Characterization and Classification of Postoperative Cysts After Strabismus Surgery: Clinical, Histological, and Anterior Segment OCT Analysis in a Large German Cohort.

INTRODUCTION: In this work, we provide a detailed characterization of a rare complication-subconjunctival cyst formation after strabismus surgery-in a large German cohort. METHODS: We conducted a retrospective analysis of 822 consecutive patients who underwent strabismus surgery between 2015 and 2022. The patients received comprehensive eye and orthoptic examinations preoperatively, at 1 day, and at 3 months postoperatively. Cysts were analyzed with slit-lamp examination, anterior segment optical coherence tomography (AS-OCT), and histopathological subsumption. RESULTS: Nineteen cases of postoperative cysts were observed (2.3%), 12 of which underwent surgical revision. Clinical evaluation including slit-lamp and AS-OCT as well as histological analysis resulted in a classification of three types of cysts: type 1, which is a single hyporeflective cyst, type 2, which is a multilobular hyporeflective cyst, and type 3, a dense hyperreflective granulomatous-like cyst. Eta (η) correlation ratio analysis could show a correlation between time of clinical appearance and type of cyst (Eta = 0.63). Most cysts developed within 20 days after surgery. Not only did cysts more frequently affect the medial rectus muscle, which in most cases underwent a shortening procedure (11/19 tucks, 4/19 resections) for intermittent exotropia (X(T)), but the cyst also formed earlier than in the lateral rectus muscle (Eta = 0.45). No correlation could be shown between the type of surgical procedure and time of cyst occurrence (Eta = 0.1). Patient age and cyst type correlated strongly (Eta = 0.47). The underlying type of strabismus did not correlate with the type of cyst observed. CONCLUSIONS: Our cases showed a strong positive correlation to the type of strabismus (X(T)), age (young patients), and the procedure (tuck/resection). We introduce a grading system for postoperative cysts after strabismus surgery, complementing histopathology and slit-lamp aspects with AS-OCT information.

Inter-observer agreement for the histological diagnosis of invasive lobular breast carcinoma.

Invasive lobular breast carcinoma (ILC) is the second most common breast carcinoma (BC) subtype and is mainly driven by loss of E-cadherin expression. Correct classification of BC as ILC is important for patient treatment. This study assessed the degree of agreement among pathologists for the diagnosis of ILC. Two sets of hormone receptor (HR)-positive/HER2-negative BCs were independently reviewed by participating pathologists. In set A (61 cases), participants were provided with hematoxylin/eosin (HE)-stained sections. In set B (62 cases), participants were provided with HE-stained sections and E-cadherin immunohistochemistry (IHC). Tumor characteristics were balanced. Participants classified specimens as non-lobular BC versus mixed BC versus ILC. Pairwise inter-observer agreement and agreement with a pre-defined reference diagnosis were determined with Cohen's kappa statistics. Subtype calls were correlated with molecular features, including CDH1/E-cadherin mutation status. Thirty-five pathologists completed both sets, providing 4,305 subtype calls. Pairwise inter-observer agreement was moderate in set A (median κ = 0.58, interquartile range [IQR]: 0.48-0.66) and substantial in set B (median κ = 0.75, IQR: 0.56-0.86, p < 0.001). Agreement with the reference diagnosis was substantial in set A (median κ = 0.67, IQR: 0.57-0.75) and almost perfect in set B (median κ = 0.86, IQR: 0.73-0.93, p < 0.001). The median frequency of CDH1/E-cadherin mutations in specimens classified as ILC was 65% in set A (IQR: 56-72%) and 73% in set B (IQR: 65-75%, p < 0.001). Cases with variable subtype calls included E-cadherin-positive ILCs harboring CDH1 missense mutations, and E-cadherin-negative ILCs with tubular elements and focal P-cadherin expression. ILCs with trabecular growth pattern were often misclassified as non-lobular BC in set A but not in set B. In conclusion, subtyping of BC as ILC achieves almost perfect agreement with a pre-defined reference standard, if assessment is supported by E-cadherin IHC. CDH1 missense mutations associated with preserved E-cadherin protein expression, E- to P-cadherin switching in ILC with tubular elements, and trabecular ILC were identified as potential sources of discordant classification.

Severe allo-immune antibody-associated peripheral and central nervous system diseases after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a curative treatment for hematologic malignancies. Acute and chronic graft-versus-host disease (GvHD) are the major immune-mediated complications after alloHSCT. However, there is controversy whether neurologic complications after alloHSCT might represent manifestations of GvHD. We report three patients who acquired distinct, severe immune-mediated peripheral or central nervous system diseases after alloHSCT without other, concomitant GvHD manifestations. One patient had been diagnosed with B-cell chronic lymphocytic leukemia and two patients with high risk myelodysplastic syndrome. Patient #1 presented as LGI1- and GAD-IgG positive immune-mediated encephalitis, patient #2 was diagnosed with MOG-IgG positive encephalomyelitis, and patient #3 had chronic inflammatory polyneuropathy associated with SSA(Ro)-IgG positive Sjögren's syndrome. 100% donor chimerism was detectable in the peripheral blood in all three. The specific antibodies were undetectable in donors' and patients' blood before alloHSCT suggesting that the antibodies had arisen from the transplanted donor immune system. Early intensive immunotherapy led to improvement of clinical symptoms and stability of the neurological disease, however, at the cost of losing the graft-versus-malignancy effect in one patient. In conclusion, we provide evidence of isolated, severe allo-immune diseases of the peripheral and central nervous system as complications of alloHSCT ("neuro-GvHD"). Interdisciplinary surveillance and thorough diagnostic work-up are needed for early diagnosis and treatment of neuro-immunologic complications after alloHSCT to improve the otherwise poor outcome.

A Rare Pathology: Low-Grade Fibromyxoid Sarcoma of the Maxilla.

Low-grade fibromyxoid sarcoma (LGFMS) is a rare tumor with a benign histologic appearance and fully malignant behavior. To date, only 5 cases of LGFMS in the maxillofacial region have been reported. This report describes the case of a 16-year-old boy who was referred to the authors' hospital with an intraosseous myxofibroblastic tumor, probably of the LGFMS type, of the right maxilla. Radical resection with wide safe margins and secondary reconstruction with a free forearm flap were performed. Six-month follow-up showed no sign of recurrence or metastasis. The authors review the scientific literature and discuss different tumor locations and treatment strategies for those in the maxillofacial region. The present case is the sixth reported case of LGFMS in the maxillofacial region (intraosseous LGFMS of the maxilla), adding another facet to the literature regarding this rare soft tissue tumor.

Dynamic obstruction of the left main coronary artery ostium by a papillary fibroelastoma.

BACKGROUND: Benign tumours of the heart are usually detected as incidental findings during echocardiography. Most cases are intracardiac tumours, with myxoma being the most frequent entity. We present images of a patient with acute myocardial infarction and a concomitant extracardiac benign tumour in the aortic root. METHODS: Transesophageal echocardiography, coronary computed tomography angiography, cardiac surgery and histology of the excised tumour were performed. RESULTS: A mobile mass was found in the aortic root obstructing the left main coronary artery ostium during diastole. Coronary CT angiography indicated severe coronary artery disease and the patient underwent bypass surgery and excision of the tumour. The excised tumour was identified as papillary fibroelastoma. CONCLUSIONS: Papillary fibroelastoma is the second most benign tumour of the heart. More than other tumours it is prone to embolization. Extracardiac location as in our case is very rare but dangerous since embolization may occur spontaneously or associated with catheterization.

Eight-year experience with cryopreserved arterial homografts for the in situ reconstruction of abdominal aortic infections.

OBJECTIVE: This study investigated short-term and long-term outcomes in patients with abdominal aortic infection (mycotic aneurysm, prosthetic graft infection, aortoenteric fistula) managed by total excision of the aneurysm or the infected vascular graft and in situ aortic reconstruction with a cryopreserved arterial homograft (CAH). METHODS: From January 2000 to December 2008, 110 consecutive patients underwent CAH implantation for treatment of vascular infections. In 57 (52%), in situ revascularization of the abdominal aorta with Y-prosthesis constructed from CAHs was performed. Early outcome included 30-day mortality and the levels of daily blood markers (leucocytes, C-reactive protein, and platelets) during the postsurgical 10-day period. We reported long-term survival and freedom from reoperation rates, including all indications for reoperation. RESULTS: Indications for operation were infected vascular graft in 31 patients (55%), aortodigestive fistulae in 11 (19%), nonruptured mycotic aneurysms in 4 (7%), and ruptured mycotic aneurysms of abdominal aorta in 11 (19%). In 39 of 57 patients (68%), the intraoperative specimens were positive for at least one microorganism, and Staphylococcus aureus was present in 14 (25%). In 32 patients (82%) with intraoperative specimens positive for microorganisms, there was no evidence of the intraoperatively detected microorganisms in the postoperative specimens (wound, blood culture, and drainage fluid). The peak value of leucocytes (13.7 +/- 4.4 x 10(3)/L) and C-reactive protein (200 +/- 75 mg/L) occurred on postoperative day 3. Platelets reached the lowest value on postoperative day 2 (178 +/- 67 x 10(9)/L). Median peak body temperature was 37.7 degrees +/- 0.6 degrees C. Thirty-day mortality was 9% (5 of 57 patients). Median follow-up was 36 months (range, 4-118 months); 3-year survival was 81%, and freedom from reoperation was 89%. Five patients (9%) required reoperation, in one patient each for postoperative bleeding, acute cholecystitis, homograft occlusion, homograft-duodenum fistula, and aneurysmal degeneration. No recurrence of infection was reported. CONCLUSION: These results demonstrate an encouraging outcome after cryopreserved allograft implantation for the treatment of vascular infections in the abdominal aorta. The data represent a basis for future comparisons with other treatment modalities for vascular infections, including silver-coated prostheses and autogenous femoral veins.

Clinical relevance of transjugular liver biopsy in comparison with percutaneous and laparoscopic liver biopsy.

BACKGROUND: Transjugular liver biopsy (TJLB) is frequently used to obtain liver specimens in high-risk patients. However, TJLB sample size possibly limits their clinical relevance. METHODS: 102 patients that underwent TJLB were included. Clinical parameters and outcome of TJLB were analyzed. Control samples consisted of 112 minilaparoscopic liver biopsies (mLLBs) and 100 percutaneous liver biopsies (PLBs). RESULTS: Fewer portal tracts were detected in TJLB (4.3 +/- 0.3) in comparison with PLB (11.7 +/- 0.5) and mLLB (11.0 +/- 0.6). No difference regarding the specification of indeterminate liver disease and staging/grading of chronic hepatitis was observed. In acute liver failure (n = 32), a proportion of hepatocellular necrosis beyond 25% was associated with a higher rate of death or liver transplantation. CONCLUSIONS: Despite smaller biopsy samples the impact on the clinical decision process was found to be comparable to PLB and mLLB. TJLB represents a helpful tool to determine hepatocellular necrosis rates in patients with acute liver failure.

Surgical treatment of a thoracoabdominal aneurysm in Cogan's syndrome.

Cogan's syndrome is a rare systemic disease which occurs predominantly in children and young adults. It was originally described as the combination of interstitial keratitis and audiovestibular disturbance. The nonspecific symptoms of the patients can be associated with numerous of systemic manifestations and, most characteristic, cardiovascular involvement. It affects large vessels (Takayasu-like) and medium size (polyarteritis nodosa-like) vessels. Here a case of extensive thoracoabdominal aortic replacement in a 28-year-old woman with Cogan's syndrome due to the symptomatic aortic aneurysm is described.

Adult Kasabach-Merritt Syndrome due to Hepatic Giant Hemangioma.

Cavernous hemangiomas are the most common benign tumors of the liver. They can reach enormous sizes and cause various complications. Kasabach-Merritt syndrome is a rare but serious complication characterized by consumptive coagulopathy caused by the hemangioma; mortality rate ranges between 10 and 37%. More than 80% of cases occur within the first year of life. Goals of the treatment are to control the coagulopathyand thrombocytopenia as well as to eradicate the hemangioma. Different nonsurgical treatment regimens are performed, includingsystemic corticosteroids, irradiation and various chemicals. Surgery should be limited to symptomatic or complicated cases. Although difficult, resection of the tumor is usually curative. Here we present a 44-year-old woman with giant hepatic hemangioma causing Kasabach-Merritt syndrome managed by enucleation.

Fibroblasts of recipient origin contribute to bronchiolitis obliterans in human lung transplants.

RATIONALE: The participation of circulating precursor cells in the development of experimental pulmonary fibrosing lesions in mice has been recently demonstrated. OBJECTIVES: This study analyzes whether circulating, bone marrow-derived, fibroblastic precursor cells contribute to the development of fibrosing lesions in human lungs, especially bronchiolitis obliterans. METHODS: The occurrence of in situ microchimerism in bronchiolitis obliterans lesions of human lung allografts (n = 12) as well as of autologous lung tissue from patients post-bone marrow transplantation (n = 2) was analyzed using laser-assisted microdissection after immunohistochemical labeling of leukocytes followed by short tandem repeat-polymerase chain reaction-based genotyping. Combined immunofluorescence and fluorescence in situ hybridization for sex chromosomes was performed for independent confirmation in cases with appropriate sex mismatch (n = 2). MEASUREMENTS AND MAIN RESULTS: The bronchiolitis obliterans lesions of all 12 lung transplant patients contained considerable numbers of recipient-derived fibroblasts (mean, 32%). The fibrosing pulmonary lesions of the two bone marrow-transplanted patients also displayed clear in situ microchimerism. The in situ detection methodology confirmed these results, although to a lower degree (6-16%). CONCLUSIONS: These data clearly demonstrate the involvement of circulating fibroblastic precursor cells in the development of human fibrosing lung lesions and provide evidence that these cells are most probably bone marrow derived. These results may open new venues regarding the prevention of fibrosis in lung transplants and potentially in other organs.

[Fibroblasts of recipient origin contribute to broncholitis obliterans in human lung transplants]. / Bronchiolitis obliterans nach Lungentransplantation enthält Empfängerfibroblasten.

RATIONALE: The participation of circulating precursor cells in the development of experimental pulmonary fibrosing lesions in mice has been recently demonstrated. OBJECTIVES: This study analyzes whether circulating, bone marrow-derived fibroblastic precursor cells contribute to the development of fibrosing lesions in human lungs, especially bronchiolitis obliterans. METHODS: The occurrence of in situ-microchimerism in bronchiolitis obliterans lesions of human lung allografts (n = 12) as well as of autologous lung tissue from patients post bone marrow-transplantation (n = 2) was analyzed using laser-assisted microdissection after immunohistochemical labeling of leukocytes followed by STR-PCR-based genotyping. Combined immunofluorescence and fluorescence in situ hybridization for sex chromsomes was performed for independent confirmation in cases with appropriate sex mismatch (n = 2). MEASUREMENTS AND MAIN RESULTS: The bronchiolitis obliterans lesions of all twelve lung transplant patients contained considerable numbers of recipient-derived fibroblasts (mean: 32 %). The fibrosing pulmonary lesions of the two bone marrow-transplanted patients displayed also clear in situ-microchimerism. The in situ detection methodology confirmed these results, although to a lower degree (6-16%). CONCLUSIONS: These data clearly demonstrate the involvement of circulating fibroblastic precursor cells in the development of human fibrosing lung lesions and provide evidence that these cells are most probably bone marrow-derived. These results may open new venues regarding the prevention of fibrosis in lung transplants and potentially other organs.

Tubular chimerism occurs regularly in renal allografts and is not correlated to outcome.

Recent studies have demonstrated an integration of recipient-derived progenitor cells into solid allografts with differentiation into parenchymal cells. Whether or to what extent this phenomenon influences allograft outcome has still to be elucidated. To detect epithelial chimerism tubular cells were harvested from sequential renal allograft biopsy samples by laser microdissection in 36 patients. Recipient-derived cells were detected by short-tandem repeat-based genotyping. In cases with gender-mismatched transplantation, chimerism was semiquantitatively evaluated by in situ hybridization for the Y-chromosome. Findings were correlated to different pathomechanisms of epithelial injury as well as to morphologic and clinical outcome. Epithelial chimerism was detectable as early as 8 d after transplantation and lasted for 8 yr. A total of 88% of the patients showed an epithelial chimerism; 72% had a stable chimerism in sequential biopsy samples. Evaluation of Y-chromosome by in situ hybridization revealed low percentages of chimerical tubular epithelial cells (2.4% to 6.6%). No correlation to morphology was found. Chimerism was detectable in inconspicuous protocol biopsy samples, cases of drug toxicity, and rejected allografts with and without chronic changes. No correlation was found to allograft function. Epithelial microchimerism is an early and persistent phenomenon after renal transplantation. There is no correlation to morphologic or functional outcome. Probably recipient-derived stem cells contribute in a minor fashion to tissue homeostasis, and cell turnover in renal allografts is predominantly enabled by donor cell renewal.

Increased chimerism of bronchial and alveolar epithelium in human lung allografts undergoing chronic injury.

Chimerism on the parenchymal level has been shown for several human allografts, including liver, heart, and kidney, with the integrated recipient-derived cells most likely originating from multipotent bone marrow precursors. We investigated whether chimerism also occurs within epithelial structures of the lung. For this purpose archival tissue biopsies from seven explanted human lung allografts were obtained. We performed laser microdissection of the target structures with subsequent short tandem repeat analysis to detect chimerism within the isolated cells. We found integration of recipient-derived cells in the bronchial epithelium, in type II pneumocytes and in seromucous glands lying adjacent to larger bronchi in all lung allografts studied. Quantitative analysis revealed that the epithelial structures displaying signs of chronic injury, such as squamous metaplasia, showed a markedly higher degree of chimerism (24% versus 9.5%). We therefore conclude that in human lungs, epithelial chimerism occurs at least within bronchi, type II pneumocytes, and seromucous peribronchial glands. Although a bone marrow origin of immigrating host-derived stem cells has been suggested by previous studies in rodents, analysis of lung biopsies from bone marrow-transplanted patients (n = 3) could not prove such delineation in this study. The observation of an enhanced integration of recipient cells into chronically damaged epithelial structures suggests that extrapulmonary precursor cells are able to contribute to pulmonary regeneration.

Electron spin resonance characterization of vascular xanthine and NAD(P)H oxidase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation.

BACKGROUND: Increased inactivation of nitric oxide by superoxide (O2*-) contributes to endothelial dysfunction in patients with coronary disease (CAD). We therefore characterized the vascular activities of xanthine oxidase and NAD(P)H oxidase, 2 major O2*--producing enzyme systems, and their relationship with flow-dependent, endothelium-mediated vasodilation (FDD) in patients with CAD. METHODS AND RESULTS: Xanthine- and NAD(P)H-mediated O*.- formation was determined in coronary arteries from 10 patients with CAD and 10 controls by using electron spin resonance spectroscopy. Furthermore, activity of endothelium-bound xanthine oxidase in vivo and FDD of the radial artery were determined in 21 patients with CAD and 10 controls. FDD was measured before and after infusion of the antioxidant vitamin C (25 mg/min i.a.) to determine the portion of FDD inhibited by radicals. In coronary arteries from patients with CAD, xanthine- and NAD(P)H-mediated O2*- formation was increased compared with controls (xanthine: 12+/-2 versus 7+/-1 nmol O2*-/ microg protein; NADH: 11+/-1 versus 7+/-1 nmol O2*-/ microg protein; and NADPH: 12+/-2 versus 9+/-1 nmol O2*-/ microg protein; each P<0.05). Endothelium-bound xanthine oxidase activity was increased by >200% in patients with CAD (25+/-4 versus 9+/-1 nmol O2*-/ microL plasma per min; P<0.05) and correlated inversely with FDD (r=-0.55; P<0.05) and positively with the effect of vitamin C on FDD (r=0.54; P<0.05). CONCLUSIONS: The present study represents the first electron spin resonance measurements of xanthine and NAD(P)H oxidase activity in human coronary arteries and supports the concept that increased activities of both enzymes contribute to increased vascular oxidant stress in patients with CAD. Furthermore, the present study suggests that increased xanthine oxidase activity contributes to endothelial dysfunction in patients with CAD and may thereby promote the atherosclerotic process.

Comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) in the diagnosis of hepatocellular carcinoma.

BACKGROUND: The histomorphological diagnosis of well differentiated hepatocellular carcinoma (HCC) may be a challenging task, because regenerative nodules and adenomas share similar microscopic features. Moreover, the differentiation of intrahepatic metastatic spread from multicentric growth in multinodular HCC is frequently not possible by histological criteria alone. Whether molecular cytogenetic analysis can contribute to the differential diagnosis of HCC was recently investigated by our group. METHODS: We applied comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) to 12 cases of hepatocellular adenoma (HCA) and 28 cases of well differentiated HCC. RESULTS: CGH revealed aberrations in 2/6 HCAs, affecting 7p in 1 sample each and 17q and 20 in the second case. In 4/4 well differentiated HCCs, aberrations occurred, with a mean of eight aberrations per case, focused on 1q, 4q, 8p, 8q, 16p, and 17p. In all HCC samples, at least two of these sites were affected. In 2 multinodular HCCs, six and four different tumor nodes, respectively, were analyzed. In the first case, aberration patterns of chromosomes 1, 4, 5, 9, 13, and 17 were almost identical in all six nodes, indicating metastatic spread. In the second case, three of the nodes showed very similar patterns of chromosome aberrations, including those of chromosomes 1, 4, 5, 7, 8, 10, 12, 14, 17, and 18. Aberrations of chromosomes 4, 5, 8, 10, 12, and 15 were shown in the fourth node, findings conclusive for both the metastatic spread and the multicentric origin of the HCC. Based on the CGH results, five probes, for chromosomes 1, 6, 7, 8, and X, were selected for FISH. Using this panel, we found no aberrations in 14 HCAs. By contrast, 13/14 HCCs demonstrated aberrations for two to five chromosomes in the FISH analysis. CONCLUSIONS: We conclude that CGH and FISH are helpful diagnostic tools for the histopathological differential diagnosis of HCC.

Detection of chromosomal imbalances in hepatocellular carcinoma.

Hepatocellular carcinoma is the most common malignant tumor of the liver. The discrimination between well-differentiated hepatocellular carcinoma and reactive lesions and benign tumors may be difficult, especially when performed on the basis of needle biopsies. A promising means of solving this problem is provided by chromosomal analysis of imbalances in hepatocellular carcinoma. This article describes the different approaches to ascertain differential diagnosis by chromosomal studies in a reliable and cost-effective manner. It is shown that in situ hybridization techniques provide a reliable means of defining chromosome alterations. These techniques allow the detection of genetic gains and losses of defined chromosomes in a histopathological context and can serve as a helpful tool in establishing diagnosis of liver cell proliferation.

Detection of chromosomal aberrations in well-differentiated hepatocellular carcinoma by bright-field in situ hybridization.

Differentiation between well-differentiated hepatocellular carcinoma (HCC) and nonmalignant lesions with increased cellular proliferation may be difficult in needle biopsies. Based on recurrent chromosome aberrations known for HCC, we developed a nonfluorescent in situ hybridization technique that allows combination with morphological analysis in bright-field microscopy. Fourteen biopsies of HCC and 31 samples of regenerative nodules (n = 10), chronic hepatitis (n = 10), fibrosis or cirrhosis of unknown origin (n = 5), focal nodular hyperplasia (n = 2), primary biliary cirrhosis (n = 2), steatosis (n = 1), and adenomatous hyperplasia (n = 1) were analyzed with probes specific for the centromeric regions of chromosomes 1, 6, 7, and 8. After microwave pretreatment and in situ hybridization, signals were detected using a tyramine-based system and AEC as substrate. Evaluation of signals was done by conventional bright-field microscopy. Using this approach, aberrant counts were seen for at least one chromosome in 12/14 cases of HCC. In contrast, none of the nonmalignant lesions revealed aberrant counts for any of the chromosomes analyzed. In conclusion, this new combination of in situ hybridization and tyramine amplification allows fast and reliable evaluation of chromosome aberrations in a histomorphological context similar to paraffin immunohistochemistry. Registration of imbalances contributes to a reliable differentiation between malignant and nonmalignant lesions of the liver.