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This article presents a rare case of nodular mucinosis of the breast, typically manifested as a painless subcutaneous mass in young women. We describe the clinical scenario of a 48-year-old woman who previously underwent benign nodule resection in her 20s at the identical site where nodular mucinosis subsequently developed. This recurrence at the previous resection site underscores the unusual nature of the condition and emphasizes the need for continued vigilance in monitoring patients with a history of such lesions.

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OBJECTIVE: The aim of this study was to systematically investigate the ultrasonographic features of nodular hidradenoma (NH). METHODS: A retrospective analysis was used to systematically summarize the ultrasonographic data of 27 patients diagnosed with NH by surgical pathology, including 13 eccrine nodular hidradenomas (ENH) and 14 apocrine nodular hidradenomas (ANH). RESULTS: All instances of NH presented as solitary, well-defined lesions that infiltrated the dermis and subcutaneous fat layer, characterized by a heterogeneous hypoechoic internal solid component on ultrasound imaging. Color Doppler ultrasound revealed blood flow signals of Grade 2 or higher within 74% (20/27) of the lesions. Solid + cystic (cystic >50%) NH (14/27, 51.4%) were typically large and predominantly had an oval shape (11/14, 78.5%). Their distinctive sonographic features included the presence of inner septa within the cystic area (8/14, 57.1%), "snow falling" sign (7/14, 50%), or "fluid-fluid level" sign (7/14, 50%). Solid + cystic (cystic ≤50%) NH exhibited a lobulated morphology in all instances (5/5, 100%). No inner septa, "snow falling" sign or "fluid-fluid level" sign was observed within the cystic regions. The solid NH (8/27, 29.7%) morphology predominantly featured lobulation (6 out of 8, 75%). Ultrasound analysis revealed distinct differences between ENH and ANH. ENH were more lobulated, while ANH were predominantly oval. ANH were mainly solid + cystic (cystic >50%), whereas ENH were mostly solid. Inner septa, "snow falling" sign, and "fluid-fluid level" sign frequencies were similar in both groups, correlating more with cystic-solid composition than pathological subtype. CONCLUSIONS: Ultrasonographic features of lobulated morphology and the presence of inner septa, "snow falling" sign or "fluid-fluid level" sign in the cystic region provide strong support for the diagnosis of NH.

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We report the case of a 54-year-old healthy Han Chinese male presenting with fever, pallor, erythematous subcutaneous nodules on the limbs, and significant anemia as indicated by routine blood tests, with no response to antimicrobial therapy. Initial skin biopsy was inconclusive. The erythematous subcutaneous nodules on the limbs rapidly progressed to widespread subcutaneous nodules across the body, with worsening anemia. Bone marrow biopsy revealed multifocal fibroblastic proliferation with focal fibrosis, classified as MF-2, and positive for the JAK2V617F mutation alongside SRSF2 positivity. Whole-body PET-CT scans did not reveal any lymph nodes or suspect lesions with high SUV uptake. A subsequent skin biopsy identified the condition as nodular panniculitis (NP), leading to a final diagnosis of primary myelofibrosis(PMF)with NP. The patient initially received treatment with oral ruxolitinib and prednisone acetate, resulting in normalization of body temperature, resolution of erythematous nodules, and normalization of blood parameters.

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Chronic nodular prurigo (CNP) is a chronic dermatological disease characterized by the presence of chronic pruritus and pruritic nodular lesions. The aim of this study was to reach consensus among a group of experts based on a non-systematic literature review and an algorithm for the clinical diagnosis of CNP. The resulting algorithm is structured in 3 blocks: 1) early identification of the patient with a possible diagnosis of CNP; 2) diagnosis and assessment of CNP; and 3) categorization of CNP (identification of the underlying causes or associated comorbidities).We believe that this clinical algorithm can facilitate the correct diagnosis of patients with CNP. Additionally, it raises awareness on the need for a multidisciplinary approach and specific treatment of CNP, steps of paramount importance to make better therapeutic decisions.

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Periventricular nodular heterotopia (PNH) is a neuronal migration defect characterized by the presence of ectopic grey matter nodules adjacent to the walls of the lateral ventricles. The main genetic etiology of PNH are variants in the Filamin A gene (FLNA, MIM #300049), located in the X chromosome. It affects mostly females (embryonic lethality in males), with about 50% of cases inherited from healthy mothers or with a mild phenotype. It is associated with epilepsy (75%-90%), cardiovascular (65%) and pulmonary pathologies (25%). A 28-year-old primigravida was referred for prenatal care in obstetrics department because of personal history of obliterative bronchiolitis. She has a family history of asthma (mother and sister) and adulthood-onset epilepsy (father). The pregnancy was uneventful up to 20 weeks and 3 days when bilateral periventricular irregularities and mega cisterna magna were identified on ultrasound in a female fetus. Neurosonography was performed, which led to the hypothesis of diffuse PNH, supported by MRI. The hypothesis of PNH associated to the FLNA gene was made. Brain MRI on the pregnant woman was requested, which confirmed a similar pattern of PNH. The arrayCGH (PerkinElmer, Prenatal filter 37K) was normal, and whole exome sequencing identified the likely pathogenic c.1554del p.(Val519fs*) variant in the FLNA gene. We present a case of X-linked hereditary PNH that highlights the value of fetal neurosonography in making a putative diagnosis. The diagnosis was supported by MRI in both fetus and mother. The investigation was supplemented by genetic studies, which confirmed the diagnosis.

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OBJECTIVES: Classic Hodgkin lymphoma (CHL) is characterized by infrequent neoplastic Hodgkin and Reed-Sternberg (HRS) cells in an inflammatory background. The diagnostic utility of CC-chemokine receptor 7 (CCR7) in CHL was explored using flow cytometry and immunohistochemistry (IHC). METHODS: Neoplastic specimens and non-neoplastic lymph nodes were immunophenotyped and CCR7 expression was measured semiquantitatively by flow cytometry (clone 3D12) and IHC (clone 150503). RESULTS: Our results showed that CCR7 was expressed on HRS cells in the vast majority of CHL cases (45/48 by flow cytometry, 57/59 by IHC) but rarely expressed in neoplastic cells in diffuse large B-cell lymphoma, not otherwise specified (1/25 by flow cytometry, 2/40 by IHC) and nodular lymphocyte predominant Hodgkin lymphoma (0/4 by flow cytometry, 1/13 by IHC). Primary mediastinal large B-cell lymphoma (PMLBCL) revealed weak CCR7 expression by flow cytometry in most cases (8/10) but only occasionally by IHC (2/12). Both cases (2/2) of T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) also showed CCR7 expression detected by flow cytometry compared with IHC (0/7). The HRS cells demonstrated a greater percentage of positive cells and greater antigen intensity than the other B-cell lymphomas by IHC. The expression identified by flow cytometry in PMLBCL and THRLBCL but not by IHC suggests that there may be differences in the detection capabilities of the 2 techniques or the 2 CCR7 clones used. CONCLUSIONS: The expression of CCR7 in HRS cells suggests its potential utility in differentiating CHL from other B-cell lymphomas. Incorporating CCR7 into flow cytometry and IHC panels may further enhance the diagnostic sensitivity of CHL.

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Primary or light-chain (AL) (lambda) amyloidosis is a rare systemic disorder that is characterized by the misfolding of autologous proteins and the extracellular deposition of abnormally folded proteins composed of immunoglobulin light chains, often caused by plasma cell dyscrasias. We present a unique case of a 57-year-old female with multiple comorbidities, including extensive smoking history and chronic kidney disease, who was incidentally discovered to have a left upper lobe lung nodule on a chest X-ray prompted by complaints of shortness of breath. The patient underwent biopsy of the lung nodule, and by utilizing the gold standard diagnostic technique of a Congo red stain, positive test results confirmed the diagnosis of AL amyloidosis. However, additional investigations, including bone marrow and fat pad biopsies, were negative for plasma cell dyscrasias. The patient subsequently underwent a wedge resection of the nodule, and a follow-up positron emission tomography-computed tomography (PET-CT) scan showed only post-surgical changes in the left upper lobe of the lung without evidence of disease progression or systemic involvement. Given the asymptomatic and multisystem symptomology of most cases, treatment options for AL amyloidosis are individualized. This case discusses pulmonary nodular AL amyloidosis and highlights the diagnostic and treatment options for this disorder.

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Background & Aims: Porto-sinusoidal vascular disorder (PSVD) is a group of vascular disorders characterized by lesions involving portal venules and sinusoids, irrespective of the presence of portal hypertension. Liver biopsy is essential for diagnosis. In a single-center study, we demonstrated high rates of PSVD in patients with persistently elevated gamma-glutamyltransferase (GGT). This multicenter study aims to establish PSVD prevalence in a larger dataset of individuals with persistent and unexplained GGT elevation, and to identify associated risk factors. Methods: The study included all patients who underwent liver biopsy for persistent and unexplained GGT elevation in five Italian hepatology units between March 2015 and December 2021. Results: A total of 144 patients met the inclusion criteria. The majority were males (76/144, 52.8%) and mean age was 51.9 years (range 19-74). Only 12 (8.3%) had liver stiffness measurements (LSM) >10 kPa, while 7 (4.8%) had ultrasound evidence of portal hypertension. Histological findings were consistent with PSVD in 96 patients (67%). Alternative diagnoses were steatohepatitis in 13 (9%), sarcoidosis in 3 (2%) and congenital hepatic fibrosis in 3 (2%) patients. Histological findings were non-specific in 29 (20%) patients. PSVD was associated with male sex (odds ratio [OR] 2.60, 95% CI 1.13-5.99), LSM <10 kPa (OR 11.05, 95% CI 2.16-56.66) and GGT <200 U/L (OR 2.69, 95% CI 1.22-5.98). Conclusions: PSVD was the main cause of persistent and unexplained elevation of GGT3. Male sex, LSM <10 kPa and GGT <200 U/L were associated with PSVD. These findings highlight the role of liver biopsy in elucidating the underlying pathology and aiding in the diagnosis of patients with persistent and unexplained GGT elevation. Impact and implications: In outpatient settings, it is common to encounter individuals with persistent and unexplained gamma-glutamyltransferase elevations. This study reveals, for the first time, a non-negligible prevalence of porto-sinusoidal vascular disorder among these individuals when they undergo liver biopsy. Male sex, liver stiffness measurement <10 kPa, and gamma-glutamyltransferase <200 IU/L predict this histological finding. These results may raise awareness of clinically relevant conditions that may be present in patients with persistent liver enzyme changes, even in the absence of signs of advanced chronic liver disease or portal hypertension. Additionally, the data may encourage further studies in the field of porto-sinusoidal vascular disorder, particularly to define its clinical evolution in patients without signs of portal hypertension at diagnosis.

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OBJECTIVE: To investigate the impact and potential mechanisms of serum extracellular nano-vesicles (sEVs) miR-412-3p released from sub-centimeter lung nodules with a diameter of ⩽ 10 mm on the malignant biological function of micro-nodular lung cancer (mnLC). METHODS: A total of 87 participants were included and divided into a mnLC group (n= 30), a benign lung nodule (BLN) group (n= 27), and a healthy people control group (n= 30). Transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blot (WB) were used to measure the morphological characteristics and surface markers of sEVs. In vitro analysis, real-time quantitative polymerase chain reaction (RT-qPCR), CCK-8 cell proliferation assay, clone formation assay, Transwell, stem cell sphere-forming assay, and WB assay were conducted to verify the effect of miR-412-3p/TEAD1 signaling axis on the biological function of lung cancer cells through, respectively. Further validation was conducted using the serum sEVs of the participants. RESULTS: The expression level of sEVs-miR-412-3p in the mnLC group was significantly higher than that in the BLN and healthy groups (P< 0.01). In lung cancer cell lines, miR-412-3p can negatively regulate the targeted gene TEAD1. The miR-412-3p/TEAD1 signaling axis is involved in promoting the EMT signaling pathway and regulating the malignant biological functions of lung cancer cell proliferation, migration, and stemness (P< 0.05). In addition, sEVs in the mnLC group significantly promoted lung cancer cell proliferation, migration, and stemness compared to the BLN and healthy groups, inhibited the expression of E-cadherin and TEAD1 in lung cancer cells, and promoted the expression of N-cadherin and Vimentin (P< 0.05). CONCLUSION: sEVs-miR-412-3p could promote the biological process of EMT, and lead to the occurrence of malignant biological behavior in sub-centimeter lung nodules. This provides evidence for the miR-412-3p/TEAD1 signaling axis as a potential therapeutic target for mnLC.

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A 10-y-old spayed female Cavalier King Charles Spaniel dog was presented to the Veterinary Teaching Hospital because of recurrent chronic abscesses on the distal pelvic limbs, fever, lethargy, lameness of unknown etiology, and chronic pancreatitis. Sterile nodular panniculitis was diagnosed after an extensive workup, and the dog initially responded to immunosuppressive therapy, but relapse and spread of cutaneous lesions and acute lameness occurred after 11 mo, and euthanasia was elected. Postmortem examination confirmed hyalinizing pancreatic adenocarcinoma with pancreatitis, panniculitis, polyarthritis (PPP), and osteomyelitis. Histopathology and bacterial and fungal cultures were supportive of a sterile process, specifically the PPP syndrome, which is a rare, potentially life-threatening, systemic manifestation of pancreatic disease in both people and animals. To our knowledge, a clinicopathologic description of a hyalinizing pancreatic adenocarcinoma associated with this rare syndrome has not been reported previously in a dog.

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Splenic nodular lesions in dogs can be either benign or malignant. They might be discovered incidentally or, in case of rupture, they may lead to hemoabdomen. Nevertheless, splenectomy followed by histopathology is essential for diagnosis and to prevent rupture. Yet, this invasive procedure might be postponed for dogs with benign splenic nodular lesions. Conversely, owners may opt for euthanasia over surgery for malignancies with poor prognosis like hemangiosarcoma. Thus, anticipating diagnosis with non-invasive biomarkers is crucial for proper patient management. In this prospective study, plasma samples were collected from 66 dogs with histologically confirmed splenic nodular lesions. A canine-specific ELISA kit was applied to assess nucleosome concentration, with histopathology of the spleen serving as the gold standard. Nucleosome concentration was found to be significantly higher in dogs with malignant splenic nodular lesions, particularly in those with hemangiosarcoma and other malignancies. The presence of hemoabdomen, more prevalent in dogs with splenic malignancy, also resulted in increased plasmatic nucleosome concentrations. Plasma nucleosomes could serve as a biomarker for detecting malignant splenic nodular lesions in dogs. More research is needed to understand how nucleosome concentration relate to disease stage and prognosis in dogs with hemangiosarcoma.

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PURPOSE: Hyperthyroidism guidelines have not been updated over the past five years, despite numerous data on the subject, and recent studies providing a wide variation in treatment success rates. We aim to compare the effectiveness and safety of treatment modalities in patients with Graves' disease or toxic nodular disease. METHODS: Single center retrospective cohort study of Graves' disease and toxic nodular disease patients treated between 1983 and 2023. RESULTS: A total of 411 patients were treated for hyperthyroidism, 245 due to Graves' disease and 166 due to or toxic nodular disease, followed for a median of 7 years. In Graves' disease, 90.2% were treated with antithyroid drugs over 250 cycles, achieving 41.7% cumulative remission. Half of all relapses (50.9%) occurred in the first year, 76.3% in the first three years, and 98.3% within nine years. Treatment periods of 12-24 months showed higher remission and lower relapse rates than longer periods. I-131 was used in 103 cycles with 82.5% remission and 7.1% relapse. A total of 29 thyroidectomies resulted in 100% remission, with no relapse. In toxic nodular disease, surgery was the most frequently used treatment (54.5%), followed by I-131 (37.1%). CONCLUSION: Our findings support antithyroid drugs as the preferential first-line treatment for Graves' disease, allowing for euthyroidism with minimal adverse effects. Given the propensity for relapse, we suggest a rigorous monitoring, particularly within the first three years. In toxic nodular disease, surgery should be the preferred option, with I-131 being reserved for single adenomas and small goiters.

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Angiomyxoma (AM) occurs almost exclusively in the soft tissues of the pelvic and perineal regions. AM is a highly uncommon condition that can be easily misdiagnosed when it is present in other regions of the body. The current study presents a case in which AM of the liver coexisted with focal nodular hyperplasia (FNH). A 56-year-old woman presented with two space-occupying lesions of the liver without any other clinical symptoms, and it was not easy to definitively diagnose the two intrahepatic lesions by imaging examinations. Due to the low incidence of AM in the liver, precise and clear clinical information on the condition is still unavailable, and the lesion was initially misdiagnosed as other hepatic tumors preoperatively. Once a tumor resection had been performed, a histopathological examination revealed that the microscopic features of the lesions were consistent with those of AM and FNH. The patient was followed up for 1 year, and no recurrence or metastasis was found. Surgical excision is an effective treatment for AM, and long-term follow-up is essential due to the risk of recurrence. The joint presentation of AM and FNH is rare in clinical practice, and although FNH of the liver is commonly reported, the difficulty of diagnosis increases when both conditions occur at the same time. Therefore, it is necessary to assist clinicians in making informed decisions regarding diagnosis and treatment.

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Nodular thyroid pathologies (NThyPs) are prevalent thyroid diseases, with a steadily increasing global incidence. Although their exact causes remain uncertain, various modifying factors, such as nutrition, influence their development. We aimed to systematically identify and synthesize the influence of dietary exposures on NThyPs risk. PubMed, Scopus, Web of Science, and EMBASE were searched on June 14, 2024, to identify relevant studies. Data extraction included study characteristics, sociodemographic factors, dietary intake assessments and exposures, and NThyPs subtypes. Out of 14,730 articles retrieved, 55 observational or experimental studies, in English, Spanish, or Portuguese, that assessed nutrition's impact on NThyPs were included, excluding non-human studies, reviews, meta-analyses, and publications outside the study's scope. Forty studies investigated how distinct dietary patterns, macronutrients, minerals, and vitamins contributed to or mitigated NThyPs development. Fish and seafood, vegetables and fruits, and meat were other dietary exposures investigated. In fourteen of previously selected studies, drink consumption was also addressed. This systematic review (CRD420234003439) suggests that reducing processed foods, sugars, meat, and dietary iodine lowers NThyPs risk, while coffee, tea, alcohol, and dairy products demonstrates potential protective roles. Fish and seafood, and fruits and vegetables also exhibit protective properties; nevertheless, further research is necessary to establish definitive conclusions.

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Aim: The differential diagnosis of intrinsic nonfibrotic conditions that may lead to portal hypertension include hepatoportal sclerosis (HPS), nodular regenerative hyperplasia (NRH), and sinusoidal obstruction syndrome (SOS). In this article, we characterize the clinical features and outcome of these lesions when they manifest as portal hypertension. Methods: Data was collected through retrospective patient medical records. Results: Patients (HPS: 28, NRH: 17, SOS: 11) were identified more frequently in recent years. All groups presented with signs and symptoms of portal hypertension. All patients had complex medical histories. An elevated serum alkaline phosphatase occurred in all groups and an elevated bilirubin with SOS. Imaging of the liver with HPS and NRH suggested cirrhosis, which was not seen with SOS. 11%, 12%, and 9% of patients in the HPS, NRH, and SOS respectively, underwent transjugular intrahepatic portosystemic shunt placement to manage the complications of portal hypertension, while 43%, 24%, and 36% of patients respectively, received a liver transplant. Conclusions: Patients with HPS, NRH, and SOS had complex medical histories, likely contributing to the development of these lesions. They are recognized more frequently now. In contrast to HPS and NRH, SOS occurred in liver transplant recipients, was associated with elevated serum bilirubin, and imaging did not suggest the presence of advanced fibrosis/cirrhosis. Liver transplantation appeared to be a viable treatment for complications related to HPS and NRH. Retransplantation for SOS yielded mixed results. HPS, SOS, and NRH should be considered when evaluating liver specimens from patients with unexplained nonfibrotic portal hypertension. Key message: Intrinsic nonfibrotic causes of portal hypertension appear to be increasing in frequency. The differential diagnosis includes NRH, HPS, and SOS. These conditions are associated with complex diseases and possibly due to treatments. Pathologists need to be aware of this differential diagnosis when presented with liver biopsies performed to assess portal hypertension.

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BACKGROUND: To develop and validate a nomogram model based on Gd-EOB-DTPA enhanced MRI for differentiation between hepatocellular carcinoma (HCC) and focal nodular hyperplasia (FNH) showing iso- or hyperintensity in the hepatobiliary phase (HBP). METHODS: A total of 75 patients with 49 HCCs and 26 FNHs randomly divided into a training cohort (n = 52: 34 HCC; 18 FNH) and an internal validation cohort (n = 23: 15 HCC; 8 FNH). A total of 37 patients (n = 37: 25 HCC; 12 FNH) acted as an external test cohort. The clinical and imaging characteristics between HCC and FNH groups in the training cohort were compared. The statistically significant parameters were included into the FAE software, and a multivariate logistic regression classifier was used to identify independent predictors and establish a nomogram model. Receiver operating characteristic (ROC) curves were used to evaluate the prediction ability of the model, while the calibration and decision curves were used for model validation. Subanalysis was used to compare qualitative and quantitative characteristics of patients with chronic hepatitis and cirrhosis between the HCC and FNH groups. RESULTS: In the training cohort, gender, age, enhancement rate in the arterial phase (AP), focal defects in uptake were significant predictors for HCC showing iso- or hyperintensity in the HBP. In the training cohort, area under the curve (AUC), sensitivity and specificity of the nomogram model were 0.989(95%CI: 0.967-1.000), 97.1% and 94.4%. In the internal validation cohort, the above three indicators were 0.917(95%CI: 0.782-1.000), 93.3% and 87.5%. In the external test cohort, the above three indicators were 0.960(95%CI: 0.905-1.000), 84.0% and 100.0%. The results of subanalysis showed that age was the independent predictor in the patients with chronic hepatitis and cirrhosis between HCC and FNH groups. CONCLUSIONS: Gd-EOB-DTPA enhanced MRI nomogram model may be useful for discriminating HCC and FNH showing iso- or hyperintensity in the HBP before surgery.

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Purpose: Even today, melanoma is a highly aggressive neoplasm with a high mortality rate. The nodular type is very aggressive and has cerebroid nests of melanocytes (CNMs) at the growth edge, morphologically similar to the poorly differentiated neoplastic epithelial cell clusters described in colorectal, breast, and endometrioid endometrial cancers. Patients and methods: We selected 25 nodular melanomas (NMs) with known molecular profiles, of which the entire paraffin-embedded lesion was available. We counted CNMs under a microscopic at a magnification of 20x (i.e., a microscopic field with a major axis of 1 mm). Based on the number of CNMs in the area, melanomas were classified into three groups: G1 (CNMs ranging from 0 to 4), G2 (CNMs ranging from 5 to 9), and G3 (CNMs ≥ 10). The presence of CNMs and their counts were compared with molecular and histopathological data. Results: Seventeen (NMs) were grouped as G1 (68%), 5 as G2 (20%), and 3 as G3 (12%) based on CNMs count. The presence of CNMs correlated with epithelioid cell morphology (p < 0.05), Clark IV and V levels (p < 0.05), vascular invasion (p < 0.05), and biological mutants (p < 0.05). Melanomas with ≥ 10 CNMs more frequently show ulceration (p < 0.02) and the BRAF V600E mutation (p < 0.02). Conclusion: CNMs count has a predictive role regardless of tumor size; their association with the BRAF V600E mutation suggests their predictive significance in response to biologics. However, further investigations are needed to strengthen this hypothesis.

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This review aimed to evidence the predisposing conditions for Salzmann nodular degeneration (SND), where particular attention was paid to its association with ocular and systemic diseases. SND is a rare disease characterized by bluish-white nodules located in the mid-periphery of the cornea, which are otherwise completely clear. SND has been found in association with different systemic and ocular diseases, and it may have unilateral or bilateral presentation. Initial forms are only diagnosed occasionally as they are asymptomatic, whereas, in advanced disease, the visual acuity might be seriously impaired. Although SND is well described, its exact etiopathology is currently still unknown and is frequently misdiagnosed. It is associated with ocular surface inflammatory conditions and previous corneal surgery, and it has been described in different systemic diseases. Diagnosis is clinically based with slit lamp examinations, and instrumental assessments with corneal topography permit one to observe the alterations of the corneal profile, whereas anterior segment-optical coherence tomography (AS-OCT) is used to investigate the stromal depth of the nodules. Therapy might be conservative with the objective of improving the ocular surface homeostasis and surgical outcomes, where the aim is to restore the corneal regularity and visual acuity. Ophthalmologists should pay particular attention when detecting nodules in patients with ocular and non-ocular inflammatory diseases to guarantee the patient a timely diagnosis and a better therapeutic outcome. Additionally, collaboration between specialists who deal with treating patients suffering from disorders potentially associated with SND is recommended.