Quantitative analysis of prion disease using an AI-powered digital pathology framework.

Prion disease is a fatal neurodegenerative disorder characterized by accumulation of an abnormal prion protein (PrPSc) in the central nervous system. To identify PrPSc aggregates for diagnostic purposes, pathologists use immunohistochemical staining of prion protein antibodies on tissue samples. With digital pathology, artificial intelligence can now analyze stained slides. In this study, we developed an automated pipeline for the identification of PrPSc aggregates in tissue samples from the cerebellar and occipital cortex. To the best of our knowledge, this is the first framework to evaluate PrPSc deposition in digital images. We used two strategies: a deep learning segmentation approach using a vision transformer, and a machine learning classification approach with traditional classifiers. Our method was developed and tested on 64 whole slide images from 41 patients definitively diagnosed with prion disease. The results of our study demonstrated that our proposed framework can accurately classify WSIs from a blind test set. Moreover, it can quantify PrPSc distribution and localization throughout the brain. This could potentially be extended to evaluate protein expression in other neurodegenerative diseases like Alzheimer's and Parkinson's. Overall, our pipeline highlights the potential of AI-assisted pathology to provide valuable insights, leading to improved diagnostic accuracy and efficiency.

Fibromatosis mimicking relapse of a neuroendocrine tumor at 68Ga-DOTATOC positron-emission tomography/computed tomography.

Mesenteric fibromatosis (desmoid tumor) is a locally aggressive fibroblastic lesion, characterized by a high recurrence rate that makes treatment challenging. Currently, there is no evidence-based treatment approach. We report the case of a female patient with a history of neuroendocrine tumor, who underwent 68Ga-DOTATOC positron-emission tomography/computed tomography (PET/CT), showing increased focal abdominal uptake suggestive of disease relapse. Histological examination revealed typical findings of fibromatosis. These findings indicate the expression of staining for somatostatin receptors (SSTRs) on fibromatosis cell surface and suggest to include fibromatosis among the potential causes of false-positive results at 68Ga PET/CT. Moreover, SSTRs expressed in desmoid tumors could be further investigated as a therapeutic target.

A Monocentric Retrospective Study about the Correlation between Histology and Cytology of Thyroid Indeterminate Nodules Classified as TIR 3A and TIR 3B, according to 2014 Italian Consensus for Classification and Reporting of Thyroid Cytology.

BACKGROUND: In 2014, the Italian Consensus for Classification and Reporting of Thyroid Cytology (ICCRTC) reviewed the previous cytological classification proposed in 2007 including the subdivision of TIR 3 category into low risk (TIR 3A) and high risk (TIR 3B). In Italian literature, different rates of malignancy have been correlated to these subcategories. OBJECTIVES: The aim of the study is to present our experience on this subclassification for the assessment of the malignancy risk of indeterminate thyroid nodules. We correlated the subdivision into TIR 3A and TIR 3B with the histological report by highlighting the rates of malignancy detected in the two subcategories. On the one hand, we aimed to check if the groups are associated with a real and significant difference risk of malignancy. On the other hand, we evaluated the use of this subdivision in the choice of the appropriate treatment. STUDY DESIGN: This is a retrospective review of all the patients with an indeterminate nodule who underwent US-FNA and had surgery at ASL Città di Torino between January 2005 and May 2018. RESULTS: 150 patients have been analyzed for the research; 62 (41.3%) had a malignant histological report. Rates of malignancy between TIR 3A (20.8%) and TIR 3B (60.3%) were significantly different (p < 0.0001). The subclassification had high sensitivity (75.8%; CI 63.3-85.8%) and NPV (79.3%; CI 68-87.8%) and low specificity (64.8%; CI 53.9-74.7%) and PPV (60.3; CI 48.5-71.2%). The measurement of the accuracy (AUC = 0.7) classified the test as "moderately accurate." Conclusions. Obtained data show a great rate of false negative (20.8%) and limited AUC (0.7). According to our logistic regression, we argue that the 2014 subclassification into TIR 3A and TIR 3B should be considered for the choice of patient treatment, but at the same time, we believe that the association with other screening tests is necessary to increase the accuracy in the future.

The "milky way" galaxy of HIV-related central nervous system immune reaction syndromes.

The landscape of central nervous system HIV infection is rapidly changing, leading to the recognition of a new constellation of overlapping syndromes and to a better insight for the elder ones. Among these, progressive multifocal leukoencephalopathy (PML) still poses several diagnostic and therapeutic challenges; nevertheless, recent developments in understanding PML in patients with multiple sclerosis may have benefitted HIV-positive patients suffering from PML too. We describe a peculiar case of PML-immune reconstitution inflammatory syndrome (IRIS) presenting a punctate pattern with "milky way" appearance on magnetic resonance imaging. Despite the fact that brain imaging and histopathology remain the mainstays for extricating through the expanding galaxy of HIV-related central nervous system dysimmune syndromes and although punctate pattern has been already well acknowledged as a suggestive finding of PML among patients on natalizumab, this radiological presentation is still poorly recognised in AIDS-related PML cases, leading to possible life-threatening diagnostic delays. This is also the first report about intravenous immunoglobulin treatment in AIDS-related PML-IRIS; the favourable clinical and radiological outcome of our case and the preliminary administrations of intravenous immunoglobulins in natalizumab-associated PML-IRIS from literature support probable benefits also among HIV-positive patients.

Clinical and neuropathological phenotype associated with the novel V189I mutation in the prion protein gene.

Prion diseases are neurodegenerative disorders which are caused by an accumulation of the abnormal, misfolded prion protein known as scrapie prion protein (PrPSc). These disorders are unique as they occur as sporadic, genetic and acquired forms. Sporadic Creutzfeldt-Jakob Disease (CJD) is the most common human prion disease, accounting for approximately 85-90% of cases, whereas autosomal dominant genetic forms, due to mutations in the prion protein gene (PRNP), account for 10-15% of cases. Genetic forms show a striking variability in their clinical and neuropathological picture and can sometimes mimic other neurodegenerative diseases.We report a novel PRNP mutation (V189I) in four CJD patients from three unrelated pedigrees. In three patients, the clinical features were typical for CJD and the diagnosis was pathologically confirmed, while the fourth patient presented with a complex phenotype including rapidly progressive dementia, behavioral abnormalities, ataxia and extrapyramidal features, and the diagnosis was probable CJD by current criteria, on the basis of PrPSc detection in CSF by Real Time Quaking-Induced Conversion assay. In all the three patients with autopsy findings, the neuropathological analysis revealed diffuse synaptic type deposition of proteinase K-resistant prion protein (PrPres), and type 1 PrPres was identified in the brain by western blot analysis. So, the histopathological and biochemical profile associated with the V189I mutation was indistinguishable from the MM1/MV1 subtype of sporadic CJD.Our findings support a pathogenic role for the V189I PRNP variant, confirm the heterogeneity of the clinical phenotypes associated to PRNP mutations and highlight the importance of PrPSc detection assays as diagnostic tools to unveil prion diseases presenting with atypical phenotypes.

Parathyroid carcinoma. A single Institution experience and a review of the international literature.

INTRODUCTION: Parathyroid carcinoma (PC) is a slow-growing and very rare malignancy, representing less than 0.005% of all cancers. The rarity of PC makes it hard to create large-scale published series of patients affected by this condition. MATERIALS AND METHODS: We present four cases of PC treated in our Institution and analyze the most salient aspects of this disease highlighted in recent international literature. DISCUSSION AND COMMENTS: In our experience, in 3/4 cases, the clinical presentation of PC was not different compared to adenoma; therefore, the diagnosis was a post-operative histopathological surprise. We noticed a clear, preoperative laboratory evidence of higher values of PTH and calcemia in patients with PC compared to adenoma. In our experience, a surgical approach consisting in parathyroidectomy associated with ipsilateral loboisthmectomy and central neck lymph node dissection offers the best prognostic chance. Moreover, surgery should be performed only in referral centers where an interdisciplinary management is guaranteed. We are confident in suggesting the surgical approach also in patients with poor clinical status due to high calcemia. If performed by experienced surgeons, the surgical risk of parathyroidectomy is low and we assisted to a progressive restoration of neurological function and an improvement in the patient's quality of life. Finally, even if our experience is limited, we observed an association between PC and thyroid cancer that deserves a validation through more comprehensive further studies. CONCLUSION: PC remains a complex disease in which a valid surgical approach represents the only curative treatment. KEY WORDS: Parathyroid, Parathyroid carcinoma, Parathyroidectomy, hormone, Surgical oncology.

Parathyroid carcinoma. A single Institution experience and a review of the international literature.

INTRODUCTION: Parathyroid carcinoma (PC) is a slow-growing and very rare malignancy, representing less than 0.005% of all cancers. The rarity of PC makes it hard to create large-scale published series of patients affected by this condition. MATERIALS AND METHODS: We present four cases of PC treated in our Institution and analyze the most salient aspects of this disease highlighted in recent international literature. DISCUSSION AND COMMENTS: In our experience, in 3/4 cases, the clinical presentation of PC was not different compared to adenoma; therefore, the diagnosis was a post-operative histopathological surprise. We noticed a clear, preoperative laboratory evidence of higher values of PTH and calcemia in patients with PC compared to adenoma. In our experience, a surgical approach consisting in parathyroidectomy associated with ipsilateral loboisthmectomy and central neck lymph node dissection offers the best prognostic chance. Moreover, surgery should be performed only in referral centers where an interdisciplinary management is guaranteed. We are confident in suggesting the surgical approach also in patients with poor clinical status due to high calcemia. If performed by experienced surgeons, the surgical risk of parathyroidectomy is low and we assisted to a progressive restoration of neurological function and an improvement in the patient's quality of life. Finally, even if our experience is limited, we observed an association between PC and thyroid cancer that deserves a validation through more comprehensive further studies. CONCLUSION: PC remains a complex disease in which a valid surgical approach represents the only curative treatment. KEY WORDS: Parathyroid, Parathyroid carcinoma, Parathyroidectomy, hormone, Surgical oncology.

When Is Thyroidectomy the Right Choice? Comparison between Fine-Needle Aspiration and Final Histology in a Single Institution Experience.

OBJECTIVES: The aim of this study was to compare SIAPEC-IAP-based cytological reports with their corresponding histological diagnoses to establish when thyroidectomy is the right choice in the management of thyroid diseases. STUDY DESIGN: This is a retrospective review of all the consecutive thyroidectomies/lobectomies performed at Maria Vittoria Hospital during the 10-year period between January 2005 and December 2015. Patients who underwent both fine-needle aspiration (FNA) and surgical procedures in our institution were included in the study. RESULTS: A total of 260 patients underwent both FNA and a thyroid surgical procedure at Maria Vittoria Hospital; 111 (42.69%) had a malignant histological report. The final cytological diagnosis was nondiagnostic (TIR-1) in 19 cases (7.31%), benign (TIR-2) in 83 cases (31.92%), indeterminate (TIR-3) in 96 cases (36.92%), suspicious for malignancy (TIR-4) in 22 cases (8.46%), and diagnostic for malignancy (TIR-5) in 40 cases (15.38%). Among the 96 cases with TIR-3 cytology, after the review, 44 (16.92%) were classified as TIR-3A and 52 (20%) as TIR-3B. The prevalence of malignancy among TIR-3A cases was 20.45% (9/44) and among TIR-3B cases 53.85% (28/52). The difference was statistically significant (p = 0.0007). CONCLUSIONS: Our data suggest that follow-up alone is not sufficient in TIR-3A patients given the high prevalence of malignancy within that diagnostic category (20.45%) and the low sensitivity (75.68%) and specificity (59.32%) in the distinction between TIR-3A and TIR-3B. Regarding patients with a multinodular goiter and TIR-2 at FNA, the surgical approach should not be excluded.

Percentage of positive prostate biopsies independently predicts biochemical outcome following radiation therapy for prostate cancer.

BACKGROUND: This work aims to definitely show the ability of percentage of positive biopsy cores (%PC) to independently predict biochemical outcome beyond traditional pretreatment risk-factors in prostate cancer (PCa) patients treated with radiotherapy. METHODS: A cohort of 2493 men belonging to the EUREKA-2 retrospective multicentric database on (PCa) and treated with external-beam radiation therapy (EBRT) as primary treatment comprised the study population (median follow-up 50 months). A Cox regression time to prostate-specific antigen (PSA) failure analysis was performed to evaluate the predictive power of %PC, both in univariate and multivariate settings, with age, pretreatment PSA, clinical-radiological staging, bioptic Gleason Score (bGS), RT dose and RT +/- ADT as covariates. RESULTS: P statistics for %PC is lower than 0.001 both in univariate and multivariate models. %PC as a continuous variable yields an AUC of 69% in ROC curve analysis for biochemical relapse. Four classes of %PC (1-20%, 21-50%, 51-80% and 81-100%) distinctly split patients for risk of biochemical relapse (overall log-rank test P<0.0001), with biochemical progression free survival (bPFS) at 5-years ranging from 88% to 58% and 10-years bPFS ranging from 80% to 38%. CONCLUSIONS: We strongly affirm the usefulness of %PC information beyond main risk factors (PSA, staging and bGS) in predicting biochemical recurrence after EBRT for PCa. The stratification of patients according to %PC may be valuable to further discriminate cases with favourable or adverse prognosis.

An unusual case of neurothekeoma of the arm in an adult.

Neurothekeomas are uncommon benign neoplasms with a peripheral nerve sheath origin. This tumor usually involves dermis and is described as a small, solitary, slow growing and reddish to flesh-colored nodule or papule. Neurothekeoma preferentially affects the central aspect of the face, the arms or shoulders of women in the second and third decades of life. This is the first case report of neurothekeoma involving the wrist developing from synovial tissue and with uncertain clinical behavior in an adult female. The tumor was completely excised under brachial plexus block. Histopathologically, the examination of the microscopic slides revealed the presence of a 20-mm diameter, well-circumscribed and multilobulated tumor composed of abundant myxoid stroma with cellular elements; with immunohistochemistry there was positivity to vimentin but S100-protein, epithelial membrane antigen, cytokeratin AE1-3, CD99 and CD34 were all negative. This pattern suggested a myxoid tumor form of neurothekeoma, mixed subtype. The patient had an atypical local recurrence and was re-operated after 3 months. After 12 months there was no evidence of clinical recurrences confirmed by magnetic resonance evaluation. Basically, our case report adds an important element in the correct clinical management of neurotecheomas: faced with a histological diagnosis with an unusual localization and mixed or hypercellular type, clinicians must consider the possibility of an early local recurrence, suggesting a close clinical and radiological follow-up.

Thyroidectomy for Painful Thyroiditis Resistant to Steroid Treatment: Three New Cases with Review of the Literature.

Thyroidal pain is usually due to subacute thyroiditis (SAT). In more severe forms prednisone doses up to 40 mg daily for 2-3 weeks are recommended. Recurrences occur rarely and restoration of steroid treatment cures the disease. Rarely, patients with Hashimoto's thyroiditis (HT) have thyroidal pain (painful HT, PHT). Differently from SAT, occasional PHT patients showed no benefit from medical treatment so that thyroidectomy was necessary. We report three patients who did not show clinical response to prolonged high dose prednisone treatment: a 50-year-old man, a 35-year-old woman, and a 33-year-old woman. Thyroidectomy was necessary, respectively, after nine-month treatment with 50 mg daily, two-month treatment with 75 mg daily, and one-month treatment with 50 mg daily. The two women were typical cases of PHT. Conversely, in the first patient, thyroid histology showed features of granulomatous thyroiditis, typical of SAT, without fibrosis or lymphocytic infiltration, typical of HT/PHT, coupled to undetectable serum anti-thyroid antibodies. Our data (1) suggest that not only PHT but also SAT may show resistance to steroid treatment and (2) confirm a previous observation in a single PHT patient that increasing prednisone doses above conventional maximal dosages may not be useful in these patients.

The collagen chaperone HSP47 is a new interactor of APP that affects the levels of extracellular beta-amyloid peptides.

Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive decline of cognitive function that represents one of the most dramatic medical challenges for the aging population. Aß peptides, generated by processing of the Amyloid Precursor Protein (APP), are thought to play a central role in the pathogenesis of AD. However, the network of physical and functional interactions that may affect their production and deposition is still poorly understood. The use of a bioinformatic approach based on human/mouse conserved coexpression allowed us to identify a group of genes that display an expression profile strongly correlated with APP. Among the most prominent candidates, we investigated whether the collagen chaperone HSP47 could be functionally correlated with APP. We found that HSP47 accumulates in amyloid deposits of two different mouse models and of some AD patients, is capable to physically interact with APP and can be relocalized by APP overexpression. Notably, we found that it is possible to reduce the levels of secreted Aß peptides by reducing the expression of HSP47 or by interfering with its activity via chemical inhibitors. Our data unveil HSP47 as a new functional interactor of APP and imply it as a potential target for preventing the formation and/or growth amyloid plaques.

Type III intestinal metaplasia, Helicobacter pylori infection and gastric carcinoma risk index in an Italian series of 1750 patients.

BACKGROUND/AIMS: To evaluate the utility of 2 biopsies of antrum and gastric body on routine endoscopy for the assessment of type III intestinal metaplasia (IM-3) and Helicobacter pylori (Hp), 1750 patients (pts) (895 males; 855 females) were considered from June'98 to June'00. METHODOLOGY: Specimens were graded 0 to 3 for atrophy, IM-3 and Hp. 610 pts treated previously with antibiotics or not eligible for biopsy were excluded from initial 2360 pts. RESULTS: IM-3 was found in 118 pts (6.7%), 100 pts (5.7%) only in the antrum. 10 of 355 pts (2.8%) with normal endoscopy and 47 of 702 (6.6%) with non-erosive endoscopic gastritis resulted IM-3 positive in the antrum. 709 pts (40.5%) were positive for Hp in antrum and/or corpus. The presence of Hp and IM-3 in the antrum was not correlated (p=0.99; Spearman test). A positive correlation (p=0.000) between duodenal ulcer and Hp was found when antral Hp positivity was taken into account. The gastric carcinoma risk index (GCRI) was found in 358 pts (20.4%); in this group 131 pts (36.6%) were Hp positive, 81 pts (22.65%) had IM-3 only in the antrum, 184 pts (51.4%) had atrophy. CONCLUSIONS: The incidence of IM-3 is low (6.7%) in routine endoscopy. Normal endoscopy doesn't exclude the presence of IM-3. Biopsy is necessary to discover IM-3 in the antrum in 5.3% of pts with normal or aspecific endoscopic gastritis. Application of the GCRI might be useful for identifying a group of patients carrying a higher risk for gastric carcinoma.

Prevalence of Helicobacter pylori infection and intestinal metaplasia in subjects who had undergone surgery for gastric adenocarcinoma in Northwest Italy.

AIM: To investigate the seroprevalence of Helicobacter pylori (H pylori) infection and its more virulent strains as well as the correlation with the histologic features among patients who had undergone surgery for gastric cancer (GC). METHODS: Samples from 317 (184 males, 133 females, mean age 69+/-3.4 years) consecutive patients who had undergone surgery for gastric non-cardia adenocarcinoma were included in the study. Five hundred and fifty-five (294 males, 261 females, mean age 57.3+/-4.1 years) patients consecutively admitted to the Emergency Care Unit served as control. Histological examination of tumor, lymph nodes and other tissues obtained at the time of surgery represented the diagnostic "gold standard". An enzyme immunosorbent assay was used to detect serum anti-H pylori (IgG) antibodies and Western blotting technique was utilized to search for anti-CagA protein (IgG). RESULTS: Two hundred and sixty-one of three hundred and seventeen (82.3%) GC patients and 314/555 (56.5%) controls were seropositive for anti-H pylori (P<0.0001; OR, 3.58; 95%CI, 2.53-5.07). Out of the 317 cases, 267 (84.2%) were seropositive for anti-CagA antibody vs 100 out of 555 (18%) controls (P<0.0001; OR, 24.30; 95%CI, 16.5-35.9). There was no difference between the frequency of H pylori in intestinal type carcinoma (76.2%) and diffuse type cancer (78.8%). Intestinal metaplasia (IM) was more frequent but not significant in the intestinal type cancer (83.4% vs 75.2% in diffuse type and 72.5% in mixed type). Among the patients examined for IM, 39.8% had IM type I, 8.3% type II and 51.9% type III(type III vs others, P = 0.4). CONCLUSION: This study confirms a high seroprevalence of H pylori infection in patients suffering from gastric adenocarcinoma and provides further evidence that searching for CagA status over H pylori infection might confer additional benefit in identifying populations at greater risk for this tumor.

Canine Vogt-Koyanagi-Harada-like Syndrome in Two Siberian Husky Dogs.

Abstract- A syndrome of uveitis, associated with depigmentation and erosion of areas of skin and mucous membrane on the head and, in one dog, on the scrotum, was observed by the authors in two male Siberian Huskies. These clinical signs are similar to the Vogt-Koyanagi-Harada syndrome in man. Histological examination of the affected skin revealed a lichenoid dermatitis of the upper dermis. Intensive topical therapy with mydriatic and cycloplegic drugs and corticosteroids coupled with systemic prednisolone and azathioprine were used to control the disease. Both subjects were monitored for 10 months and retained useful vision. The skin and oral lesions resolved. Résumé- Un syndrome d'uvéite idiopathique, non traumatique, associée à une dépigmentation et une érosion de zones cutanée et muqueuse sur la tête et, chez un chien, sur le scrotum, a été observé par les auteurs sur deux mâles Siberian Huskies. Ces signes cliniques évoquent le syndrome de Vogt-Koyanagi-Harada de l'homme. Un examen histologique de la peau atteinte a montré l'existence d'une dermatite lichénoide du derme superficiel. Un traitement topique intensif par des médicaments mydriatiques et cyclopégiques, ausociéà l'administration systémique de prednisolone et d'azathioprine a été utilisé pour controler la maladie. Les 2 sujets ont été observés pendant 10 mois et ont retrouvé une vision utile. Les lésions cutanées et orales ont guéri. Zusammenfassung- Bei zwei Husky-Rüden wurden von dem Autoren ein Krankheitssyndrom aus idiopathischer, nicht-traumatisch bedingter Uveitis, Depigmentierung einzelner Haut- und Schleimhautbezirke am Kopf und-bei einem Hund-am Skrotum festgestellt. Diese Symptome ähneln dem Vogt-Koyanagi-Harada-Syndrom beim Menschen. Bei der histologischen Untersuchung von Biopsien der erkrankten Hautbezirke wurde eine lichénoide Dermatitis der oberen Dermisschichten diagnostiziert. Durch eine intensive örtliche Behandlung mit Mydriatica, Cycloplegica und Corticosteroiden in Kombination mit systemischer Prednisolon- und Azathioptringabe konnte die Erkrankung unter Kontrolle gehalten werden. Beide Patienten wurden 10 Monate überwacht und sahen zufriedenstellend aus. Die Veränderungen an Haut und Mundhöhle bildeten sich zurück. Resumen Los autores describen un síndrome de uveitis no traúmatica idiopática asociada a una despigmentación y erosión de áreas de la piel y de las membranas cutáneas de la cabeza, en un perro y del escroto en otro perro. Ambos animales pertenecían a la raza Siberian Husky. Estos signos clínicos se asemejan en los descritos en la síndrome de Vogt-Koyanagi-Harada de las personas. El examen histológico mostró la presencia de un infiltrado inflamatorio liquenoide en la dermis superficial. Para el tratamiento a la enfermedad se aplicaron corticosteroides y fármacos midriáticos y ciclopéjicos de forma tópica y prednisona de forma sistémica. Ambos animales fueron controlados durante diez meses y mantuvieron la visión. Las lesiones orales y cutáneas se resolvieron por completo.