[Benign mesothelial tumors]. / Benigne Tumoren des Mesothels.

Benign mesothelial tumors are rarer than malignant mesotheliomas and are often found in the peritoneum as incidental findings in women. They include the adenomatoid tumor (AT), the well-differentiated mesothelial tumor (WDPMT), the mesothelioma in situ (MIS), and the solid papillary mesothelial tumor (SPMT). ATs are always benign and predominantly manifest in the genital tract. WDPMTs can develop multifocally and are prone to recurrence, particularly in the case of incomplete resection. Only MISs are considered a confirmed precursor lesion of malignant mesothelioma according to the currently valid World Health Organization (WHO) classifications. As with malignant mesothelioma, alterations of BAP1, MTAP, and p16 are detectable for MIS in contrast to the other three tumors. SPMTs cannot be clearly assigned to the other mesothelial tumors and have so far only been described in the peritoneum in women with a benign course.

Dimensionality reduction for deep learning in infrared microscopy: a comparative computational survey.

While infrared microscopy provides molecular information at spatial resolution in a label-free manner, exploiting both spatial and molecular information for classifying the disease status of tissue samples constitutes a major challenge. One strategy to mitigate this problem is to embed high-dimensional pixel spectra in lower dimensions, aiming to preserve molecular information in a more compact manner, which reduces the amount of data and promises to make subsequent disease classification more accessible for machine learning procedures. In this study, we compare several dimensionality reduction approaches and their effect on identifying cancer in the context of a colon carcinoma study. We observe surprisingly small differences between convolutional neural networks trained on dimensionality reduced spectra compared to utilizing full spectra, indicating a clear tendency of the convolutional networks to focus on spatial rather than spectral information for classifying disease status.

Explanted Skull Flaps after Decompressive Hemicraniectomy Demonstrate Relevant Bone Avitality-Is Their Reimplantation Worth the Risk?

BACKGROUND: Reimplantations of autologous skull flaps after decompressive hemicraniectomies (DHs) are associated with high rates of postoperative bone flap resorption (BFR). We histologically assessed the cell viability of explanted bone flaps in certain periods of time after DH, in order to conclude whether precursors of BRF may be developed during their storage. METHODS: Skull bone flaps explanted during a DH between 2019 and 2020 were stored in a freezer at either -23 °C or -80 °C. After their thawing process, the skulls were collected. Parameters of bone metabolism, namely PTH1 and OPG, were analyzed via immunohistochemistry. H&E stain was used to assess the degree of avital bone tissue, whereas the repeated assays were performed after 6 months. RESULTS: A total of 17 stored skull flaps (8 at -23 °C; 9 at -80 °C) were analyzed. The duration of cryopreservation varied between 2 and 17 months. A relevant degree of bone avitality was observed in all skull flaps, which significantly increased at the repeated evaluation after 6 months (p < 0.001). Preservation at -23 °C (p = 0.006) as well as longer storage times (p < 0.001) were identified as prognostic factors for higher rates of bone avitality in a linear mixed regression model. CONCLUSIONS: Our novel finding shows a clear benefit from storage at -80° C, which should be carefully considered for the future management and storage of explanted skull flaps. Our analysis also further revealed a significant degree of bone avitality, a potential precursor of BFR, in skull flaps stored for several weeks. To this end, we should reconsider whether the reimplantation of autologous skull flaps instead of synthetic skull flaps is still justified.

DAXX, ATRX, and MSI in PanNET and Their Metastases: Correlation with Histopathological Data and Prognosis.

INTRODUCTION: Studies on pancreatic neuroendocrine tumors (PanNETs) regarding loss of ATRX, DAXX, or frequency of microsatellite instability (MSI) show inconclusive results. So far, data on corresponding metastaseshave not been published. METHODS: We performed immunohistochemistry (IHC) of ATRX, DAXX, MSH2, MSH6, MLH1, and PMS2 on 74 PanNETs and 19 metastases. ATRX- and DAXX-negative PanNETs were further sequenced for mutations. We used polymerase chain reaction for MSI on cases with IHC loss of MSH2, MSH6, MLH1, and PMS2. RESULTS: Immunohistochemical loss of DAXX and ATRX was observed in 8/74 (11%) and 6/74 (8%) PanNETs. Loss of DAXX immunoreactivity was statistically associated with higher tumor grade and showed a tendency toward a decreased overall survival. Sequencing of DAXX- (7/11 [64%]) and ATRX-negative (5/11 [45%]) PanNETs revealed a mutation in 6/7 (86%) and 2/5 (40%). The specificity of immunohistochemical loss of DAXX and ATRX for mutation was 80% and 67%, respectively. The expression status of DAXX compared to primary tumor differs in 2/12 (17%) lymph node metastases. We further identified 3/74 (4%) tumors as MSI, associated with a poor prognosis. DISCUSSION/CONCLUSION: Our study supports the hypothesis that a loss of DAXX immunoreactivity can identify a more aggressive subtype of PanNET with high confidence, while ATRX loss is a weaker indicator. Our results also strengthen the role of DAXX immunolabeling as a prognostic marker. We could show that ATRX might be less suitable as a surrogate for sequencing. Our results indicate that IHC of DAXX and ATRX may identify PanNET subtypes as targets for more aggressive therapy.

[Histopathological evaluation of nonalcoholic fatty liver disease : Automated evaluation of liver biopsies]. / Histopathologische Evaluierung der nichtalkoholischen Fettleber : Automatisierte Auswertung von Leberstanzen.

Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent chronic liver diseases with a rising incidence in industrial countries. This is accompanied by an increased prevalence for NAFLD-associated liver cirrhosis and an increased risk for developing hepatocellular carcinoma. The current gold standard in the diagnostics is a liver biopsy. The histopathological evaluation is performed through semiquantitative scoring. To optimize the standardization and quantification of the existing scoring systems, in the coming years procedures with artificial intelligence, such as deep learning models could be used. Fields of application could be the supplementation of conventional histopathological diagnostics, the identification of new predictive parameters for estimating the prognosis and the prediction of a possible response to treatment.

[Complete response after neoadjuvant therapy : How certain is the pathology?] / Komplettresponse nach neoadjuvanter Therapie : Wie sicher ist die Pathologie?

Histopathologic evaluation of tumors after neoadjuvant therapy is performed by tumor regression grading (TRG) systems, which reflect the proportion of vital residual primary tumor in relation to the previous total tumor. The World Health Organization (WHO) tumor grading is replaced by TRG in tumor classification. The histopathological work-up of a tumor is based on the criteria of the TNM classification even after neoadjuvant therapy. A uniform TRG does not exist. For various tumors TRGs based on the tumor entity have been established, consisting of a 3-stage or 5­stage grading system. Complete histopathological tumor regression is only present if no vital tumor cells are detectable in the histopathological examination of the primary surgical specimens (primary tumor and accompanying locoregional lymph nodes) and there are no distant metastases.

Applying machine learning to optical coherence tomography images for automated tissue classification in brain metastases.

PURPOSE: A precise resection of the entire tumor tissue during surgery for brain metastases is essential to reduce local recurrence. Conventional intraoperative imaging techniques all have limitations in detecting tumor remnants. Therefore, there is a need for innovative new imaging methods such as optical coherence tomography (OCT). The purpose of this study is to discriminate brain metastases from healthy brain tissue in an ex vivo setting by applying texture analysis and machine learning algorithms for tissue classification to OCT images. METHODS: Tumor and healthy tissue samples were collected during resection of brain metastases. Samples were imaged using OCT. Texture features were extracted from B-scans. Then, a machine learning algorithm using principal component analysis (PCA) and support vector machines (SVM) was applied to the OCT scans for classification. As a gold standard, an experienced pathologist examined the tissue samples histologically and determined the percentage of vital tumor, necrosis and healthy tissue of each sample. A total of 14.336 B-scans from 14 tissue samples were included in the classification analysis. RESULTS: We were able to discriminate vital tumor from healthy brain tissue with an accuracy of 95.75%. By comparing necrotic tissue and healthy tissue, a classification accuracy of 99.10% was obtained. A generalized classification between brain metastases (vital tumor and necrosis) and healthy tissue was achieved with an accuracy of 96.83%. CONCLUSIONS: An automated classification of brain metastases and healthy brain tissue is feasible using OCT imaging, extracted texture features and machine learning with PCA and SVM. The established approach can prospectively provide the surgeon with additional information about the tissue, thus optimizing the extent of tumor resection and minimizing the risk of local recurrences.

[CUP in the liver]. / CUP in der Leber.

Hepatic involvement is one of the most common manifestations in cancer of unknown primary (CUP) syndrome. The most frequent secondary neoplasms of the liver are carcinomas and malignant melanomas. Most common carcinoma metastases are adenocarcinomas originating from the digestive system or metastases of breast and lung carcinomas. Therefore, hepatic CUP syndrome is an exclusion diagnosis. Immunohistochemistry and molecular examinations are an important part of histopathological diagnosis. They do not only serve to identify the tissue of histologically origin or possible primary tumor, but also contribute to the selection of a personalized targeted therapy by detecting so-called druggable targets in the interdisciplinary management.

Smad7 in intestinal CD4+ T cells determines autoimmunity in a spontaneous model of multiple sclerosis.

Environmental triggers acting at the intestinal barrier are thought to contribute to the initiation of autoimmune disorders. The transforming growth factor beta inhibitor Smad7 determines the phenotype of CD4+ T cells. We hypothesized that Smad7 in intestinal CD4+ T cells controls initiation of opticospinal encephalomyelitis (OSE), a murine model of multiple sclerosis (MS), depending on the presence of gut microbiota. Smad7 was overexpressed or deleted in OSE CD4+ T cells to determine the effect on clinical progression, T cell differentiation, and T cell migration from the intestine to the central nervous system (CNS). Smad7 overexpression worsened the clinical course of OSE and increased CNS inflammation and demyelination. It favored expansion of intestinal CD4+ T cells toward an inflammatory phenotype and migration of intestinal CD4+ T cells to the CNS. Intestinal biopsies from MS patients revealed decreased transforming growth factor beta signaling with a shift toward inflammatory T cell subtypes. Smad7 in intestinal T cells might represent a valuable therapeutic target for MS to achieve immunologic tolerance in the intestine and suppress CNS inflammation.

Chronic ectopic pregnancy: case report and systematic review of the literature.

BACKGROUND: Chronic ectopic pregnancy (CEP) is a variant of ectopic pregnancy (EP) characterized by low or absent serum human chorionic gonadotropin (hCG) levels, resistance to methotrexate (MTX), and an adnexal mass with fibrosis, necrosis, and blood clots due to repeated and gradual fallopian tube wall disintegration. CEP may complicate the course of patients with EP and is difficult to diagnose. CASE PRESENTATION: The case of a 36-year-old woman with EP, low serum hCG levels, a small echogenic adnexal mass, and resistance to MTX is presented. Salpingectomy was performed and histology demonstrated CEP with fibrosis, necrosis, and a hematocele within degenerated chorionic villi. SYSTEMATIC LITERATURE REVIEW: In a database search, 19 case reports, 3 case-control studies, and 3 case series describing 399 patients with CEP were identified. Serum hCG was negative in 40/124 cases (32%) with reported levels of serum hCG. The most common presenting symptom was abdominal pain (284/399 [71%]), followed by irregular vaginal bleeding (219/399 [55%]), and fever (20/399 [5%]). 73/399 (18%) women were asymptomatic. An adnexal mass was seen in 144/298 (48%) cases with perioperative ultrasound examination and with a mean largest diameter of 6.8 cm. Data on treatment modalities and outcomes were available for 297 women. Of these, 89% underwent surgery as first-line therapy. Laparoscopy was performed in most cases. MTX was the first-line therapy in a minority of cases. Complete resolution was achieved by first-line therapy in 287/297 (97%) cases. Adverse events were reported in 218 patients with CEP. Among those, adverse events ≥ grade 3 were seen in 186/218 (85%) cases. There was no case of treatment-related mortality. CONCLUSION: CEP is a variant of EP with low or absent trophoblast activity. A prolonged clinical course is typical and surgery is the mainstay of treatment.

Refractory Epstein-Barr Virus (EBV)-Related Post-transplant Lymphoproliferative Disease: Cure by Combined Brentuximab Vedotin and Allogeneic EBV-Specific T-Lymphocytes.

Post-transplant lymphoproliferative disease (PTLD) represents a serious complication following allogeneic hematopoietic stem cell transplantation (alloHSCT). Previously, survival rates of PTLD have improved due to the introduction of rituximab. However, reports on curative management of refractory PTLD are scarce. Today, there is no consensus how to treat rituximab-refractory PTLD, especially in highly aggressive disease. Here, we describe successful management of refractory EBV-associated PTLD, specifically DLBCL, with combined brentuximab vedotin and third-party EBV-specific T-cells in a multidisciplinary treatment approach.

Rare finding in peripheral nerve surgery: an unicentric Castleman disease presenting as median nerve tumour.

A 51 year old man presented with progressive swelling in the upper arm. MRI revealed a solitary mass extending from the median nerve. Intraoperative finding was a tumour extending within the nerve in its proximal fibres. The histological result showed a Castleman disease.

Neuroendocrine carcinoma of the cervix: a systematic review of the literature.

BACKGROUND: Neuroendocrine carcinoma of the cervix (NECC) is a rare variant of cervical cancer. The prognosis of women with NECC is poor and there is no standardized therapy for this type of malignancy based on controlled trials. METHODS: We performed a systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials to identify clinical trials describing the management and outcome of women with NECC. RESULTS: Three thousand five hundred thirty-eight cases of NECC in 112 studies were identified. The pooled proportion of NECC among women with cervical cancer was 2303/163470 (1.41%). Small cell NECC, large cell NECC, and other histological subtypes were identified in 80.4, 12.0, and 7.6% of cases, respectively. Early and late stage disease presentation were evenly distributed with 1463 (50.6%) and 1428 (49.4%) cases, respectively. Tumors expressed synaptophysin (424/538 cases; 79%), neuron-specific enolase (196/285 cases; 69%), chromogranin (323/486 cases; 66%), and CD56 (162/267; 61%). The most common primary treatment was radical surgery combined with chemotherapy either as neoadjuvant or adjuvant chemotherapy, described in 42/48 studies. Radiotherapy-based primary treatment schemes in the form of radiotherapy, radiochemotherapy, or radiotherapy with concomitant or followed by chemotherapy were also commonly used (15/48 studies). There is no standard chemotherapy regimen for NECC, but cisplatin/carboplatin and etoposide (EP) was the most commonly used treatment scheme (24/40 studies). Overall, the prognosis of women with NECC was poor with a mean recurrence-free survival of 16 months and a mean overall survival of 40 months. Immune checkpoint inhibitors and targeted agents were reported as being active in three case reports. CONCLUSION: NECC is a rare variant of cervical cancer with a poor prognosis. Multimodality treatment with radical surgery and neoadjuvant/adjuvant chemotherapy with cisplatin and etoposide with or without radiotherapy is the mainstay of treatment for early stage disease while chemotherapy with cisplatin and etoposide or topotecan, paclitaxel, and bevacizumab is appropriate for women with locally advanced or recurrent NECC. Immune checkpoint inhibitors may be beneficial, but controlled evidence for their efficacy is lacking.

Intraventricular melanocytoma diagnosis confirmed by gene mutation profile.

Primary leptomeningeal melanocytic tumors (PLMTs) are rare. They usually arise along the spinal cord and at the skull base. Here we report on a patient with a very rare intraventricular melanocytoma. Histologically, a melanocytic tumor was clearly diagnosed. However, to make the uncommon diagnosis of an intraventricular melanocytoma, metastatic melanoma needed to be excluded. Next generation sequencing covering gene mutations that may occur in PLMTs and cutaneous melanoma was performed. The unique gene mutation profile detected, consisting of an activating CYSLTR2 L129Q mutation and EIF1AX G9R mutation and a lack of mutations in genes known to occur in metastatic melanoma (i.e. BRAF or NRAS) confirmed the diagnosis of an intraventricular melanocytoma. This case report is the second intraventricular melanocytoma published to date and demonstrates the value of applying novel genetic assays to make this diagnosis.

The asbestos fibre burden in human lungs: new insights into the chrysotile debate.

The traceability of asbestos fibres in human lungs is a matter of discussion especially for chrysotile. This issue is of high significance for differential diagnosis, risk assessment and occupational compensation. At present no intra-individual longitudinal information is available. This study addresses the question whether the asbestos fibre burden in human lungs decreases with time after exposure cessation.The database of the German Mesothelioma Register was screened for patients with asbestos body counts of at least 500 fibres per gram of wet lung, which had been analysed twice from different tissue excisions at minimum intervals of 4 years.Twelve datasets with individual longitudinal information were discovered with a median interval of about 8 years (range 4-21 years). Both examinations were performed after exposure cessation (median: surgery, 9.5 years; autopsy, 22 years). Pulmonary asbestos fibre burden was stable between both examinations (median 1623/4269 asbestos bodies per gram wet lung). Electron microscopy demonstrated a preponderance of chrysotile (median 80%).This study is the first to present longitudinal intra-individual data about the asbestos fibre burden in living human lungs. The high biopersistence of amphiboles, but also of chrysotile, offers mechanistic explanations for fibre toxicity, especially the long latency period of asbestos-related diseases.

Histologic evaluation of in vivo femtosecond laser-generated capsulotomies reveals a potential cause for radial capsular tears.

PURPOSE: To compare histologically the size and appearance of capsule disks after femtosecond laser-assisted cataract surgery and conventional cataract surgery. METHODS: In 100 eyes of 100 patients with visually significant cataracts, a femtosecond laser capsulotomy or a capsulorhexis with an aimed diameter of 5.0 mm was performed by one experienced surgeon. The diameter, area, circularity, and cut quality was histologically examined with light microscopy and scanning electron microscopy. RESULTS: The mean diameter of the manual and the femtosecond laser capsule disk group were not statistically significantly different (manual 4.91 ± 0.34; femtosecond: 4.93 ± 0.03; p = 0.58). The mean area of the capsule disks was 18.85 ± 2.69 mm2 in the manual and 19.03 ± 0.26 mm2 in the femtosecond group (p = 0.64). The capsules of the femtosecond group (0.95 ± 0.02) were significantly more circular than the ones of the manual group (0.81 ± 0.07; p<0.0001). The femtosecond laser capsule disks displayed a more saw blade-like structure created through the single laser spots. The histologic examination combined with prospective video analysis revealed respiratory movement of the eye during the capsulotomy as a potential risk factor for redial tears. CONCLUSIONS: Femtosecond laser can perform a capsulotomy with high reliability. In comparison to a highly experienced cataract surgeon, the achieved results in size are similar. In terms of circularity, the femtosecond laser was superior the manual procedure. Better refractive outcomes based on a 360°-degree optic overlap seem to be possible, especially for less experienced surgeons.

Histological sections of corneal incisions in OCT-guided femtosecond laser cataract surgery.

PURPOSE: To investigate the quality and accuracy of three-dimensional spectral-domain optical coherence tomography (OCT)-guided corneal incisions with the Catalys precision femtosecond laser system (OptiMedica, Sunnyvale, CA) in living human tissue. METHODS: In vivo cataract and intrastromal corneal incisions were made with a femtosecond laser designed for cataract surgery with a patient scheduled for enucleation. RESULTS: An accurate correlation between the pre-incision spectral-domain OCT and the post-incision histology was demonstrated. CONCLUSIONS: The OCT-guided femtosecond laser is capable of creating accurate, precise, and histologically demonstrable incisions in preselected intrastromal locations.

Salinomycin increases chemosensitivity to the effects of doxorubicin in soft tissue sarcomas.

BACKGROUND: Chemotherapy for soft tissue sarcomas remains unsatisfactory due to their low chemosensitivity. Even the first line chemotherapeutic agent doxorubicin only yields a response rate of 18-29%. The antibiotic salinomycin, a potassium ionophore, has recently been shown to be a potent compound to deplete chemoresistant cells like cancer stem like cells (CSC) in adenocarcinomas. Here, we evaluated the effect of salinomycin on sarcoma cell lines, whereby salinomycin mono- and combination treatment with doxorubicin regimens were analyzed. METHODS: To evaluate the effect of salinomycin on fibrosarcoma, rhabdomyosarcoma and liposarcoma cell lines, cells were drug exposed in single and combined treatments, respectively. The effects of the corresponding treatments were monitored by cell viability assays, cell cycle analysis, caspase 3/7 and 9 activity assays. Further we analyzed NF-κB activity; p53, p21 and PUMA transcription levels, together with p53 expression and serine 15 phosphorylation. RESULTS: The combination of salinomycin with doxorubicin enhanced caspase activation and increased the sub-G1 fraction. The combined treatment yielded higher NF-κB activity, and p53, p21 and PUMA transcription, whereas the salinomycin monotreatment did not cause any significant changes. CONCLUSIONS: Salinomycin increases the chemosensitivity of sarcoma cell lines - even at sub-lethal concentrations - to the cytostatic drug doxorubicin. These findings support a strategy to decrease the doxorubicin concentration in combination with salinomycin in order to reduce toxic side effects.