Noninferiority of Artificial Intelligence-Assisted Analysis of Ki-67 and Estrogen/Progesterone Receptor in Breast Cancer Routine Diagnostics.

Image analysis assistance with artificial intelligence (AI) has become one of the great promises over recent years in pathology, with many scientific studies being published each year. Nonetheless, and perhaps surprisingly, only few image AI systems are already in routine clinical use. A major reason for this is the missing validation of the robustness of many AI systems: beyond a narrow context, the large variability in digital images due to differences in preanalytical laboratory procedures, staining procedures, and scanners can be challenging for the subsequent image analysis. Resulting faulty AI analysis may bias the pathologist and contribute to incorrect diagnoses and, therefore, may lead to inappropriate therapy or prognosis. In this study, a pretrained AI assistance tool for the quantification of Ki-67, estrogen receptor (ER), and progesterone receptor (PR) in breast cancer was evaluated within a realistic study set representative of clinical routine on a total of 204 slides (72 Ki-67, 66 ER, and 66 PR slides). This represents the cohort with the largest image variance for AI tool evaluation to date, including 3 staining systems, 5 whole-slide scanners, and 1 microscope camera. These routine cases were collected without manual preselection and analyzed by 10 participant pathologists from 8 sites. Agreement rates for individual pathologists were found to be 87.6% for Ki-67 and 89.4% for ER/PR, respectively, between scoring with and without the assistance of the AI tool regarding clinical categories. Individual AI analysis results were confirmed by the majority of pathologists in 95.8% of Ki-67 cases and 93.2% of ER/PR cases. The statistical analysis provides evidence for high interobserver variance between pathologists (Krippendorff's α, 0.69) in conventional immunohistochemical quantification. Pathologist agreement increased slightly when using AI support (Krippendorff α, 0.72). Agreement rates of pathologist scores with and without AI assistance provide evidence for the reliability of immunohistochemical scoring with the support of the investigated AI tool under a large number of environmental variables that influence the quality of the diagnosed tissue images.

Rectourethral fistula following LDR brachytherapy.

Modern LDR brachytherapy has drastically reduced rectal toxicity and decreased the occurrence of rectourethral fistulas to <0.5% of patients. Therefore, symptoms of late-onset sequelae are often ignored initially. These fistulas cause severe patient morbidity and require interdisciplinary treatment. We report on the occurrence and management of a rectourethral fistula which occurred 4 years after (125)I seed implantation.

Mucoepidermoid carcinoma of palatinal glands with exuberant foreign-body giant cell reaction.

A 69-year-old man with a 0.6 cm yellowish polypoid lesion in the lateral soft palate for 2 years is presented. Histological examination of the tumor revealed a small, well-differentiated, mucoepidermoid carcinoma dominated by densely packed cholesterol clefts in association with an exuberant foreign-body reaction with several giant cells. The tumor entity 'mucoepidermoid carcinoma with foreign-body giant cells' might be differentiated from 'mucoepidermoid carcinoma with an osteoclast-like giant cell stromal reaction' because differences in pathogenesis and tumor behavior are assumed.

Hodgkin disease-like posttransplantation lymphoproliferative disorder of donor origin in a renal allograft recipient.

Posttransplantation lymphoproliferative disorder (PTLD) develops in 1.6% of renal allograft recipients. More than 90% are of recipient origin. There are only a few reports of Hodgkin disease-like PTLD in allograft patients. We report the case of a Hodgkin disease-like PTLD of donor origin in a 16-year-old renal allograft recipient. Fourteen months after transplantation, an increasing inhomogeneous structure in the hilar region of the transplanted kidney became apparent and was excised. Histological examination showed Hodgkin- and Sternberg-Reed-like cells. Immunostaining showed CD20-positive and CD15-negative cells and Epstein-Barr virus (EBV) involvement (EBV-encoded small nonpolyadenylated RNA and EBV-determined nuclear antigen 2). DNA fingerprinting analysis proved the lymphoma to be of donor origin. Treatment consisted of nephrectomy, discontinuation of immunosuppression therapy, and local radiation. Three years after lymphoma removal, the patient was still without relapse and underwent retransplantation with stable function of the second allograft for more than 2 years now.

Expression analysis of mammaglobin A (SCGB2A2) and lipophilin B (SCGB1D2) in more than 300 human tumors and matching normal tissues reveals their co-expression in gynecologic malignancies.

BACKGROUND: Mammaglobin A (SCGB2A2) and lipophilin B (SCGB1D2), two members of the secretoglobin superfamily, are known to be co-expressed in breast cancer, where their proteins form a covalent complex. Based on the relatively high tissue-specific expression pattern, it has been proposed that the mammaglobin A protein and/or its complex with lipophilin B could be used in breast cancer diagnosis and treatment. In view of these clinical implications, the aim of the present study was to analyze the expression of both genes in a large panel of human solid tumors (n = 309), corresponding normal tissues (n = 309) and cell lines (n = 11), in order to evaluate their tissue specific expression and co-expression pattern. METHODS: For gene and protein expression analyses, northern blot, dot blot hybridization of matched tumor/normal arrays (cancer profiling arrays), quantitative RT-PCR, non-radioisotopic RNA in situ hybridization and immunohistochemistry were used. RESULTS: Cancer profiling array data demonstrated that mammaglobin A and lipophilin B expression is not restricted to normal and malignant breast tissue. Both genes were abundantly expressed in tumors of the female genital tract, i.e. endometrial, ovarian and cervical cancer. In these four tissues the expression pattern of mammaglobin A and lipophilin B was highly concordant, with both genes being down-, up- or not regulated in the same tissue samples. In breast tissue, mammaglobin A expression was down-regulated in 49% and up-regulated in 12% of breast tumor specimens compared with matching normal tissues, while lipophilin B was down-regulated in 59% and up-regulated in 3% of cases. In endometrial tissue, expression of mammaglobin A and lipophilin B was clearly up-regulated in tumors (47% and 49% respectively). Both genes exhibited down-regulation in 22% of endometrial tumors. The only exceptions to this concordance of mammaglobin A/lipophilin B expression were normal and malignant tissues of prostate and kidney, where only lipophilin B was abundantly expressed and mammaglobin A was entirely absent. RNA in situ hybridization and immunohistochemistry confirmed expression of mammaglobin A on a cellular level in endometrial and cervical cancer and their corresponding normal tissues. CONCLUSION: Altogether, these data suggest that expression of mammaglobin A and lipophilin B might be controlled in different tissues by the same regulatory transcriptional mechanisms. Diagnostic assays based on mammaglobin A expression and/or the mammaglobin A/lipophilin B complex appear to be less specific for breast cancer, but with a broader spectrum of potential applications, which includes gynecologic malignancies.

Histopathology of the gastroesophageal junction: a study on 36 operation specimens.

The entire gastroesophageal junction of 36 patients who had been operated for squamous cell carcinoma of the upper or middle esophagus was examined. Hematoxylin and eosin-stained slides were evaluated by two pathologists for the following histologic details: minimal and maximal length of cardiac mucosa (CM) and oxyntocardiac mucosa (OCM, mixture of cardiac and fundic glands), degree of inflammation in CM and OCM, and presence of intestinal metaplasia or pancreatic metaplasia. Sections of gastric corpus mucosa were evaluated for the presence of gastritis and infection; sections of esophageal squamous epithelium were evaluated for the presence of reflux esophagitis. CM was present in the entire circumference of the gastroesophageal junction in 20 cases, in parts of the circumference in 15 cases, and entirely absent in one case. The maximal length per case ranged between 1 and 15 mm (median 5 mm). OCM was circumferentially present in 22 cases and partially present in 14 cases. The maximal length ranged between 2 and 24 mm (median 7 mm). Locations of CM/OCM over submucosal esophageal glands or squamous epithelium-lined ducts, both indicating a location in the esophagus, were found in eight cases (22%) and in four cases (11%), respectively. In 18 cases (50%) intestinal metaplasia was present in CM/OCM; pancreatic metaplasia was found in 22 cases (61%). A statistically not significant trend for increase of minimal length of CM, OCM, and the sum of both was found in the presence of gastroesophageal reflux disease. Neither the presence of intestinal metaplasia nor of pancreatic metaplasia in CM/OCM was correlated with gastroesophageal reflux disease. In conclusion, the high variability in length, the frequent occurrence of intestinal metaplasia and pancreatic metaplasia, and the frequent extension into the esophagus suggest that CM/OCM is a dynamic structure that probably mirrors the influence of underlying gastroesophageal diseases. Because of the short length and incomplete circumferential extension of CM/OCM, future endoscopic-bioptic investigations will probably have to be based on more extensive sampling of the gastroesophageal junction.

Histochemical distribution and expression of aquaporin 1 in the peritoneum of patients undergoing peritoneal dialysis: relation to peritoneal transport.

BACKGROUND: Aquaporin 1 (AQP-1) channels have been claimed to be responsible for osmotically driven free-water movement across the peritoneal membrane. Data about AQP-1 expression and its location in the human peritoneum related to clinical findings concerning ultrafiltration (UF) and free-water transport are still lacking. METHODS: Fifty-seven peritoneal biopsy specimens obtained from peritoneal dialysis (PD) patients were investigated. AQP-1 expression was detected by means of immunohistochemistry and a semiquantitative scoring system. Histological findings were related to peritoneal transport properties measured by means of an extended peritoneal equilibration test (PET) using dextran 70 as a volume marker. RESULTS: AQP-1 expression in the peritoneum was detected in both vascular endothelial cells (capillaries and small venules; score, 2.96 +/- 0.92) and the mesothelial cell layer (score, 2.31 +/- 1.54). There was significantly greater AQP-1 expression in vascular endothelial cells of patients showing increased thickness of the submesothelial fibrous layer of the peritoneum greater than 400 microm compared with less than 400 microm. Free-water transport through AQP-1 was 42% +/- 12% from total UF after 1 hour. There was a significant correlation between AQP-1 expression and free-water transport after 1 hour of equilibration with 3.86% glucose in the PET (r = 0.753; P < 0.001). CONCLUSION: Our data indicate that AQP-1 is located not only in the endothelial cell layer of capillaries and small vessels in the peritoneum of PD patients, but also in the mesothelial cell layer. AQP-1 expression correlated with free-water transport after 1 hour of equilibration, reaching a significant part from total UF at this time.

Distinction between intestinal metaplasia in the cardia and in Barrett's esophagus: the role of histology and immunohistochemistry.

Intestinal metaplasia in Barrett's esophagus (BIM) is a precancerous condition, whereas the carcinogenic potential of intestinal metaplasia of the cardia (CIM) is uncertain. Although clinically important, histological distinction between both conditions by endoscopic biopsies is considered problematic. In the present study, 4-mm samples of BIM (n=31) and CIM (n=9) were selected from esophagectomy specimens that had been resected for esophageal cancer. Slides were coded and stained with hematoxylin and eosin (H&E), Alcian blue-periodic acid-Schiff (PAS), cytokeratins (CK) 7 and 20, and CD10, which labels the intestinal brush border. The predictive value of these stains for the recognition of BIM and CIM was evaluated independently by two senior pathologists. With the use of H&E-stained slides exclusively, BIM samples were categorized correctly in 93.5% and 83.9% of cases (pathologists 1 and 2, respectively), and CIM samples, in 100% and 88.9% of cases. Alcian blue-PAS-positive goblet cells were identified by both investigators in all BIM and CIM samples. BIM-typical CK 7 and 20 immunostaining pattern was identified in 90.3%/83.9% of BIM but only in 11.1%/11.1% of CIM. CD10-positive brush border was present in 32.3%/25.8% of BIM and in 88.9%/88.9% of CIM. When HE-stained slides and immunohistologically stained slides were used together for tissue recognition, BIM were categorized correctly in 90.3%/80.6% of cases, and CIM, in 88.9%/88.9% of cases. In conclusion, BIM and CIM can be usually distinguished on the basis of HE sections. CK 7 and CK 20 expression pattern analysis discriminates correctly between BIM and CIM in the majority of cases. CD10-positive intestinal brush border is present in the majority of CIM but only in a minority of BIM. However, immunohistochemical investigations could not improve the diagnostic accuracy of HE histology alone.

[Contrast-enhanced sonography using Levovist is decisive for staging and therapeutic schedule in hepatocellular carcinoma]. / Kontrastmittelsonographie der Leber als wegweisende Untersuchung für die Therapieplanung des hepatozellulären Karzinoms.

In a 65-year-old female patient, B-mode sonography detected a single focal lesion in the right liver lobe with a diameter < 3 cm. Histopathologic examination revealed a low differentiated hepatocellular carcinoma (HCC; G3). Tumor staging was performed by CT (computed tomography) scan and Resovist MRI (magnetic resonance imaging). Both examinations found a single liver lesion without signs of additional focal hepatic lesions. In addition, phase-inversion sonography in the late phase was performed using the ultrasound contrast agent Levovist. This examination of late-phase Levovist uptake detected more than five additional focal hepatic lesions in the right liver lobe, which were invisible by CT scan and Resovist MRI. This finding of multiloculated HCC was very important to decide on the patient's correct therapy. While liver transplantation is the treatment of choice in single HCC < 3 cm, it is contraindicated in multicentric HCC. In the patient described here, hemihepatectomy of the right liver lobe was performed. The histopathologic examination of the resected liver confirmed the diagnosis of multicentric HCC, which was noninvasively diagnosed only by contrast-enhanced sonography, but not by CT scan or MRI.

Biofunctional electrolyte-gated organic field-effect transistors.

The surface modification of solution-gated organic field-effect transistors is investigated. The introduction of different surface groups leads to a control of the pH sensitivity, determined by the pKa value of the added surface moiety. Together with the successful demonstration of enzyme modification of the surface, this work reveals the large potential of organic SGFETs for biosensor applications.

New treatment option for adult-onset limbal xanthogranuloma.

PURPOSE: The purposes of this study are to report a case of adult-onset juvenile xanthogranuloma and suggest a new treatment option. METHODS: A 35-year-old man presented with an isolated mass of the limbus. Biopsy revealed a histiocytic tumor with Touton's giant cells staining positive for CD68 and S-100 but negative for CD1a, consistent with JXG. Two intratumoral injections of triamcinolone acetonide 6 weeks apart were performed. The main outcome measure was 6-months follow up clinically and by ultrasound biomicroscopy. RESULTS: The lesion regressed, and corneal thickness returned to normal 3 months after the first injection. An increase in intraocular pressure required topical treatment. No recurrence was seen throughout follow up. CONCLUSION: Limbal juvenile xanthogranuloma can be successfully treated with intralesional triamcinolone acetonide, thus avoiding a lamellar keratectomy approach.

Lessons from a patient with an unusual hepatic overlap syndrome.

BACKGROUND: A 24-year-old white male was diagnosed as having Crohn's disease by clinical, endoscopic and histological assessments, and long-term remission was successfully induced with short-course prednisolone. While the Crohn's disease was still in remission, the patient presented with cholestasis and hyperbilirubinemia but normal alanine aminotransferase levels, negative results for serological tests for infectious causes of hepatopathy and normal gamma-globulin levels. INVESTIGATIONS: Repeated laboratory and serological tests, ultrasonography, endoscopic retrograde cholangiopancreatographies, CT scan, magnetic resonance cholangiopancreatography and liver biopsies. DIAGNOSIS: Autoimmune hepatitis-primary sclerosing cholangitis (AIH-PSC) overlap syndrome on the background of PSC with a rare course of sequential manifestations of the different disease components. MANAGEMENT: Combined immunosuppression with prednisolone and treatment with ursodeoxycholic acid (UDCA), endoscopic treatment of dominant stenoses, bile duct stent implantation, and close follow-up.

Treatment of chronic hepatitis delta with pegylated interferon-alpha2b.

BACKGROUND/AIMS: Chronic hepatitis D is difficult to treat. The present pilot study investigated the efficacy and tolerability of pegylated (PEG)-interferon (IFN)-alpha2b in chronic hepatitis D. PATIENTS AND METHODS: Twelve patients with chronic hepatitis D were prospectively treated with 1.5 microg/kg PEG-IFN-alpha2b for 48 weeks and followed for 24 weeks. Sustained response (SR) was defined as undetectable hepatitis delta virus (HDV) RNA by reverse transcriptase-polymerase chain reaction and normalization of alanine aminotransferase (ALT) at 6 months after treatment. Investigations included HDV RNA kinetics, determination of hepatitis B virus (HBV) and HDV genotypes and histological evaluation. RESULTS: An SR was achieved in two out of 12 of patients (17%). The negative predictive value of a less than 3 log HDV RNA decrease at month 6 was 100%. The positive predictive value of a more than 3 log HDV RNA decrease at month 6 was 67%. A marked ALT reduction at the end of treatment was observed in responders and nonresponders. Ishak histological score was comparable at baseline and significantly improved in responders compared with nonresponders at the end of follow-up (13.5 vs. 8.0; P<0.02). CONCLUSION: The present study indicates that PEG-IFN-alpha2b is a promising treatment option in chronic hepatitis D. Nonresponders could be identified by a less than 3 log decrease of HDV RNA at 6 months of treatment.

[High-grade osteosarcoma of the maxillary sinus. A case report]. / Fallbericht eines high-grade Osteosarkoms der Kieferhöhle.

BACKGROUND: Osteosarcoma of the jaw (JOS) constituting 5% to 13% of all osteosarcoma is a locally aggressive malignant mesenchymal tumor with high tendency to local recurrence and the ability to produce tumor osteoid. Compared to osteosarcoma of the remaining skeleton (SOS) JOS metastasizes relatively rarely and relatively late. It differs significantly from SOS in its biological behaviour. CASE REPORT: The presented case deals with a 60-year-old male patient suffering from a newly occurred polypous mucosal tumor of the right-sided maxillary alveolar ridge bioptically diagnosed as a granulation tissue polyp first. After transmaxillary resection of the tumor and consultation of a bone tumor reference center the final diagnosis of a high-grade chondroblastic osteosarcoma could be made. The recommended radical resection of the tumor was declined by the patient because of the expected cosmetic consequences. After surgical reduction of the rapidly growing sarcoma chemotherapy according to the COOS/EURO-B.O.S.S. protocol was initiated at a stage when computed tomography showed diffuse metastatic disease to the lungs. Chemotherapy could delay the progress of the disease only temporarily. The patient died from respiratory insufficiency. CONCLUSION: In JOS radical surgical resection is the therapy of first choice. For substantiation of the diagnosis and central registration of the cases a bone tumor reference center should be contacted.

Efficacy of unilateral nerve sparing in radical perineal prostatectomy.

AIM: We determine the efficacy of unilateral nerve-sparing radical perineal prostatectomy in preserving the sexual function. PATIENTS AND METHODS: Ninety-two patients with histologically confirmed unilateral prostate cancer were scheduled for contralateral nerve preservation. The perioperative morbidity was assessed using the patients' chart reviews. Postoperative health-related quality of life, urinary continence, and potency were evaluated prospectively with questionnaires provided before surgery and then after 6, 12, and 24 months. RESULTS: Unilateral nerve preservation was performed in 88 of the 92 patients. Due to extensive scarring or prostatic size, the procedure was terminated as regular radical prostatectomy in 4 other patients. The perioperative complication rate was low and of minor significance, except in 1 patient who experienced a significant myoglobulinuria due to a prolonged procedure. Blood transfusions were necessary in 5 (5.4%) patients. Ureteral reimplantation was performed in 1 patient because of ureteral stricture. Positive surgical margins were present in 12 (18%) of 67 pT2 patients and in 8 (35%) of 23 pT3 patients. A proportion of 48% (15/31) of the patients followed for more than 24 months and who had a good erectile function prior to surgery reported unassisted sexual intercourse. However, only 4 of these patients were completely satisfied with all aspects of sexual performance, as asked in a short version of the International Index of Erectile Function questionnaire. CONCLUSIONS: Unilateral nerve-sparing radical perineal prostatectomy is technically feasible and yields excellent results in terms of potency preservation for prostates <60 ml. However, the quality of erections is decreased, even in patients with erections sufficient for intercourse. Hence, appropriate sexual counseling in conjunction with medical therapy should be offered to all patients.

Combination treatment of IFNalpha2b and ribavirin in patients with chronic hepatitis C and persistently normal ALTs.

Combination therapy of interferon-alpha2b and ribavirin was prospectively evaluated in 20 patients with chronic replicative hepatitis and persistently normal ALTs. Patients with normal ALTs on three or more occasions within 6 months received interferon-alpha2b 3 MU three times a week with ribavirin 1000-1200 mg everyday for 12 months and had a follow-up of 6 months. HCV genotype 1 was found in 16, and HCV genotype 2 or 3 in 4 patients. No patient experienced an ALT elevation during therapy. Ten of 20 patients (50%) cleared virus at the end of treatment. In an intent-to-treat analysis, a sustained virological response (SR) was achieved in 8 of 20 patients (40%). Nonresponse occurred in 5 patients. Relapse and breakthrough were seen in 2 patients each. Treatment was discontinued in 3 patients due to side effects. Interferon (IFN) ribavirin combination therapy is effective in patients with normal ALTs and appears superior to IFN monotherapy.

HFE mutations and chronic hepatitis C: H63D and C282Y heterozygosity are independent risk factors for liver fibrosis and cirrhosis.

BACKGROUND/AIMS: The impact of heterozygous HFE mutations on the course of chronic hepatitis C and iron indices was studied. METHODS: Ferritin, transferrin saturation (TS), serum iron, C282Y and H63D mutations were determined in 401 patients with chronic hepatitis C virus (HCV) infection and 295 healthy controls. Liver histologies were available in 217 and HCV genotypes in 339 patients. RESULTS: Allele frequencies of the C282Y and H63D mutation did not differ between HCV patients and healthy controls (6.95 vs. 6.2%; 14.75 vs. 16.4%; n.s.). HFE heterozygous HCV patients had higher ferritin (349+/-37 vs. 193+/-15 microg/l; P<0.0005), TS (38+/-2 vs. 32+/-1%; P<0.0005), serum iron (144+/-6 vs. 121+/-3 microg/dl; P<0.0005), semiquantitative liver iron staining (0.26+/-0.07 vs. 0.09+/-0.03; P<0.006) and fibrosis scores (1.9+/-0.2 vs. 1.4+/-0.1; P<0.003) compared to HFE wildtypes. By multivariate regression analysis odds ratios for liver cirrhosis were 5.9 (confidence interval (CI) 1.6-22.6; P<0.009) for C282Y heterozygotes and 2.9 (CI 1.0-8.4; P<0.05) for H63D heterozygotes compared to HFE wildtypes. Considering all HFE heterozygous HCV patients, odds ratios of 3.6 (CI 1.4-9.3; P<0.009) for cirrhosis and 3.1 (CI 1.3-7.3; P<0.009) for fibrosis were calculated. CONCLUSIONS: C282Y or H63D heterozygosity is an independent risk factor for liver fibrosis and cirrhosis in HCV infected individuals. Screening for HFE mutations should be considered in HCV infection.