Posttraumatic Ocular Hypotony Through Epithelial Downgrowth. / Posttraumatische Bulbushypotonie durch Epithelinvasion.

BACKGROUND: Intraocular epithelial downgrowth is a rare but potentially devastating posttraumatic complication. If left untreated, this may result in corneal decompensation, secondary angle-closure glaucoma, retinal detachment and blindness. PATIENT AND METHOD: A 10-year-old patient with penetrating globe injury and delayed wound management elsewhere presented with corneal melting and decompensation, retinal detachment and ocular hypotony. Following penetrating keratoplasty, cyclopexy and vitrectomy, corneal melting in the interface with renewed retinal detachment was noted within days. The hopeless prognosis required enucleation of the globe. RESULTS: Optical coherence tomography revealed not only corneal melting, but also markedly hyperreflective structures posterior to the cornea. Immunohistology demonstrated diffuse multi-layered nonkeratinised squamous cell epithelium on the posterior corneal surface, iris, ciliary bodies, and retina, as well as below the choroid, with renewed tractional retinal detachment. CONCLUSION: Posttraumatic epithelial downgrowth may result in tractional retinal detachment, cyclodialysis cleft and/or corneal melting. Hyperreflective membrane deposits on OCT may be indicative of diffuse epithelial downgrowth. Especially in children, prompt wound closure in globe injuries is vital to avoid this serious posttraumatic complication.

IGF2BP1 is the first positive marker for anaplastic thyroid carcinoma diagnosis.

Anaplastic thyroid carcinomas (ATC) are rare, but represent the most lethal malignancy of the thyroid. Selective molecular markers and drivers distinguishing ATC from other thyroid carcinomas of follicular origin remain largely unknown, limiting advances in diagnosis and treatment. In a retrospective study, we analyzed gene expression in 36 ATC, 18 poorly differentiated, 132 papillary, and 55 follicular thyroid carcinoma, as well as 124 paired and unpaired normal thyroid tissues in three independent cohorts by RNA-sequencing and immunohistochemistry. RNA-sequencing data in the test cohort suggested selective ATC protein biomarkers. Evaluation of these revealed that ATCs are characterized by the de novo expression of various testis antigens, including melanoma-associated antigen A3 (MAGEA3), but most importantly the oncofetal IGF2 mRNA binding protein 1 (IGF2BP1). Shallow whole genome sequencing essentially excluded that IGF2BP1 upregulation results from gene copy number alterations. Immunohistochemical analyses in all three tumor cohorts confirmed the selective de novo expression of IGF2BP1 protein in ATC. In sum, 75% (27/36) of all tested ATC and 0.5% (1/204) of poorly and well-differentiated thyroid carcinoma tissue samples were positive for IGF2BP1 protein. This indicates that IGF2BP1 protein expression identifies ATC with a diagnostic odds ratio of 612 (95% CI: 74.6-5021). In addition, we found that MAGEA3 is exclusively, although less consistently upregulated in ATC, presenting with an odds ratio of 411 (95% CI: 23.8-7098.7). Importantly, we provide confirmatory evidence that IGF2BP1 and MAGEA3 expression distinguishes ATC from poorly differentiated thyroid carcinoma. IGF2BP1 furthermore identified ATC foci within low-grade follicular thyroid carcinoma. In conclusion, IGF2BP1 represents the most promising single-gene marker available for ATC, followed by MAGEA3, improving on current techniques. Robust markers are essential to help distinguish this high-grade malignancy from other thyroid carcinomas, to guide surgical decision making, therapy and post-resection/therapy monitoring strategies.

[Orbital Amyloidosis - Comparison of Two Different Clinical Courses]. / Orbitale Amyloidose ­ Vergleich zweier unterschiedlicher klinischer Verläufe.

BACKGROUND: Primary localised orbital amyloidosis (PLOA) is a very rare disease. In contrast to the isolated manifestation, systemic involvement can be associated with potentially life-threatening consequences. However, the isolated involvement of the orbit can also lead to serious complications. MATERIAL AND METHODS: Two cases of PLOA are described and the necessary ophthalmic, internistic and immunohistochemical diagnostic testing are explained. RESULTS: The first case describes a 71-year-old woman with PLOA. In the clinic, a yellow-orange bumpy prominence in the nasal lower quadrant without further ophthalmological abnormalities was found. Extensive diagnostic testing found no systemic manifestation. The patient herself was free of complaints. In the follow-up over 4 years, patient showed slow progression without ocular complications. The second case is a 72-year-old male patient with similar clinical signs but localisation in the temporal superior quadrant. During the clinical course, multiple ophthalmological complications developed (ptosis, protrusio bulbi, diplopia, secondary glaucoma, perforated corneal ulcer in neurotrophic keratopathy). Perforating keratoplasty had to be performed. Fractioned radiotherapy led to stabilisation of the disease. The follow-up period was 4 years. CONCLUSION: PLOA can lead to visual and organ threatening complications. Accurate diagnosis is required for further diagnostic and therapeutic procedures and to counteract potential local and systemic complications. Interindividual differences in the course have to be considered.

MAGE-A expression in oral and laryngeal leukoplakia predicts malignant transformation.

Leukoplakia is a potential precursor of oral as well as laryngeal squamous cell carcinoma. Risk assessment of malignant transformation based on the grade of dysplasia of leukoplakia often does not lead to reliable results. However, oral squamous cell carcinoma, laryngeal squamous cell carcinoma, and leukoplakia express single or multiple members of the melanoma-associated antigens A (MAGE-A) family, while MAGE-A are absent in healthy mucosal tissue. The present study aimed at determining if there is an association between the expression of MAGE-A in leukoplakia and malignant transformation to oral or laryngeal squamous cell carcinoma. Paraffin-embedded tissues of 205 oral and laryngeal leukoplakia, 90 corresponding tumors, and 40 healthy oral mucosal samples were included in the study. The grade of dysplasia of the leukoplakia samples was determined histopathologically. The leukoplakia samples were divided into lesions that transformed to oral and laryngeal squamous cell carcinoma (n = 91) and lesions that did not (n = 114) during a 5 years follow-up. The expression of MAGE-A3/6 and MAGE-A4 was analyzed by real-time RT-PCR. The expression of MAGE-A 1-4, 6, and 12 was determined by immunohistochemistry. A total of 59.3% of the transforming leukoplakia expressed at least one of the examined antigens as opposed to an expression rate of 3.5% of all non-transforming leukoplakia. There was no MAGE-A expression in healthy oral mucosa. The risk of malignant transformation was statistically significantly associated with MAGE-A expression in immunohistochemistry (p < 0.001) and real-time RT-PCR (MAGE-A3/6, p = 0.001; MAGE-A4, p = 0.002) analyses. There was no significant association between MAGE-A expression and the grade of dysplasia ("low-grade", D0/D1; "high-grade", D2/D3) in immunohistochemistry (p = 0.412) and real-time RT-PCR (MAGE-A3/6, p = 0.667; MAGE-A4, p = 0.756). It seems that the analysis of the MAGE-A expression profile may support the identification of leukoplakia at risk for malignant transformation. Therefore, efforts should be made to establish this analysis as a routine procedure in addition to conventional histopathology.

Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5.

Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and are often associated with progression from benign to invasive stages with metastatic potential. Mutations inactivate tumor suppression by p53, and some endow the protein with novel gain of function (GOF) properties that actively promote tumor progression and metastasis. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells, we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 target gene, which functions as a uridine 5'-diphosphatase (UDPase) in the endoplasmic reticulum (ER) to promote the folding of N-glycosylated membrane proteins. A comprehensive pan-cancer analysis revealed a highly significant correlation between p53 GOF mutations and ENTPD5 expression. Mechanistically, mutp53 is recruited by Sp1 to the ENTPD5 core promoter to induce its expression. We show ENTPD5 to be a mediator of mutant p53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals folding of N-glycosylated membrane proteins in the ER as a mechanism underlying the metastatic progression of tumors with mutp53 that could provide new possibilities for cancer treatment.

Tubular, lactating, and ductal adenomas are devoid of MED12 Exon2 mutations, and ductal adenomas show recurrent mutations in GNAS and the PI3K-AKT pathway.

Adenomas of the breast are rare benign tumors although single cases with malignant behavior have been reported. However, the genetic basis of these tumors is unknown. Employing targeted next generation sequencing of 50 cancer-related genes as well as Sanger sequencing, we profiled a cohort of 18 mammary adenomas comprising 9 ductal, 6 tubular, and 3 lactating adenoma. Missense mutations were detected in 8 of the 18 cases (44%). Specifically, five (56%) ductal adenomas and three (50%) tubular adenomas harbored mutated genes. No mutations were detected in lactating adenomas. Three of the nine ductal adenomas showed mutant AKT1 (p.E17K) with two of them harboring an additional GNAS mutation (p.R201C). One case had mutant PIK3CA (p.H1047R) and another case a mutation in GNAS (p.R201C). The three cases of mutated tubular adenomas showed mutations in either MET or FGFR3. Of note, we did not detect copy number changes and none of the cases including tubular adenomas had mutations in exon 2 of MED12. Our results suggest that ductal adenomas are related to papillomas of the breast and screening for mutations in exon 2 of MED12 might help to facilitate differential diagnosis between tubular adenoma and fibroadenoma in difficult cases. Lastly, our data exemplarily demonstrate that mutations in cancer-related genes per se do not indicate malignancy but occur in benign tumors. © 2016 Wiley Periodicals, Inc.

Monoclonal origin of peritoneal implants and lymph node deposits in serous borderline ovarian tumors (s-BOT) with high intratumoral homogeneity.

Molecular studies have shown that the most prevalent mutations in serous ovarian borderline tumors (s-BOT) are BRAF and/or KRAS alterations. About one third of s-BOT represent peritoneal implants and/or lymph node involvement. These extraovarian deposits may be monoclonal or polyclonal in origin. To test both the hypotheses, mutational analyses using pyrosequencing for BRAF codon 600 and KRAS codon 12/13 and 61 of microdissected tissue was performed in 15 s-BOT and their invasive and noninvasive peritoneal implants. Two to 6 implants from different peritoneal sites were examined in 13 cases. Lymph node deposits were available for the analysis in 3 cases. Six s-BOT showed mutation in exon 2 codon 12 of the KRAS proto-oncogen. Five additional cases showed BRAF p.V600E mutation representing an overall mutation rate of 73.3%. Multiple (2-6) peritoneal implants were analyzed after microdissection in 13 of 15 cases. All showed identical mutational results when compared with the ovarian site of the disease. All lymph node deposits, including those with multiple deposits in different nodes, showed identical results, suggesting high intratumoral mutational homogeneity. The evidence presented in this study and the majority of data reported in the literature support the hypothesis that s-BOT with their peritoneal implants and lymph node deposits show identical mutational status of BRAF and KRAS suggesting a monoclonal rather than a polyclonal disease regarding these both tested genetic loci. In addition, a high intratumoral genetic homogeneity can be suggested. In conclusion, the results of the present study support the monoclonal origin of s-BOT and their peritoneal implants and lymph node deposits.

Total spondylectomy for solitary bone plasmacytoma of the lumbar spine in a young woman: a case report and review of literature.

INTRODUCTION: Solitary bone plasmacytoma (SP) is a rare diagnosis for which the primary treatment is local radiotherapy. There is no established consensus suggesting a total spondylectomy in spinal SP. MATERIALS AND METHODS: We report the case of a 43-year-old woman with solitary plasmacytoma of the lumbar spine treated with complete vertebral resection. Radiographs, CT scan and MRI showed a single osteolytic lesion of the third lumbar vertebra. Further diagnostics following recommended algorithm for tumour screening were negative. Two times, biopsy showed no histological pathologies. Due to the instability of the spine with suspicious unknown lesion, we decided to perform a dorsal lumbar approach and instrumentation with complete resection of the posterior parts to prepare for a complete resection if mandatory. Resamples were taken and the bone surfaces sealed. Consecutive findings were positive for plasma cell infiltration of the respective vertebra, however not on the first pass, but after diagnostic pathological reference. Surgery was completed by total spondylectomy. Reference histological findings with restaging and cytogenetic risk analysis confirmed a non-high-risk solitary bone plasmacytoma, and the patient was scheduled for localized radiotherapy with 40 Gy. RESULTS: Follow-up examinations (53 months) showed no local recurrence or disease progression. DISCUSSION: There is no consensus in the literature regarding appropriate surgical approach and perioperative strategies in the treatment of solitary plasmacytoma. The finding of a solitary plasmacytoma of the spine was the determining factor for our decision to perform radical surgery with subsequent radiotherapy. The rationale for the chosen approach was to minimize the risk of local recurrence and to avoid conversion into multiple myeloma. The follow-up with 53 months is limited. However, discussion remains, if radical surgery in addition to local radiotherapy could be an alternative therapeutic approach depending on paraclinical parameters, age and cytogenetic risk analysis.

Late recurrence of a single gland primary hyperparathyroidism-Atypical parathyroid adenoma or misdiagnosed parathyroid carcinoma.

Key Clinical Message: This case report aims to raise awareness of differential diagnoses of hypercalcemia and primary hyperparathyroidism, including parathyroid carcinoma and atypical adenoma, and to highlight the diagnostic challenges. Abstract: Parathyroid carcinoma is a rare and often fatal cause of primary hyperparathyroidism and hypercalcemia. To date, there is still no clear-cut diagnostic pathway for parathyroid carcinoma established, which results in major diagnostic ambiguity and complexity. Clinical differentiation between benign parathyroid adenoma and carcinoma is challenging and ultimately the diagnosis remains histopathological. We present a case of a 58-year-old female patient with parathyroid tumor recurrence after parathyroidectomy because of primary hyperparathyroidism. The first tumor was histologically classified as an atypical parathyroid adenoma by a specialized endocrine pathologist. Eleven years after the primary tumor resection a new tumor recurred. Retrospectively, after the tumor recurrence, the primary diagnosis of the atypical adenoma was questioned, and the tumor was temporarily classified to rather be a parathyroid carcinoma. This case aims to raise awareness for the diagnostic challenge of parathyroid carcinomas as a rare cause of primary hyperparathyroidism and therewith to improve treatment and prognosis.

A Case Report Demonstrating Preservation of Vestibular Receptor Function after Transcochlear Removal of an Intracochlear Schwannoma with Extension to the Fundus of the Internal Auditory Canal.

Preservation of function is an important goal during surgical management of cochleovestibular schwannomas. We here demonstrate the relief of vertigo and the preservation of function of all five vestibular receptors after removal of an intracochlear schwannoma with extension to the fundus of the internal auditory canal. A 61-year-old male with a five-year history of left-sided deafness, tinnitus, vertigo attacks, and an MRI consistent with an intracochlear schwannoma with limited extension through the modiolus to the fundus of the internal auditory canal (IAC) underwent transcanal, transcochlear total tumor removal and-due to a cerebrospinal fluid leak from the fundus of the IAC-revision surgery with lateral petrosectomy and blind sac closure of the external auditory canal. Despite complete removal of the cochlear partition of the inner ear (total cochlectomy), the patient's vestibular receptors remained functional, and the vertigo symptoms disappeared. These results show that vestibular labyrinthine function may not only be preserved after partial or subtotal cochlectomy but also after complete cochlear removal. This further confirms the vestibular labyrinth's robustness and encourages surgical management of transmodiolar schwannomas with limited extension to the fundus of the IAC.

Concurrent KRAS p.G12C mutation and ANK3::RET fusion in a patient with metastatic colorectal cancer: a case report.

BACKGROUND: Colorectal cancer (CRC) frequently involves mutations in the KRAS gene, impacting therapeutic strategies and prognosis. The occurrence of KRAS mutations typically precludes the presence of RET fusions, with current medical literature suggesting a mutual exclusivity between these two genetic alterations. We present a unique case that challenges this notion. CASE PRESENTATION: An 85-year-old female with metastatic CRC was found to have a combination of genetic anomalies that is to the best of our knowledge not yet described in the medical literature: a KRAS p.G12C mutation, associated with oncogenesis and treatment resistance, and an ANK3::RET fusion, an infrequent but targetable mutation in CRC. This molecular profile was uncovered through comprehensive genomic sequencing after the patient experienced metachronous tumor dissemination. The presence of both genetic events complicates the treatment approach. CONCLUSIONS: The identification of both a KRAS p.G12C mutation and an ANK3::RET fusion in the same CRC patient adds a new layer to the oncogenic landscape and treatment considerations for CRC. It highlights the intricate decision-making required in the era of precision medicine, where targeted therapies must be carefully chosen and potentially combined to combat complex genetic profiles. The case emphasizes the urgency of investigating the clinical effects of concurrent or sequential use of KRAS p.G12C and RET inhibitors to inform future therapeutic guidelines and improve patient outcomes in similar cases.

Unilateral Multifocal Inner Ear and Internal Auditory Canal or Cerebellopontine Angle Cochleovestibular Schwannomas-Genetic Analysis and Management by Surgical Resection and Cochlear Implantation.

OBJECTIVE: To describe the genetic characteristics and the management of two very rare cases of unilateral multifocal inner ear and internal auditory canal or cerebellopontine angle cochleovestibular schwannomas not being associated to full neurofibromatosis type 2-related schwannomatosis. PATIENTS: In a 29-year-old man and a 55-year-old woman with single-sided deafness multifocal unilateral cochleovestibular schwannomas were surgically resected, and hearing was rehabilitated with a cochlear implant (CI). Unaffected tissue was analyzed using next generation sequencing of the NF2 gene. Tumor tissue was analyzed using a 340-parallel sequencing gene panel. MAIN OUTCOME MEASURES: Mutations in the NF2 gene, word recognition score for monosyllables at 65 dB SPL (WRS 65 ) with CI. RESULTS: No disease-causing mutation was detected in the examined sequences in blood leucokytes. All tumor samples revealed, among others, somatic pathogenic NF2 mutations. While the anatomically separate tumors in case 1 were likely molecular identical, the tumors in case 2 showed different genetic patterns. WRS 65 was 55% at 6 years of follow-up and 60% at 4.5 years of follow-up, respectively. CONCLUSIONS: The occurrence of multifocal unilateral cochleovestibular schwannomas without pathogenic variants in NF2 in non-affected blood leucocytes can be associated with mosaic NF2 -related schwannomatosis (case 1), or with likely sporadic mutations (case 2) and may be overlooked due to their extreme rarity. Although challenging, successful hearing rehabilitation could be achieved through surgical resection of the tumors and cochlear implantation.

JAK2 p.V617F allele burden in myeloproliferative neoplasms one month after allogeneic stem cell transplantation significantly predicts outcome and risk of relapse.

The risk profile and prognosis of patients with myelofibrosis is well described by the Dynamic International Prognostic Scoring System risk categorization. Allogeneic stem cell transplantation is considered for intermediate-2/high risk disease. However, indicators of prognosis after transplantation are still lacking. Seventy simultaneously collected pairs of trephine and blood samples were quantified for JAK2 p.V617F allele burden to compare test sensitivity. The course of 30 patients with JAK2 p.V617F-positive myeloproliferative neoplasia was correlated with allele burden after transplantation. Monitoring can be performed on full blood samples as well as trephine biopsies, provided that techniques with ample sensitivity (0.01% to 0.001%) are available. Measurement of allele burden on day 28 after transplantation discriminates two prognostic groups: patients with a JAK2 p.V617F allele burden >1% have a significantly higher risk of relapse of JAK2 p.V617F positive neoplasia (P=0.04) and a poorer overall survival (P<0.01). In conclusion, measurement of JAK2 p.V617F allele burden early after transplantation is an important predictive parameter in monitoring patients following this treatment. As this might provide an important tool in early management of imminent early relapse it will be important to define consensus guidelines for optimal monitoring.

Repetitive Bleomycin-Based Electrochemotherapy Improves Antitumor Effectiveness in 3D Tumor Models of Conjunctival Melanoma.

BACKGROUND: Conjunctival melanoma (CM) is associated with a high rate of local recurrence and poor survival rate. Novel therapeutic options are needed to reduce recurrence rate. The objective of the study was to demonstrate the improved effectiveness of electrochemotherapy (ECT) on CM using repetitive application. METHODS: Tumor spheroids of three CM cell lines (CRMM1, CRMM2, CM2005.1) were treated repetitively with ECT using the chemotherapeutic agent bleomycin on days 3, 5, and 7 of culture. Application of bleomycin alone and electroporation alone served as controls. The cytotoxic effect was analyzed on day 10 compared to untreated control using an independent t-test. The spheroid outgrowth rate was measured. RESULT: CM tumor spheroid size (median value: 78%, SD: 32%) and viability (median value: 11%, SD: 11%) were dramatically reduced after repetitive ECT treatment (p-value < 0.001). Decreased proliferation capacity (down to 8%) and an increase of apoptotic cells were observed. In most repetitive ECT-treated spheroids, no viable or proliferating cells were detected. Only 33-40% of repetitive ECT-treated spheroids exhibited single outgrowing cells with a delay of time up to 38 days. CONCLUSION: Repetitive ECT application effectively induces cytotoxic effects in CM spheroids by inducing apoptosis, inhibiting proliferation and decreasing the percentage of surviving tumor cells. Thus, repetitive ECT results in improved antitumor effectiveness in CM and could be an alternative therapy option.

Aortic Paraganglioma Masking as Intramural Hematoma: When You Hear Hoofbeats Think Zebras, Not Horses.

A 52-year-old woman presented dyspnea and angina. The computed tomography scan indicated an intramural hematoma, and the patient underwent surgery, during which a structure was excised that was identified as aortic paraganglioma. This case report underlines the importance of a multiprofessional interdisciplinary team to diagnose and treat cardiac masses. (Level of Difficulty: Advanced.).

Clinicopathologic and molecular characteristics of small-scale ROS1-mutant non-small cell lung cancer (NSCLC) patients.

BACKGROUND: ROS1 fusions are well treatable aberrations in NSCLC. Besides solvent-front mutations (SFM) in resistance to targeted therapy, small-scale ROS1 mutations are largely unknown. We exploratively analyzed the clinical and molecular characteristics of small-scale ROS1 mutations in NSCLC patients without activating ROS1 fusions or SFMs. METHODS: Next-generation sequencing was performed on tissue samples from NSCLC patients within the Network Genomic Medicine. Patients with ROS1 fusions and SFMs were excluded. We analyzed clinical characteristics of patients harboring small-scale ROS1-mutations, ROS1- and co-occurring mutations, and their response to systemic therapy. RESULTS: Of 10,396 patients analyzed, 101 (1.0%) patients harbored small-scale ROS1 mutations. Most patients were male (73.3%) and smokers (96.6%). Nearly half of the patients presented with squamous-cell carcinoma (SqCC, 40.4%). Most mutations were transversions (50.5%), and 66% were in the kinase domain. Besides TP53 mutations (65.3%), KRAS (22.8%), EGFR (5.9%), PIK3CA (9.9%) and FGFR1-4 mutations (8.9%) co-occurred. In 10 (9.9%) patients, ROS1 mutation was the only aberration detected. Median overall survival (mOS) differed significantly in patients with or without KRAS co-mutations (9.7 vs 21.5 months, p = 0.02) and in patients treated with or without immune-checkpoint blockade (ICB) during treatment (21.5 vs 4.4 months, p = 0.003). CONCLUSION: The cohort's clinical characteristics contrasted ROS1-fused cohorts. Co-occurrence of KRAS mutations led to shortened survival and patients benefited from ICB. Our data does not support the idea of ROS1 small-scale mutations as strong oncogenic drivers in NSCLC, but rather as relevant bystanders altering the efficacy of treatment approaches.

Abandoning node dissection for desmoplasia-negative encapsulated unifocal sporadic medullary thyroid cancer.

BACKGROUND: Predictive criteria to determine the absence of node metastases from thyroid specimens are scarce for sporadic medullary thyroid cancer. METHODS: Histopathologic stratification of patients with unifocal sporadic medullary thyroid cancer ≤25 mm with ≥10 neck nodes at thyroidectomy to evaluate the suitability of desmoplasia (7 increments) and tumor capsule integrity (5 decrements) for intraoperative prediction of node metastasis in unifocal sporadic medullary thyroid cancer. RESULTS: Paraffin-embedded thyroid specimens were available for 139 eligible patients. Significant (P < .001) associations were found between increasing desmoplasia and decreasing tumor capsule integrity and nodal disease (from 0 to 79% and 0 to 62%); the number of node metastases (medians, from 0 to 3 and 0 to 2 nodes); and biochemical cure (from 100 to 36% and 100 to 58%). Desmoplasia (low-moderate to high, with fibrosis >10%) and breach of the tumor capsule (>3 extensions; 1 extension >3 mm in width; or diffuse growth without tumor capsule) yielded excellent sensitivity and negative predictive value (100%), with moderate specificity (57 and 48%) and positive predictive value (50 and 46%). In retrospect, node dissection proved unnecessary in 55 (57%) and 47 (48%) patients who harbored desmoplasia-negative and encapsulated tumors. When available frozen sections were histopathologically compared with matching paraffin-embedded thyroid tumor specimens, concordance was 98% (53 of 54 pairs): 1 of 7 upgrades changed the diagnosis to desmoplasia, whereas 1 of 3 downgrades shifted the diagnosis of tumor capsule breach from "present" to "absent." CONCLUSIONS: Patients with desmoplasia-negative encapsulated sporadic medullary thyroid cancer may forgo node dissection at specialist centers.

New Safety Aspects in Corneal Donation-Studies on SARS-CoV-2-Positive Corneal Donors.

In the tissue donation field, to prevent pathogen transmission, all donors are screened by postmortem swabs for SARS-CoV-2 using qRT-PCR. Corneas from donors who tested positive for SARS-CoV-2 were subjected to further investigations. Corneal transplants and culture medium from positive donors were cultured under appropriate safety conditions for further analyses. Cornea tissue samples, including sclera/limbus/cornea, and culture media were taken at different time points for testing for SARS-CoV-2 using qRT-PCR, immunohistochemistry (IHC) and subgenomic RNA (sgRNA) analysis. Between January and May 2021, in four donors with initial negative premortem rapid tests, SARS-CoV-2 was detected post-mortem using qRT-PCR. In these cases, SARS-CoV-2 was observed at the beginning of cultivation in both tissue and culture medium using qRT-PCR and IHC. The virus was mainly localized in the limbus epithelial cells, with a stable detection level. Premortem rapid tests are potentially insufficient to exclude SARS-CoV-2 infection in corneal donors. While, for SARS-CoV-2, the risk of infection via transplants is considered low, a residual risk remains for presymptomatic new infections. However, our investigations provide the first indications that, with organ cultures, the risk of virus transmission is minimized due to the longer minimum culture period.

Treatment of RET-Positive Advanced Medullary Thyroid Cancer with Multi-Tyrosine Kinase Inhibitors-A Retrospective Multi-Center Registry Analysis.

BACKGROUND: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. METHODS: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. RESULTS: In total, 44/48 (92%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66%) cases. In total, 2/32 (6%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3%) patient with a germline RET variant, additional variants were found. Only 1/48 (2%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95% CI (95% confidence interval), 32-NR (not reached); n = 36), and the median PFS was 21 months (12-39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13-79; n = 22), and the median PFS was 3.5 months (2-14; n = 22) in RET-positive cases. CONCLUSIONS: RET variants were highly prevalent in patients with advanced MTC. The treatment results in RET-positive cases were similar to those reported in unselected cohorts.