Intratumor morphologic and transcriptomic heterogeneity in V600EBRAF-mutated metastatic colorectal adenocarcinomas.

BACKGROUND: Intratumor heterogeneity (ITH) is described as the presence of various clones within one tumor, each with their own unique features in terms of morphology, inflammation, genetics or transcriptomics. Heterogeneity provides the fuel for drug resistance; therefore, an accurate assessment of tumor heterogeneity is essential for the development of effective therapies. The purpose of this study was to dissect morphologic and molecular ITH in colorectal adenocarcinoma. MATERIALS AND METHODS: A series of 120 V600EBRAF-mutated (V600EBRAFmt) consecutive metastatic colorectal adenocarcinomas was assessed for morphologic heterogeneity. The two heterogeneous components of each specimen underwent a histopathological, immunohistochemical and molecular characterization to evaluate: histologic variant, grading, tumor-infiltrating lymphocytes (TILs), mismatch repair proteins' expression, KRAS/BRAF/NRAS mutations, microsatellite instability (MSI) status and consensus molecular subtype (CMS). RESULTS: Thirty-one out of 120 (25.8%) V600EBRAFmt primary colorectal adenocarcinomas presented a heterogeneous morphology. Among these, eight cases had adequate material for molecular profiling. Five out of the eight (62.5%) cases resulted instable at MSI testing. The majority (62.5%) of the samples showed a CMS4 phenotype based on gene expression profiling. Heterogeneity in CMS classification was observed in four out of eight cases. One out of eight cases presented significant heterogeneity in the number of TILs between the two components of the tumor. CONCLUSIONS: Although the distribution of the immune infiltrate appears relatively conserved among heterogeneous areas of the same tumor, changes in gene expression profile and CMS occur in 50% of V600EBRAFmt adenocarcinoma cases in our small series and might contribute to variability in response to anticancer therapy and clinical outcomes. Assessment of morphological and molecular ITH is needed to improve colorectal cancer classification and to tailor anticancer treatments and should be included in the pathology report.

Cutaneous manifestations in a series of 417 patients with SARS-CoV-2 infection: epidemiological and clinical correlates of chilblain like lesions.

A variety of dermatological lesions have been described in COVID-19, although the prevalence and pathogenic relationship remain unclear particularly for chilblain-like lesions. Dermatological examination was performed in a prospective cohort of consecutive patients seen at the service for SARS-CoV-2 infection. Out of 417 patients with confirmed SARS-CoV-2 infection [median age 29.5 years (range 15-65); 62.5% males], dermatological lesions were detected in 7 (1.7%). Three patients had acral lesions; their age (range) was 15-29 years; all had a negative nasopharyngeal swab and developed IgG and/or IgM-specific antibodies; all presented none or mild symptoms. A fourth patient remained negative at repeated testing; mother, father and sister had a documented mild COVID-19. Non-acral lesions were observed in four older patients, with severe COVID-19. Chilblain-like lesions may be the sole manifestation of SARS-CoV-2 infection; their presence in asymptomatic school children and adolescents should be considered a potential signal of familial or community spread of the virus.

Onset of Schamberg Disease and Resolution of Alopecia Areata During Treatment of Atopic Dermatitis With Dupilumab

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Plexiform fibromyxoma of the gallbladder.

We report the unusual case of a plexiform fibromyxoma, occasionally assessed in a lithiasic gallbladder. The full thickness assessment of the gallbladder wall revealed an intra-mural, well demarked multi-nodular tumor (1 cm), consisting of a plexiform growth of spindle cells, included within a fibromyxoid stroma with a rich micro-vascular network. The tumor cells featured no nuclear atypia, nor mitotic activity. At the immunohistochemical profiling, the spindle shaped cells unequivocally featured vimentin, SMA, HHF35, collagen IV, and CD34; no cells expressed CD117, PDGFRA, CD10, desmin, GFAP, EMA, and S-100. Faint STAT6 nuclear expression was observed in isolated tumor cells. The molecular profiling did not revealed any CKIT and PDGFRA genes mutations. The uncommon site of the tumor presentation and its aberrant CD34 expression both confer to the reported case a unique place among the myxoid tumors of the gastrointestinal tract.

Verrucous sarcoidosis of the skin simulating squamous cell carcinoma.

Here, we report a case of a 38-year-old woman with a history of systemic sarcoidosis who developed cutaneous verrucous sarcoidosis simulating a squamous cell carcinoma. This modality of presentation is unusual in both caucasic patients and in woman and may represent a diagnostic challenge for dermatologists.

Fluoxetine may worsen hyperoxia-induced lung damage in neonatal rats.

Fluoxetine shows controversial lung effects as it prevents pulmonary hypertension in adult rats but exposure during gestation causes pulmonary hypertension in neonatal rats. In the present study, we tested the null hypothesis that the antidepressant drug fluoxetine does not modify the development of bronchopulmonary dysplasia (BPD) in neonatal rats. Experimental categories included I: room air (controls) with daily injection of saline; II: room air with daily injection of 10 mg/kg fluoxetine, i.p., during two weeks; III: 60% oxygen with daily injection of saline; and IV: 60% oxygen with daily injection of 10 mg/kg fluoxetine, i.p., during two weeks. Hyperoxia resulted in significant reduction in alveolar density and an increase in pulmonary endocrine cells, as well as increases in muscle layer areas of bronchi and arteries. Fluoxetine treatment generated a further increase in muscularisation and did not significantly modify the hyperoxia-induced reductions in alveolar density and increases in the endocrine cells. In hyperoxia, Real-Time PCR showed a lower pulmonary expression of vascular endothelial growth factor (VEGF) with no significant changes in the expression of matrix metalloproteinases (MMP) 2 and 12. Fluoxetine did not affect VEGF or MMP-2 expression but it significantly increased MMP-12 mRNA in both normoxic and hyperoxic groups. Zymographic analysis of MMP-2 activity in bronchoalveolar fluid showed a significantly reduced MMP-2 activity in hyperoxia, while fluoxetine treatment restored MMP-2 activity to levels comparable with the normoxic group. In conclusion, our data show that fluoxetine may worsen bronchial and arterial muscularisation during development of BPD and may up-regulate MMP expression or activity.

Ear melanoma: influence of perichondrium involvement in evaluating surgical strategy.

Adequate treatment of melanomas of the external ear offers unique surgical challenges because of the complex anatomical features of the auricle and the need for proper oncologic aggressiveness, as well as for valid aesthetic results. In this study, we evaluated nine different cases of melanoma of the auricle treated in our Institute between 1994 and 2008. Every enrolled patient underwent surgical excision, nonetheless reconstruction was performed with different surgical techniques. In accordance with histological reports, we could observe the absence of neoplastic cells in perichondral bone and in cartilagenous tissue, providing further assurance concerning the importance of preserving the outer ear in expectation of reconstruction. As a matter of fact, it has been proven that it is possible to reconstruct the auricle while guaranteeing oncologic safety in melanomas with a Breslow thickness >1 mm. Therefore, an excision preserving the cartilagenous tissue, thus allowing an efficient full-thickness cutaneous grafting may guarantee good functional and aesthetic results. In conclusion, the suggested therapeutic management may be considered in <1 mm melanomas without taking further unnecessary oncologic risks.

Masson's disease in hand surgery: a clinicopathologic study of four cases.

Intravascular papillary endothelial hyperplasia (IPEH), also known as Masson's tumour, is an uncommon benign vascular lesion characterized by small multiple, endothelial-lined, papillary structures with hyaline stalks. It appears to be a reactive condition involving excessive proliferation of endothelial cells in normal blood vessels or in vascular malformations, perhaps in response to blood vessel injury or thrombosis. The lesions are small, superficial, reddish-blue nodules, usually in the head, neck or hand. Distinction from pyogenic granuloma and angiosarcoma usually requires pathological examination. Complete surgical excision is the treatment of choice. Four cases affecting the finger are presented together with histological features.

Early detection by magnetic resonance imaging of fetal cerebral damage in a fetus with hydrops and cytomegalovirus infection.

We discuss the use of magnetic resonance imaging (MRI) to reveal early fetal neurological involvement of cytomegalovirus (CMV) infection. A woman presented at 21 weeks of pregnancy with active CMV infection. Cerebral ultrasound examination had been normal. An MRI scan revealed a thickened germinal matrix, which was histologically confirmed, associated with underdevelopment of the gyri. Brain MRI proved particularly useful in identifying the findings not disclosed by routine ultrasound during pregnancy and subsequently confirmed at histology.

Prognostic value of bcl-2, p53 and Ki-67 in invasive squamous carcinoma of the uterine cervix.

The aim of this study was to evaluate the immunohistochemical expression of the markers bcl-2, p53 and Ki67 and their relation to the classical clinical-pathological prognostic factors in invasive squamous cellular carcinoma of the cervix. Since bcl-2 and p53 are implicated in the regulation of programmed cell death, very probably they play a role in carcinogenesis and consequently become prognostic factors.

Prognostic value of protein p53 and ki-67 in invasive vulvar squamous cell carcinoma.

The aim of this research was to detect new valid prognostic indicators that allow us to choose the best therapy and follow-up for patients with a poor prognosis. One hundred and twenty-nine patients with invasive squamous carcinoma of the vulva treated at the Gynecology Clinic of the University of Padua between January 1, 1975 and December 31, 1999 have been evaluated: Protein p53 and ki-67 were studied by immunohistochemical investigations and their prognostic significance was evaluated. The relation with the classic clinico-pathological prognostic factors was also studied. The results showed a close association between tissue overexpression of the two proteins and clinico-pathological characteristics of the aggressivity of the neoplasm. Moreover, the group of positive p53 patients with a diffuse distribution pattern of ki-67 resulted in having a somewhat shorter survival with respect to the groups with negative p53 and/or a focal pattern. Such negative prognostic significance was confirmed by the results of the multivariate analysis performed with the Cox model which shows that patients with p53 positive values and a diffuse pattern have a higher relative risk of death compared to patients with p53 negative values and focal pattern (p=0.0001). The statistical significance of the prognostic value of the association of p53 and ki-67 thus seems to give these two factors greater weight with respect to the others we investigated.

cDNA cloning and characterization of PD1: a novel human testicular protein with different expressions in various testiculopathies.

A novel human cDNA sequence has been isolated from human testis cDNA library. This sequence, named PD1, reveals an open reading frame encoding a protein of 520 amino acids. A partial sequence similarity has been found with the RBM gene involved in the regulation of human spermatogenesis. Northern blot analysis for PD1 mRNA from several human tissues demonstrated two distinct transcripts of 2.7 (more abundant) and 4.0 kb and revealed that PD1 is expressed in testis and to a lesser extent also in spleen, thymus, and prostate. Immunohistochemical analysis of human testis showed that this protein is detected in the cytoplasm of Sertoli cells. Antibodies against a rhPD1 fragment were used for Western blot analysis, which confirmed the presence of a 60-kDa molecule in crude extract of human testicular cells obtained from fine-needle aspiration and showed different patterns in various testiculopathies, suggesting a role for such gene in human spermatogenesis.

Primary central nervous system lymphomas: clinico-pathologic and immunohistochemical analysis of 30 cases.

AIMS AND BACKGROUND: Primary Central Nervous System lymphomas are attracting mounting interest because of their increasing incidence in an immunocompetent population and as sporadic tumors. A new lymphoma classification has been proposed, based on new morphologic entities and on advanced immunologic and molecular techniques. METHODS AND RESULTS: The study concerns the clinical and pathologic characterization of 30 cases of primary central nervous system non-Hodgkin's lymphomas in non-HIV patients using a wide monoclonal antibodies panel. Comparative evaluation of effectiveness and reliability between surgery and stereotactic biopsies was made according to Kiel and Real lymphoma classifications. There were 24 high-grade and only 3 low-grade lymphomas. Three stereotactic biopsies were not diagnostic. CONCLUSIONS: Stereotactic procedures were confirmed as the most immediate and least aggressive approach to CNS tumors, but inadequate sampling caused a deadlock to a full lymphoma diagnosis, which requires immunohistochemical and sometimes also molecular studies. However, it should be stressed that morphologic criteria (tumor cell cytology and neoplastic cuffing of the vascular walls) maintain their diagnostic effectiveness.