Incidence Trends and Main Features of Gastro-Intestinal Stromal Tumours in a Mediterranean Region: A Population-Based Study.

Gastro-Intestinal Stromal Tumours (GISTs) are a kind of neoplasm whose diagnosis in common clinical practice just started in the current century, implying difficulties for proper registration. Staff from the Cancer Registry of Murcia, in southeastern Spain, were commissioned by the EU Joint Action on Rare Cancers into a pilot study addressing GIST registration that also yielded a population-based depiction of GISTs in the region, including survival figures. We examined reports from 2001 to 2015 from hospitals as well as cases already present in the registry. The variables collected were sex, date of diagnosis, age, vital status, primary location, presence of metastases, and risk level according to Joensuu's Classification. In total, 171 cases were found, 54.4% occurred in males, and the mean age value was 65.0 years. The most affected organ was the stomach, with 52.6% of cases. Risk level was determined as "High" for 45.0%, with an increment of lower levels in recent years. Incidence for the year 2015 doubled that of 2001. Overall, the 5-year net survival estimation was 77.0%. The rising incidence magnitude is consistent with trends in other European countries. Survival evolution lacked statistical significance. A more interventional approach in clinical management could explain the increase in the proportion of "Low Risk GISTs" and the first occurrence of "Very Low Risk" in recent years.

Lower limb cutaneous melanoma surgery: location matters.

The anatomical location of cutaneous melanoma is a relevant independent prognostic factor in melanoma. The aim of the study is to know the prognosis of lower limb cutaneous melanoma related to their location within the limb, regardless of the histological type, and if there are any other influencing variables. A real-world data observational study was developed. The lesions were divided depending on the location of the melanoma (thigh, leg and foot). Bivariate and multivariate analysis were performed, and melanoma-specific survival and disease-free survival rates were calculated. When these analysis were done, the results showed that, in melanomas of the lower limb, location on the foot presented a lower melanoma-specific survival rate compared to more proximal locations, and only the anatomical location presents statistical significance to discriminate cases with a higher mortality risk and a lower disease-free survival rate among distal melanomas (mainly on the foot). In conclusion, this study confirms that a more distal location of lower limb cutaneous melanoma is a relevant prognostic factor.Trial registration number NCT04625491 retrospectively registered.

Biomarkers of Early Liver Graft Damage in Circulatory Death and Brain Death Donors: A Propensity Score Matching Analysis.

BACKGROUND: Donation after circulatory death (DCD) is related to a warm ischemia time and more complications compared with traditional donors (donation after brain death [DBD]). METHODS: This study included biopsy samples retrospectively collected from November 2014 to December 2018 to compare histologic and biological markers of DCD and DBD liver grafts. The analysis includes marker of early apoptosis (p21), senescence (telomerase reverse transcriptase [TERT]), cell damage (caspase-3 active), endothelial damage (vascular endothelial growth factor), stem cell (CD90), hypoxia (HIF1A), inflammatory activation (COX-2), and cross-organ allograft rejection (CD44). A propensity score matching (PSM) was used to match patients receiving DCD livers to those receiving DBD livers. We analyzed the immunohistochemical initial liver damage-related warm ischemia time. RESULTS: Positive staining expression of liver damage biomarkers (COX-2, CD44, TERT, HIF1A, and CD90) was found, but no significant differences were found between DCD and DBD and with ischemic cholangiopathy. After PSM, there was a significant relationship between CD90 and male donors (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.07-0.91), TERT with donor sodium (OR, 1.11; 95% CI, 1.02-1.2), HIF1A with steatosis (OR, 0.33; 95% CI, 0.13-0.83), and CD44 with donor vasoactive drugs (OR, 0.36; 95% CI, 0.13-1) and glutamic oxaloacetic transaminase 1 week increase (OR, 1.01; 95% CI, 1-1.03). CONCLUSIONS: DCD immunohistochemical initial liver damage was found to behave similarly to DBD. The increase in complications and cholangiopathy associated with warm ischemia could be related to a different later phenomenon.

MITF induces escape from innate immunity in melanoma.

BACKGROUND: The application of immune-based therapies has revolutionized cancer treatment. Yet how the immune system responds to phenotypically heterogeneous populations within tumors is poorly understood. In melanoma, one of the major determinants of phenotypic identity is the lineage survival oncogene MITF that integrates diverse microenvironmental cues to coordinate melanoma survival, senescence bypass, differentiation, proliferation, invasion, metabolism and DNA damage repair. Whether MITF also controls the immune response is unknown. METHODS: By using several mouse melanoma models, we examine the potential role of MITF to modulate the anti-melanoma immune response. ChIP-seq data analysis, ChIP-qPCR, CRISPR-Cas9 genome editing, and luciferase reporter assays were utilized to identify ADAM10 as a direct MITF target gene. Western blotting, confocal microscopy, flow cytometry, and natural killer (NK) cytotoxicity assays were used to determine the underlying mechanisms by which MITF-driven phenotypic plasticity modulates melanoma NK cell-mediated killing. RESULTS: Here we show that MITF regulates expression of ADAM10, a key sheddase that cleaves the MICA/B family of ligands for NK cells. By controlling melanoma recognition by NK-cells MITF thereby controls the melanoma response to the innate immune system. Consequently, while melanoma MITFLow cells can be effectively suppressed by NK-mediated killing, MITF-expressing cells escape NK cell surveillance. CONCLUSION: Our results reveal how modulation of MITF activity can impact the anti-melanoma immune response with implications for the application of anti-melanoma immunotherapies.

Efficiency of Machine Learning Algorithms for the Determination of Macrovesicular Steatosis in Frozen Sections Stained with Sudan to Evaluate the Quality of the Graft in Liver Transplantation.

Liver transplantation is the only curative treatment option in patients diagnosed with end-stage liver disease. The low availability of organs demands an accurate selection procedure based on histological analysis, in order to evaluate the allograft. This assessment, traditionally carried out by a pathologist, is not exempt from subjectivity. In this sense, new tools based on machine learning and artificial vision are continuously being developed for the analysis of medical images of different typologies. Accordingly, in this work, we develop a computer vision-based application for the fast and automatic objective quantification of macrovesicular steatosis in histopathological liver section slides stained with Sudan stain. For this purpose, digital microscopy images were used to obtain thousands of feature vectors based on the RGB and CIE L*a*b* pixel values. These vectors, under a supervised process, were labelled as fat vacuole or non-fat vacuole, and a set of classifiers based on different algorithms were trained, accordingly. The results obtained showed an overall high accuracy for all classifiers (>0.99) with a sensitivity between 0.844 and 1, together with a specificity >0.99. In relation to their speed when classifying images, KNN and Naïve Bayes were substantially faster than other classification algorithms. Sudan stain is a convenient technique for evaluating ME in pre-transplant liver biopsies, providing reliable contrast and facilitating fast and accurate quantification through the machine learning algorithms tested.

Controlled donation after circulatory death up to 80 years for liver transplantation: Pushing the limit again.

Our main objective was to compare liver transplant (LT) results between donation after circulatory death (DCD) and donation after brainstem death (DBD) in our hospital and to analyze, within the DCD group, the influence of age on the results obtained with DCD donors aged >70 years and up to 80 years. All DCD-LTs performed were analyzed prospectively. The results of the DCD group were compared with those of a control group who received a DBD-LT immediately after each DCD-LT. Later, the results obtained within the DCD group were analyzed according to the age of the donors, considering 2 subgroups with a cut-off point at 70 years. Survival results for LT with DCD and super rapid recovery were not inferior to those obtained in a similar group of patients transplanted with DBD livers. However, the cost of DCD was a higher rate of biliary complications, including ischemic cholangiopathy. Donor age was not a negative factor.

[The value of immunohistochemistry using SMARCA4/BRG1 in the diagnosis of small cell ovarian carcinoma hypercalcemic type. A report of two cases]. / Valor de la determinación inmunohistoquímica de SMARCA4/BRG1 en el diagnóstico del carcinoma de ovario de célula pequeña variante hipercalcémica. Presentación de dos casos.

Small cell carcinoma of ovary-hypercalcemic type is an undifferentiated carcinoma. We describe two cases in women aged 32 and 29. Both presented with large masses and complete surgical extirpation was impossible. Histologically, the images were similar, with diffuse cell proliferation, accompanied by the presence of follicle-like spaces. In both cases it was necessary to make a differential diagnosis with entities such as adult or juvenile granulosa cell tumour, small cell carcinoma of pulmonary type, dysgerminoma and even peripheral neuroectodermal tumour. The absence of SMARCA4/BRG1 immunostaining proved very useful in the diagnosis of hypercalcemic small cell ovarian carcinoma.

An ulcerated gastric ulcer and pseudotumour with pancreatic affectation associated with immunoglobulin G4-related disease: a case report and literature review.

We report the case of a 67 year old male who presented with a nine year history of a gastric ulcer with symptoms of hematemesis and melena. Histological analysis identified fibrotic lesions and the accumulation of immunoglobulin G4-positive plasma cells with no evidence of malignancy. The lesion extended into the pancreas, where histological lesions and gastric lesions were also observed. This is a case of an ulcerated gastric ulcer and pseudo-tumor with pancreatic affection that is associated with immunoglobulin G4-related disease.

Molecular characterization and clinical interpretation of BRCA1/BRCA2 variants in families from Murcia (south-eastern Spain) with hereditary breast and ovarian cancer: clinical-pathological features in BRCA carriers and non-carriers.

This is the first study performed in Murcia (south-eastern Spain) in which 592 families with hereditary breast and ovarian cancer were identified thanks to Genetic Counselling Units from this area over 6 years. Diagnostic performance was 18.1% and 194 different genetic variants were obtained. Variants with uncertain significance accounted for only 5.6% of the total number of reports, so our population has been well characterised. In BRCA1 gene, two novel variants were found (c.1859delT and c.3205C > T) and the most frequently detected mutations were c.68_69delAG, c.212 + 1G > A, c.5123C > A, c.211A > G and c.1918C > T, which together represented 56.67% of total pathogenic mutations. In BRCA2 gene, four recurrent variants were described (deletion of entire exon 2, c.9117G > A, c.3264dupT and c.3455T > G) representing 43.5% of the mutations in this gene. Mutation c.68_69delAG and deletion of entire exon 2 in BRCA1 and BRCA2 genes respectively were the most prevalent variants in our population. Regarding the genotype-phenotype relation, mutation c.212 + 1G > A appeared in an important percentage of breast and ovarian cancer cases, c.5123C > A in bilateral breast cancer and c.9117G > A in bilateral breast cancer and ovarian cancer. With respect to clinical-pathological characteristic, BRCA1/BRCA2 mutation carriers showed earlier onset age of breast tumour and higher risk of developing contra lateral breast cancer than non-informative cases. Moreover, association between either molecular subtype triple negative breast cancer or ovarian cancer and BRCA1 carriers was obtained.

Primary Signet-Ring Cell/Histiocytoid Carcinoma of the Eyelid: A "Binocle" Presentation of the "Monocle Tumor".

Primary cutaneous signet-ring cell carcinoma is a rare and aggressive neoplasm which diffusely involves dermis and subcutis of the eyelid or axillae. Neoplastic cells show a signet-ring cell or histiocytoid morphology in variable number, and can be found intermingled among collagen bundles, sparing the epidermis. This neoplasm typically appears in the eyelids of elderly men, in the form of a painless infiltration and swelling but with no other specific clinical feature, and frequently causes diagnostic retardation and worse prognosis. Frequent involvement of both eyelids of the same eye has given it the name of monocle tumor. Only 29 cases have been described in English literature to date, of which 7 developed metastases, mainly on regional lymph nodes. The authors present a case of involvement of contralateral eyelid, which has only been described previously in 2 cases. The immunohistochemical profile of the involvement in the contralateral eye, and the absence of other metastasis, suggest that it is locally spread from the initial lesion. However the possibility of being a second primary tumor or metastasis cannot be readily ruled out.

Prognostic factors of follicular thyroid carcinoma.

INTRODUCTION: Most prognostic studies in differentiated carcinoma have included a high number of papillary carcinomas and few follicular carcinomas, and not all of their conclusions therefore apply to the latter. OBJECTIVE: To analyze the prognostic factors of follicular thyroid carcinoma. SELECTION CRITERIA: Patients with histological diagnosis of follicular carcinoma who had undergone potentially curative surgery, had no disseminated disease at diagnosis, and had been followed up for at least 5 years. STUDY VARIABLES: Tumor recurrence was defined as: 1) tumor lesions with cytological analysis suggesting malignancy and/or 2) patients with total thyroidectomy with thyroglobulin levels >2 ng/mL. Clinical, therapeutic, and histological parameters were analyzed to assess prognostic factors. RESULTS: Recurrence was found in 25 (38%) of the 66 study patients during a follow-up period of 99 ± 38 months. Most patients with recurrence (n=20) had increased Tg levels without anatomical location, and were initially treated with radioactive I131. In the remaining 5 cases, surgical excision of the lesion was performed, and three patients required surgery during the follow-up period. Two patients died due to the disease (3%), and two other patients (3%) currently have distant metastases. Mean disease-free interval was 154 ± 14 months, and rates of disease-free patients at 5, 10, 15, and 20 years were 71, 58, 58, and 58% respectively. Clinical factors influencing recurrence included 1) age (p=0.0035); 2) sex (p=0.0114); and 3) cervical pain (p=0.0026). Histological/surgical factors associated with recurrence included 1) infiltration into neighboring structures (p=0.0000); 2) type of carcinoma (p=0.0000); 3) size (p=0.0162); 4) vascular invasion (p=0.0085); and 5) adenopathies (p=0.046). In the multivariate study, cervical pain (p=0.018) and extrathyroid invasion (p=0.045) continued to be significant factors. CONCLUSIONS: In follicular carcinoma, rates of disease-free patients are 71% at 5 years and 58% at 10 years, and the main predictive factors are presence of local clinical symptoms and infiltration into neighboring structures.

Expression profiles of ProEx C and Ki67 in squamous cell carcinoma in situ of the skin and their relationship with human papillomavirus genotypes.

BACKGROUND: ProExC is a new marker for identification of precursor lesions of cervical carcinoma. Its utility in noncervical squamous cell carcinoma in situ (SCCIS) such as Bowen's disease (BD) and actinic keratosis (AK) where human papillomavirus (HPV) plays a role has not been elucidated. Our aim was to ascertain the immunohistochemical features and clinical utility of ProExC in SCCIS of the skin. METHODS: HPV presence was tested in SCCIS (38 BD and 7 AK) using GP5+/6+ and Short PCR fragment (SPF) primers and subsequently genotyped. Histopathologic sections were stained for ProExC and Ki67. A set of non-neoplastic skin proliferative lesions were included for immunohistochemical evaluation [14 psoriasis (PS) and 6 psoriasiform dermatitis (PSD)]. RESULTS: HPV was detected in 18.9% BD. ProExC and Ki67 in the whole epidermis thickness was observed in 86.5 and 37.1% BD, respectively (p < 0.0001). ProExC and Ki67 were restricted to the lower third of the epidermis in PS and PSD. CONCLUSIONS: ProExC expression is not associated with HPV in SCCIS of the skin. Proliferating cells are better delineated in SCCIS by ProExC which may be useful to assess the extent of these lesions. Different immunohistochemical profiles seen in neoplasic and non-neoplastic skin lesions suggest diverse alteration of cell-cycle kinetics.

Validation of a nomogram to predict the presence of sentinel lymph node metastases in melanoma.

BACKGROUND: Lymph node involvement is a very important prognostic factor for cutaneous melanoma. In this paper we try to validate a nomogram that was created at the Memorial Sloan-Kettering Cancer Center, New York, to predict the probability of metastases in the sentinel nodes of patients with cutaneous melanoma. METHODS: Values of the following variables were collected in 218 patients with cutaneous melanoma and sentinel lymph node: age, thickness, level of Clark, location of the lesion, and ulceration or not, and the nomogram was applied to assess the probability of sentinel node involvement in each patient. The discrimination of the nomogram was assessed by calculating the area under the receiver operating characteristics (ROC) curve, and to assess the accuracy of the nomogram actual probabilities were plotted against the nomogram-calculated predicted probability. RESULTS: The overall predictive accuracy of the nomogram was 0.869 (95% confidence interval 0.813-0.925). Mean predicted probability of sentinel node metastasis was highly correlated to the observed risk (r = 0.953; P < 0.012). CONCLUSION: The nomogram is a useful diagnostic tool that provides an adequate accurate prediction of the probability of sentinel lymph node metastases in patients with cutaneous melanoma.

Impact of recipient HLA-C in liver transplant: a protective effect of HLA-Cw*07 on acute rejection.

The involvement of the human leukocyte antigen (HLA) in liver graft acceptance is controversial, but the frequency of acute rejection (AR) remains high in spite of the use of the modern immunosuppressive agents. The present study was aimed at determining whether an association exists between liver recipient HLA-C polymorphism and AR development that could influence graft acceptance. Four hundred and forty-six liver recipients and 473 controls were studied within the framework of a collaborative study carried out by the Spanish Transplant Immunotolerance Group (RED-GIT). HLA-A and -B were typed by the standard microlymphocytotoxicity technique, and HLA-C by polymerase chain reaction-sequence-specific oligonucleotide probes (PCR-SSOP). A statistically significant decrease in the HLA-Cw*07 allele frequency was found in liver recipients suffering AR episodes compared to those without AR (NAR). Studies regarding the possible influence of the Asn80 and Lys80 epitopes showed that the Asn80 epitope also could be associated with AR. However, further analysis considering Asn80 alleles others than HLA-Cw*07, confirmed that the apparent protective effect of the Asn80 epitope was actually from the HLA-Cw*07 allele. In conclusion, the HLA-Cw*07 allele carried by the liver recipient is negatively associated with AR development, and could be considered a predictive factor for liver graft acceptance.

Elevated basal calcitonin levels in a patient with a hurthle-cell carcinoma of the thyroid and neuroendocrine differentiation: report of a case.

A thyroid nodule with elevated plasma levels of calcitonin is usually suggestive of a medullary thyroid carcinoma (MTC); however, thyroid and extrathyroid conditions have been reported with elevated plasma calcitonin levels in the absence of MTC. We report the case of a patient with a thyroid nodule and an elevated basal plasma calcitonin level of 315 pg/ml (normal value <100 pg/ml) who underwent a left hemithyroidectomy. Interestingly, histopathological examination revealed a Hurthle-cell carcinoma with positive neuroendocrine (NE) markers such as calcitonin and synapthophysin, but not with chromogranin staining. Thus, we discuss the phenomenon of non-NE tumors showing positivity for NE markers.

[Anatomical location of the primary tumor as a variable to be considered in sentinel node biopsy of cutaneous melanoma]. / Localización anatómica del tumor primario como variable a considerar en la biopsia selectiva del ganglio centinela del melanoma cutáneo.

INTRODUCTION: The anatomical location of cutaneous melanoma has been suggested to be an independent prognostic factor. The aim of the present study was to determine whether the location of the primary tumor influences sentinel node detection in cutaneous melanoma. PATIENTS AND METHOD: Two hundred twelve patients with primary cutaneous melanoma (96 of the limbs, 89 of the trunk and 27 of the head or neck) who underwent sentinel lymph node biopsy were studied. Adequate lymphoscintigraphic and surgical localization was evaluated and epidemiological and histopathological variables, the number of lymph nodes draining the site of the primary lesion, sentinel nodes per drainage basin, and tumor-positive nodes were compared. RESULTS: Localization was less successful for tumors of the head and neck (88.8%), both with lymphoscintigraphy (P<.001) and surgery (P<.0005), especially for lymph nodes adjacent to salivary glands (P<.0005). Melanomas of the trunk showed a greater number of nodes per lesion and wider variability in drainage pathways (P<.0005), although there were no differences in the number of sentinel nodes per drainage basin (P=.455). CONCLUSIONS: Sentinel node detection with less successful in cutaneous melanomas located in the head and neck. Location of the sentinel node adjacent to a salivary gland is a factor that influences its detection. Cutaneous melanomas of the trunk showed a higher number of draining nodes per lesion than those located in the limbs or head and neck.

[Fatal evolution of a renal angiosarcoma]. / Evolución fatal de angiosarcoma renal.

OBJECTIVES: Report a new case of renal angiosarcoma treated by surgery and adjuvant chemotherapy with bad results. METHODS: 72-year-old male undergoing right nephrectomy for renal tumor. Pathology reports renal angiosarcoma. RESULTS: Three months after surgery patient refers lumbar pain and hemoptysis and CT scan reveals the existence of multiple bone and lung metastasis; a regimen of systemic chemotherapy with Doxorrubicine+ Ifosfamide was started without response; he died two months later. CONCLUSIONS: Primary renal angiosarcoma is very rare, with less than 10 cases in the literature before 1998, and it is always associated with bad prognosis. Diagnosis is based on immunohistochemical studies (antibodies against CD31, CD34 and factor VIII related antigen) to define the endothelial differentiation of the tumor. There is no experience to define the best therapeutic strategy against this entity.

Tc99m-sestamibi scintigraphy and cell proliferation in primary hyperparathyroidism: a causal or casual relationship?

BACKGROUND: Sestamibi scintigraphy has become the fundamental technique for preoperative location of hyperfunctioning glands responsible for hyperparathyroidism, especially in the case of adenomas. However, little is known about the mechanisms of tracer uptake and retention by these glands, mechanisms that have been related to an increased gland metabolism. Our goal was to determine whether there is a relationship between the positive result of gammagraphy with sestamibi, for diagnosing the location of parathyroid adenomas, and the cell proliferation index. PATIENTS AND METHODS: Six glands corresponding to sestamibi false negatives and 12 true positives were studied in patients with single-adenoma primary hyperparathyroidism. The following data were recorded in all the patients: age, gender, clinical and analytical data, gland weight, and parathyroid hormone (PTH)/gland weight ratio. An immunohistochemical study of the glands was also done with the use of Ki67, with determination of the mean proliferation index of each group for comparison purposes. RESULTS: On comparing the 2 groups, we found no differences between the clinical or analytical parameters. Differences were found only for proliferation index-(5.7% in true positive glands versus 0.3% in false negative glands (P <.004). CONCLUSION: Tracer (sestamibi) uptake by hyperfunctioning parathyroid adenomas in primary hyperparathyroidism might be linked to a higher gland metabolism activity, probably related to cell proliferation.