions and protein function. More specifically, proteomic analysis of body fluids and tissues in a given medical and clinical setting can aid in the identification of cancer biomarkers and novel therapeutic targets. Achieving this goal requires the development of a robust and reproducible clinical proteomic platform that encompasses automated biobanking of patient samples, tissue sectioning and histological examination, efficient protein extraction, enzymatic digestion, mass spectrometry-based quantitative protein analysis by label-free or labelling technologies and/or enrichment of peptides with specific PTMs. By combining data from, e.g. phosphoproteomics and acetylomics, the protein expression profiles of different melanoma stages can provide a solid framework for understanding the biology and progression of the disease. When complemented by proteogenomics, customised protein sequence databases generated from patient-specific genomic and transcriptomic data aid in interpreting clinical proteomic biomarker data to provide a deeper and more comprehensive molecular characterisation of cellular functions underlying disease progression. In parallel to a streamlined, patient-centric, clinical proteomic pipeline, mass spectrometry-based imaging can aid in interrogating the spatial distribution of drugs and drug metabolites within tissues at single-cell resolution. These developments are an important advancement in studying drug action and efficacy in vivo and will aid in the development of more effective and safer strategies for the treatment of melanoma. A collaborative effort of gargantuan proportions between academia and healthcare professionals has led to the initiation, establishment and development of a cutting-edge cancer research centre with a specialisation in melanoma and lung cancer. The primary research focus of the European Cancer Moonshot Lund Center is to understand the impact that drugs have on cancer at an individualised and personalised level. Simultaneously, the centre increases awareness of the relentless battle against cancer and attracts global interest in the exceptional research performed at the centre.

[Colorectal cancer heterogeneity: the clinical impact of sporadic lesions arising via the serrated pathway]. / Heterogén vastagbéldaganat: a fogazott útvonalon kialakuló, sporadikus laesiók jelentosége a klinikai gyakorlatban.

Today, colorectal cancer is regarded as a heterogeneous disease. Its heterogeneity is caused by genetic alterations, molecular aberrations, different developing pathways as well as by micro- and macroenviromental agents. In the last decade, beside the classic genetic model for colorectal tumuorgenesis that follows the adenoma-carcinoma sequence, an alternative pathway has been identified. This pathway is called the serrated pathway and it is responsible for approximately one third of all colorectal lesions. Beyond their dissimilar molecular characteristics, these tumours also show different macroscopic and histologic appearance. Moreover, their malignant potency and progressive ability distinguish them from tumours of the classic genetic model. The aim of this review is to summarize the molecular and pathologic features of serrated lesions and the serrated pathway to colorectal cancer and to highlight their clinical impact. Orv Hetil. 2018; 159(6): 206-2014.

Urachal Carcinoma of the Bladder: Impact of Clinical and Immunohistochemical Parameters on Prognosis.

PURPOSE: Urachal carcinoma of the bladder is a rare malignancy. Its histological phenotype is similar to that of primary bladder and colorectal adenocarcinoma. The aim of this study was to explore the expression and prognostic relevance of 6 select protein markers of urachal carcinoma of the bladder, including p53, Ki67, RHAMM, BGN, IMP3 and MMP-7, which were formerly shown to be prognostic in urothelial carcinoma and colorectal adenocarcinoma. MATERIALS AND METHODS: Clinical and followup data were obtained on a total of 26 patients with urachal carcinoma of the bladder treated at 2 university hospitals. Immunohistochemical analysis of p53, Ki67, RHAMM, BGN, IMP3 and MMP-7 expression was performed in samples from 15 patients. Clinicopathological parameters and immunohistochemical results were tested for prognostic value on univariable and multivariable analyses. RESULTS: Followup was 50 months. Five-year overall and progression-free survival was 46% and 32%, respectively. On multivariable analysis a positive resection margin was an independent predictor of poor overall survival (p = 0.025). RHAMM (p = 0.0431), IMP3 (p = 0.0052), Ki67 (p = 0.0006) and p53 (p = 0.0024) expression rates were significantly increased in urachal carcinoma of the bladder cells compared to normal urothelium. IMP3 was elevated in Sheldon tumor stage IIIA compared to IIIB or greater (p = 0.0048). None of the analyzed protein markers was associated with survival. CONCLUSIONS: The independent prognostic value of a positive resection margin underlines the importance of complete surgical removal of urachal carcinoma of the bladder combined with en bloc resection of the median umbilical ligament and umbilicus. Our results in a limited number of samples show that Ki67, p53, RHAMM and IMP3 expression is enhanced but has no prognostic significance in urachal carcinoma of the bladder.

Evaluation of p40 as a Myoepithelial Marker in Different Breast Lesions.

OBJECTIVE: The identification of myoepithelial cells (MEC) is a valuable clue in the differential diagnosis of breast lesions. A series of breast lesions with occasional absence of or decrease in the staining for some MEC markers was analyzed for the expression of a novel marker, p40, and results were compared to the p63 staining profile. METHODS: Samples (n = 34) from patients with benign sclerosing lesions (n = 11), ductal carcinoma in situ (n = 13) and adenomyoepithelial lesions (n = 10) and associated normal breast tissues (n = 31) were selected to evaluate the differential expression of p40 and p63 using immunohistochemistry. Triple-negative, cytokeratin 5 (CK5)-expressing invasive breast carcinomas (n = 19) were also assessed for p40 expression. RESULTS: Normal structures showed similar diffuse and strong MEC positivity using p40 and p63 in all 31 cases. The two antibodies performed similarly in all 34 breast lesions acknowledged to present altered expression of MEC markers; focal losses of expression occurred in a parallel fashion. CK5-positive carcinomas expressed p40 more frequently than p63 (18/19 vs. 8/19) and the staining was more marked. CONCLUSIONS: It seems that both antibodies can be used interchangeably for MEC identification, but show differences in the labeling at least in a subset of tumor cells in triple-negative carcinomas.

[Occurrence, intratumoral heterogeneity, prognostic and predictive potential of microsatellite instability following surgical resection of primary colorectal carcinomas and corresponding liver metastases]. / Mikroszatellita-instabilitás elofordulása, intratumoralis heterogenitása, prognosztikus és prediktív potenciálja primer colorectalis carcinomák és párosított májáttéteik sebészi kezelését követoen.

INTRODUCTION: Besides clinicopathological parameters, molecular markers can be very important, and further characterize colorectal carcinomas into chromosomally unstable, microsatellite instable and "CqG-island methylator phenotype" groups. AIM: To study the frequency of microsatellite instability using immunohistochemical evaluation of MLH1, MSH2, MSH6 and PMS2 proteins in colorectal carcinoma. METHOD: 122 colorectal carcinomas as well as in 69 paired liver metastases were evaluated. Additionally, prognostic and predictive potential of mismatch repair status was tested. RESULTS: Microsatellite instable phenotype was identified in 11.5% (14/122) of the tumours. There were no differences regarding staining intensity of tumour regions. Mismatch repair status was discordant in primaries vs. metastases in 20.2%. There was no difference in progression free- and overall survival according to mismatch repair status. The mismatch repair status was not predictive for survival within systemic therapy regimen groups. CONCLUSIONS: The subgroups of colorectal carcinomas could be evaluated in a larger and homogenised patient cohort to predict prognosis and response to therapy.

Transitional cell and clear cell renal carcinoma: differentiation of distinct histological types with multiphase CT.

BACKGROUND: Transitional cell carcinoma (TCC) may mimic renal cell carcinoma (RCC) when it develops in a similar location, therefore, differentiation with imaging techniques might be challenging. Preoperative differentiation may have a significant role indicating the type of surgical treatment (nephrectomy vs. ureteronephrectomy). PURPOSE: To retrospectively analyze the differences in the contrast enhancement of TCC and RCC. MATERIAL AND METHODS: Images of 20 RCC and 12 TCC (mean ages, 62.3 ± 14.1 and 67.4 ± 12.0 years, respectively) were analyzed from patients who underwent multiphase computed tomography (CT) examinations following 1.5 mL/kg non-ionic contrast agent administration. Unenhanced corticomedullary (30-45 s), nephrographic (70-90 s), and excretory (300-480 s) phases were imaged. The attenuation characteristics of RCC and TCC were compared to the attenuation of the normal renal cortex. RESULTS: Significant differences were found in the attenuation ratios between RCC or TCC in the corticomedullary (P = 0.040) and nephrographic (P = 0.004) phases using three regions of interest (ROIs) of 10 mm(2) size. If measuring ROIs comprising the complete tumor lesion instead of three small ROIs, no significant difference was observed in the attenuation ratios between RCC in TCC in any phases. CONCLUSION: Our study reports significant attenuation differences between RCC and TCC in the corticomedullary and nephrographic phases by multiphase CT. The findings underscore the importance of multiphase CT in the differentiation of these two different entities. Using multiple small (three) ROIs is more accurate than measuring the whole tumor attenuation.

[Is it radical enough? Transanal endoscopic microsurgery for the treatment of rectal neoplasia -- clinicopathological viewpoint]. / Kelloen radikális? Transanalis endoscopos mikrosebészeti technika szerepe a rectum daganatainak ellátásában -- egy év tapasztalatainak klinikopatológiai értékelése.

The transanal endoscopic microsurgery (TEM) provides lower relapse and complication rate for the the surgical treatment of the neoplasms of the middle and lower third of the rectum in selected cases. Hence, it can be an alternative method of the conventional approaches, if it does not compromise oncological radicality. The TEM procedure has been started at the 1st Department of Surgery, Semmelweis University in the fall of 2013. In this short study we have evaluated the clinicopathological characteristics of patients undergoing TEM between September 2013 and September 2014. Fourty-four patients were included in our retrospective analysis. 12 patients had low grade adenoma, 14 patients had high grade adenoma, 17 patients had invasive adenocarcinoma, while one was operated for a neuroendocrine tumor. There was no difference in the size of neoplasms between the low and high grade adenomas or adenocarcinomas (p = 0.210), tumors below the size of 30 mm or over 30 mm displayed no significant difference either (p = 0.424). The surgical margins were free of tumor in 41 cases (95.3%). In 13 out of 44 cases the preoperative histology proposed a lower grade neoplasm than the final report (p < 0.001). These results demonstrate that the surgical treatment of large adenomas with TEM technique, which involves excision of the whole bowel wall, is more appropriate than the fractionated removal or polypectomy supplemented by mucosectomy. The pT2 stage tumours might be subjected to the TEM method in selected cases (e.g. following neoadjuvant treatment or palliative care), but this has to be confirmed with prospecively evaluated large series clinical studies which are currently ongoing.

Identifying Ferroptosis Inducers, HDAC, and RTK Inhibitor Sensitivity in Melanoma Subtypes through Unbiased Drug Target Prediction.

The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem. Here we mine large scale MM proteogenomic data integrating it with MM cell line dependency screen, and drug sensitivity data to identify druggable targets and forecast treatment efficacy and resistance. Leveraging protein profiles from established MM subtypes and molecular structures of 82 cancer treatment drugs, we identified nine candidate hub proteins, mTOR, FYN, PIK3CB, EGFR, MAPK3, MAP4K1, MAP2K1, SRC and AKT1, across five distinct MM subtypes. These proteins serve as potential drug targets applicable to one or multiple MM subtypes. By analyzing transcriptomic data from 48 publicly accessible melanoma cell lines sourced from Achilles and CRISPR dependency screens, we forecasted 162 potentially targetable genes. We also identified genetic resistance in 260 genes across at least one melanoma subtype. In addition, we employed publicly available compound sensitivity data (Cancer Therapeutics Response Portal, CTRPv2) on the cell lines to assess the correlation of compound effectiveness within each subtype. We have identified 20 compounds exhibiting potential drug impact in at least one melanoma subtype. Remarkably, employing this unbiased approach, we have uncovered compounds targeting ferroptosis, that demonstrate a striking 30x fold difference in sensitivity among different subtypes. This implies that the proteogenomic classification of melanoma has the potential to predict sensitivity to ferroptosis compounds. Our results suggest innovative and novel therapeutic strategies by stratifying melanoma samples through proteomic profiling, offering a spectrum of novel therapeutic interventions and prospects for combination therapy. Highlights: (1) Proteogenomic subtype classification can define the landscape of genetic dependencies in melanoma (2) Nine proteins from molecular subtypes were identified as potential drug targets for specified MM patients (3) 20 compounds identified that show potential effectiveness in at least one melanoma subtype (4) Proteogenomics can predict specific ferroptosis inducers, HDAC, and RTK Inhibitor sensitivity in melanoma subtypes.

Predicting immune checkpoint therapy response in three independent metastatic melanoma cohorts.

While Immune checkpoint inhibition (ICI) therapy shows significant efficacy in metastatic melanoma, only about 50% respond, lacking reliable predictive methods. We introduce a panel of six proteins aimed at predicting response to ICI therapy. Evaluating previously reported proteins in two untreated melanoma cohorts, we used a published predictive model (EaSIeR score) to identify potential proteins distinguishing responders and non-responders. Six proteins initially identified in the ICI cohort correlated with predicted response in the untreated cohort. Additionally, three proteins correlated with patient survival, both at the protein, and at the transcript levels, in an independent immunotherapy treated cohort. Our study identifies predictive biomarkers across three melanoma cohorts, suggesting their use in therapeutic decision-making.

A 3-gene proliferation score (TOP-FOX-67) can re-classify histological grade-2, ER-positive breast cancers into low- and high-risk prognostic categories.

The goal of this study was to assess the prognostic value of a 3-gene (TOP2A, FOXM1, and MKI67) proliferation score and use it to risk stratify grade-2, estrogen receptor (ER)-positive breast cancers into low- and high-risk groups. We used 4 different breast cancer gene expression datasets including two cohorts of patients who received no systemic adjuvant therapy (Mainz: n = 206, TRANSBIG: n = 134) and two other cohorts that received adjuvant tamoxifen (JBI: n = 227, MDACC/SET: n = 192). We compared individual and combined expression values of the 3 genes between grade 1, 2, and 3 tumors and plotted distant metastasis-free survival (DMFS) curves by the 3-gene score for grade-2 cancers. We compared the prognostic value of the 3-gene score to the Genomic Grade Index (GGI). The individual and combined expression of TOP2A, FOXM1, and MKI67 were significantly different between the 3 histological grade groups with the highest expression in grade-3 and the lowest in grade-1 cancers. Expression levels were variable in grade-2 cancers. Grade-2 tumors with high expression of the 3 genes (>median) showed significantly worse DMFS in one prognostic and one tamoxifen-treated set and showed a similar but non-significant trend for worse survival in the remaining two datasets. The 3-gene score performed equally well in risk stratification as the GGI. A 3-gene proliferation score shows similar prognostic value as the GGI in ER-positive, grade-2 cancers and may serve as basis for a PCR-based assay that could aid prognostic prediction for clinically intermediate-risk cancers.

[MicroRNA-profiling in breast- and salivary gland-derived adenoid cystic carcinomas]. / Mikro-RNS-expresszió vizsgálata adenoid cysticus emlo- és nyálmirigy-carcinomákban.

INTRODUCTION: Adenoid cystic carcinoma is a salivary gland-derived malignant tumor, but rarely it can originate from the breast, too. The salivary gland-derived form shows a very aggressive clinical outcome, while adenoid cystic carcinoma of the breast has mostly a very good prognosis. AIM: The aim of the authors was to compare the miRNA-expression profile of breast- and salivary gland-derived cases. METHOD: The miRNA-profiles of two salivary gland derived and two breast-derived adenoid cystic carcinoma tissues as well as one normal breast and one salivary gland tissues were analysed using the Affymetrix® Gene Chip. RESULTS: The expression of some miRNAs differed in the tumor tissues compared to their controls: the let-7b was overexpressed in salivary gland-derived adenoid cystic carcinoma, while decreased in breast-derived adenoid cystic carcinoma. In addition, the miR-24 was decreased in salivary gland-derived but overexpressed in breast-derived adenoid cystic carcinomas. The miR-181a-2* was only detected in salivary gland-derived adenoid cystic carcinomas. CONCLUSIONS: Through post-transcriptional regulation of the genes, the diverse expression of some miRNAs may partially explain the diverse clinical outcome of salivary gland-derived and breast-derived adenoid cystic carcinomas.

[Simplified, low-cost gene expression profiling for the prediction of outcome in breast cancer based on routine histologic specimens]. / Egyszerusített, alacsony költségu génexpressziós teszt az emlodaganatos betegségek kimenetelének elorejelzésére rutin patológiai blokkok felhasználásával.

BACKGROUND: Grade 2 breast carcinomas do not form a uniform prognostic group. AIM: To extend the number of patients and the investigated genes of a previously identified prognostic signature described by the authors that reflect chromosomal instability in order to refine characterization of grade 2 breast cancers and identify driver genes. METHODS: Using publicly available databases, the authors selected 9 target and 3 housekeeping genes that are capable to divide grade 2 breast carcinomas into prognostic groups. Gene expression was investigated by polymerase chain reaction in 249 formalin-fixed, paraffin-embedded breast tumors. The results were correlated with relapse-free survival. RESULTS: Histologically grade 2 carcinomas were split into good and a poor prognosis groups. Centroid-based ranking showed that 3 genes, FOXM1, TOP2A and CLDN4 were able to separate the good and poor prognostic groups of grade 2 breast carcinomas. CONCLUSION: Using appropriately selected control genes, a limited set of genes is able to split prognostic groups of breast carcinomas independently from their grade.

[Evaluation of thrombocytosis as predictive factor in colorectal cancer]. / A thrombocytosis mint prediktív faktor értékelése colorectalis tumorokban.

UNLABELLED: INTRODUCTION/AIM OF THE STUDY: Preoperative thrombocytosis proved to be a negative prognostic factor in several solid tumor. However, there is still debate in the literature regarding colorectal cancer. The aim of our study was to examine whether thrombocytosis is an independent risk factor for metastasis development and predictor of survival in colorectal cancer. MATERIALS AND METHODS: Clinicopathological data of 336 patients with colorectal cancer (CRC) and 118 patients with liver metastasis of colorectal cancer (mCRC) who had operation between 2001 and 2011 were collected retrospectively. Thrombocytosis was defined as 400 G/L < platelet count. Disease-free survival (DFS) and overall survival (OS) were determined with Kaplan-Meier method supported by log-rank test. RESULTS: Both in the CRC and the mCRC group OS was significantly shorter in patients who had elevated platelet count (HR = 2.2, p < 0.001 and HR = 2.9, p = 0.018, respectively). Multivariate analysis confirmed that elevated platelet count was an independent prognostic factor of both CRC (HR = 1.7, p = 0.035) and mCRC (HR = 3.1, p = 0.017). DFS was significantly shorter in patients with elevated platelet count in the CRC group (HR = 2.0, p = 0.011). DISCUSSION: The platelet count is a valuable and cheap prognostic marker for the prediction of survival in patients both with CRC and mCRC.

Inter- and intratumoral proteomics and glycosaminoglycan characterization of ALK rearranged lung adenocarcinoma tissues: a pilot study.

Lung cancer is one of the most common types of cancer with limited therapeutic options, therefore a detailed understanding of the underlying molecular changes is of utmost importance. In this pilot study, we investigated the proteomic and glycosaminoglycan (GAG) profile of ALK rearranged lung tumor tissue regions based on the morphological classification, mucin and stromal content. Principal component analysis and hierarchical clustering revealed that both the proteomic and GAG-omic profiles are highly dependent on mucin content and to a lesser extent on morphology. We found that differentially expressed proteins between morphologically different tumor types are primarily involved in the regulation of protein synthesis, whereas those between adjacent normal and different tumor regions take part in several other biological processes (e.g. extracellular matrix organization, oxidation-reduction processes, protein folding) as well. The total amount and the sulfation profile of heparan sulfate and chondroitin sulfate showed small differences based on morphology and larger differences based on mucin content of the tumor, while an increase was observed in both the total amount and the average rate of sulfation in tumors compared to adjacent normal regions.

Corrigendum: A potential bioelectromagnetic method to slow down the progression and prevent the development of ultimate pulmonary fibrosis by COVID-19.

[This corrects the article DOI: 10.3389/fimmu.2020.556335.].

Long-term psychological and sexual outcomes of severe penile hypospadias repair.

INTRODUCTION: Hypospadias is the most common penis malformation, and there exist a variety of surgical approaches used to correct the abnormal position of the meatus. Although the long-term outcomes of surgery are considered important for psychosexual development, only a few attempts have been made to evaluate patient satisfaction. AIM: The aim of our study was to evaluate surgical results and psychosocial adaptations in a homogeneous group of subjects with severe penile hypospadias who underwent the same types of surgical repairs during childhood and compare the results to data obtained from age-matched healthy controls. METHODS: In this cross-sectional study, 104 men (between 24 and 42 years old) who underwent an uncomplicated two-stage hypospadias repair in their childhood and 63 age-matched healthy men without genital malformations completed the questionnaire. MAIN OUTCOME MEASURES: Difference in self-perception assessed by a 15-item questionnaire regarding psychosexual well-being and penile appearance between subjects with corrected hypospadias and healthy participants. RESULTS: On average, subjects with a hypospadias repair were less satisfied with their genital appearance; however, they were more satisfied with their sex lives compared to healthy controls. The meatus distance was approximately 1.5 cm from the tip of the penis after surgical correction. None of the postoperative surgical results correlated with patient satisfaction. Furthermore, the small percentage of patients (11%) who were very unsatisfied with their surgical outcomes had no significant differences in surgical outcomes compared to satisfied patients. However, there was a significant difference between the two groups in almost all psychological outcome measures. CONCLUSIONS: In adults who underwent an uncomplicated ventral repair of a severe penile hypospadias 20-30 years earlier, healthy psychosexual development was achieved despite the lack of a glanular meatus. Early identification of unsatisfied patients is important for appropriate long-term follow-up and counseling.