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Objectives Cerebral hyaline protoplasmic astrocytopathy (HPA) is a clinicopathologic entity characterized by eosinophilic cytoplasmic inclusions within astrocytes. It has been observed in a subset of patients with early-onset epilepsy, brain malformations, and developmental delay. The exact association of this entity with epilepsy is still unknown. This report, with its review of the literature, aims to summarize HPA features to raise awareness regarding this entity. Methods We report on 2 HPA cases and critically review the literature. Results Approximately 42 cases of HPA have been reported, including the 2 cases presented here, consisting of 23 female and 19 male patients. Patient age ranged from 3 to 39 years. All patients had early-onset seizures (3-20 months of age), ranging from partial to generalized, that were refractory despite treatment with antiepileptic drugs. Postoperative follow-up intervals ranged from 2 to 93 months, and the clinical outcome was graded according to the Engel classification, showing variable results. Conclusions Clinicians should consider HPA in differential diagnosis in patients with intractable seizures, especially when they are associated with developmental delay and brain malformations. Increasing awareness of this entity among pathologists may promote better understanding of this condition as well as better diagnosis and treatment for these patients.

Background Meningiomas are mainly benign brain tumors, although about 20% of histologically benign cases are clinically aggressive and recur after resection. We hypothesize that meningioma brain invasiveness and recurrence may be related to the presence of cancer stem cells and their high responsiveness to the CXCL12-CXCR4/CXCR7 chemokine axis. The aim of this study was to isolate meningioma stem cells from human samples, characterize them for biological features related to malignant behavior, and to identify the role of CXCR4/CXCR7 in these processes. Methods Meningioma stem cells were isolated from patient-derived primary cultures in stem cell-permissive conditions, and characterized for phenotype, self-renewal, proliferation and migration rates, vasculogenic mimicry (VM), and in vivo tumorigenesis, in comparison with differentiated meningioma cells and stem-like cells isolated from normal meninges. These cell populations were challenged with CXCL12 and CXCL11 and receptor antagonists to define the chemokine role in stem cell-related functions. Results Stem-like cells isolated from meningioma cultures display higher proliferation and migration rates, and VM, as compared to meningioma non-stem cells or cells isolated from normal meninges and were the only tumorigenic population in vivo. In meningioma cells, these stem-like functions were under the control of the CXCR4/CXCR7 chemokine axis. Conclusions We report a role for CXCL11 and CXCL12 in the control of malignant features in stem-like cells isolated from human meningioma, providing a possible basis for the aggressive clinical behavior observed in subsets of these tumors. CXCR4/CXCR7 antagonists might represent a useful approach for meningioma at high risk of recurrence and malignant progression.

High-grade gliomas (HGGs; WHO grades III and IV) are invariably lethal brain tumors. Low-dose hyper-radiosensitivity (HRS) of HGG is a well-established phenomenon in vitro. However, possibly linked to the unavailability of accurate animal models of the diseases, this therapeutic effect could not be consistently translated to the animal setting, thus impairing its subsequent clinical development. The purpose of this study was to develop radiotherapeutic (RT) schedules permitting to significantly improve the overall survival of faithful animal models of HGG that have been recently made available. We used primary glioma initiating cell (GIC)-driven orthotopic animal models that accurately recapitulate the heterogeneity and growth patterns of the patients' tumors, to investigate the therapeutic effects of low radiation doses toward HGG. With the same total dose, RT fractions ≤0.5 Gy twice per week [ultra-hyper-fractionation (ultra-hyper-FRT)] started at early stages of tumor progression (a condition that in the clinical setting often occurs at the end of the guidelines treatment) improved the effectiveness of RT and the animal survival in comparison to standard fractions. For the same cumulative dose, the use of fractions ≤0.5 Gy may permit to escape one or more tumor resistance mechanisms thus increasing the effectiveness of RT and the overall animal survival. These findings suggest investigating in the clinical setting the therapeutic effect of an ultra-hyper-FRT schedule promptly extending the conventional RT component of the current guideline ("Stupp") therapeutic protocol.

A 13-year-old female patient was admitted for acute psychotic symptoms after two months of non-periodic mild fever and progressive behavioral changes. Hallucinations, delirium, disinhibition, coprolalia, and defiant behavior required admission to the Psychiatric Unit. Neurological examination and EEG werenormal. An extensive lesion involving the right frontal lobe was depicted in brain MRI. Psychiatric symptoms completely resolved after surgery. Histological diagnosis was of an Oligodendroglioma grade II, IDH mutant, and 1p/19q co-deleted. Presentation of a brain tumor with isolated psychiatric symptoms is exceptional in pediatric ages. Since acute psychotic symptoms may be misdiagnosed with a purely psychiatric disorder, the possibility of an underlying cerebral lesion must be kept in mind whatever the patient's age.

Objectives To verify the incidence of calcified brain metastases (CBM), illustrating the different presentation patterns and histology of primary tumor. Methods A series of 1002 consecutive brain computed tomography (CT) scans of patients with known primary tumors was retrospectively assessed. CBM were defined by the presence of calcification within intra-axial-enhancing lesions; identification of CBM was based on visual examination and ROI analysis (> 85 Hounsfield units). Also, calcifications in the primary tumor of all patients with brain metastases were evaluated. In CBM patients, we investigated the type of calcifications (punctate, nodular, cluster, ring, coarse), the histology of primary tumor, and if a previous RT was performed. Results Among 190 (18.9%) patients with brain metastatic disease, 34 presented with CBM (17.9%). Sixteen patients were previously treated with RT, while 18 presented calcifications ab initio (9.5% of all brain metastases). The majority of patients with CBM had a primitive lung adenocarcinoma (56%), followed by breast ductal invasive carcinoma (20%) and small cell lung carcinoma (11.8%). CBM were single in 44.1% of patients and multiple in 55.9%. With regard to the type of calcifications, the majority of CBM were punctate, without specific correlations between calcification type and histology of primary tumor. No patients with ab initio CBM had calcifications in primary tumor. Conclusion In conclusion, our data show that CBM are more common than usually thought, showing an incidence of 9.5% ab initio in patients with brain metastases. This study underlines that neuroradiologists should not overlook intraparenchymal brain calcifications, especially in oncologic patients. Key Points • Among the differential diagnosis of brain intraparenchymal calcifications, metastases are considered uncommon and found predominantly in patients treated with radiotherapy (RT). • Our data show that CBM are more common than usually thought, showing an incidence of 9.5% ab initio in patients with brain metastases. • A proportion of intraparenchymal brain calcifications, especially in oncologic patients, might represent evolving lesions and neuroradiologists should not overlook them to avoid a delay in diagnosis and treatment.

Background: A current, albeit unproven, hypothesis is that an acceleration of cellular senescence is involved in impaired renal repair and progression of glomerular diseases. Focal segmental glomerulosclerosis (FSGS) is a glomerular disease with a substantial risk for progression to ESRD. However, if and to what extent cell senescence predicts a negative outcome in FSGS is still unknown. Methods: The hypothesis that cell senescence represents a proximate mechanism by which the kidney is damaged in FSGS (NOS phenotype) was investigated in 26 consecutive kidney biopsies from adult FSGS cases (eGFR 72 ± 4 mL/min, proteinuria 2.3 ± 0.6 g/day) who were incident for 2 years in a Northern Italian nephrology center and had a 6-year clinical follow-up. Results: Cell senescence (p16INK4A, SA-β-galactosidase [SA-β-Gal]) was upregulated by ∼3- to 4-fold in both glomerular and tubular cells in kidney biopsies of FSGS as compared to age-matched controls (p < 0.05–0.01). Tubular SA-β-Gal correlated with proteinuria and glomerulosclerosis, while only as a trend, tubular p16INK4A was directly associated with interstitial fibrosis. At univariate analysis, basal eGFR, proteinuria, and tubular expression of SA-β-Gal and p16INK4A were significantly directly related to the annual loss of eGFR. No correlation was observed between glomerular p16INK4A and eGFR loss. However, at multivariate analysis, eGFR, proteinuria, and tubular p16INK4A, but not SA-β-Gal, contributed significantly to the prediction of eGFR loss. Conclusions: The results indicate that an elevated cell senescence rate, expressed by an upregulation of p16INK4A in tubules at the time of initial biopsy, represents an independent predictor of progression to ESRD in adult patients with FSGS.

Anastomising hemangioma is a rare benign neoplasm originally described in urogenital organs [1]. Even if it is seldom encountered in routine diagnostic sign out, it is important for pathologist...

Background: Oligodendroglioma with ganglioglioma-like maturation is a rare entity not included in the 2016 World Health Organization Classification of Tumors of the Central Nervous System. To date, only a few cases were described in the literature. We report a case of this tumor, along with a review of the previous case reports/ series. Case Description: A 63-year-old man with a left frontal mass and a 2-month history of seizures underwent surgical resection in our center. Grossly, the specimen appeared as a yellowish mass with prominent hemorrhagic component. Microscopically, the lesion was composed by small round cells often surrounded by a clear halo and, near the hemorrhagic area, by scattered large cuboidal cells with vesicular nuclei and prominent eosinophilic nucleoli. On immunohistochemical stains, both cells components tested positive for ATRX, p53, and GFAP; larger ganglion-like cells showed synaptophysin and chromogranin-A expression. IDH1 codon 132 mutation, 1p-19q-codeletion, and MGMT methylation were observed. Eventually, a diagnosis of oligodendroglioma (the WHO grade II) with ganglioglioma-like maturation was rendered. The patient received adjuvant chemotherapy and is currently alive and asymptomatic. Conclusion: Recognition of ganglioglioma-like maturation in oligodendrogliomas may prevent undertreatment of these neoplasms. To this end, fluorescence in situ hybridization assays are crucial for defining the 1p-19q status.

Background Cerebral intraparenchymal masses represent usually a neoplastic, or infectious differential diagnostic workup in neurology or infectious disease units. Case presentation Our patient was an 82-year-old male presenting with seizures, cerebral masses and a history of past treated pulmonary tuberculosis. Initial workup included a differential diagnosis of an infectious mass/multiple abscess. After exclusion of infectious or primary neoplastic origins by negative HIV serology, the absence of immune suppression, endocarditic lesions, negative results of blood cultures and bronchoalveolar lavage, negative cerebrospinal fluid workout on spinal tap led to exclusion of infectious causes. A surgical procedure was performed to access one of the lesions. This yielded a firm, cyst-like mass of histiocytic granulomatous tissue with a conspicuous plasmacellular component and a relevant IgG4 plasmacellular component consistent with IgG4-related disease. Steroid treatment determined conspicuous improvement and led to discharge of the patient. Conclusion Parenchymal IgG4-related disease may be included as a new entity in the differential diagnosis of single or multiple cerebral masses in addition to infectious or neoplastic etiology.

First-generation somatostatin receptor ligands (fg-SRLs), such as octreotide (OCT), represent the first-line medical therapy in acromegaly. Fg-SRLs show a preferential binding affinity for somatostatin receptor subtype-2 (SST2), while the second-generation ligand, pasireotide (PAS), has high affinity for multiple SSTs (SST5 &gt, SST2 &gt, SST3 &gt, SST1). Whether PAS acts via SST2 in somatotroph tumors, or through other SSTs (e.g., SST5), is a matter of debate. In this light, the combined treatment OCT+PAS could result in additive/synergistic effects. We evaluated the efficacy of OCT and PAS (alone and in combination) on growth hormone (GH) secretion in primary cultures from human somatotroph tumors, as well as on cell proliferation, intracellular signaling and receptor trafficking in the rat GH4C1 cell line. The results confirmed the superimposable efficacy of OCT and PAS in reducing GH secretion (primary cultures), cell proliferation, cAMP accumulation and intracellular [Ca2+] increase (GH4C1 cells), without any additive effect observed for OCT+PAS. In GH4C1 cells, co-incubation with a SST2-selective antagonist reversed the inhibitory effect of OCT and PAS on cell proliferation and cAMP accumulation, while both compounds resulted in a robust internalization of SST2 (but not SST5). In conclusion, OCT and PAS seem to act mainly through SST2 in somatotroph tumor cells in vitro, without inducing any additive/synergistic effect when tested in combination.

We report two cases of pediatric low-grade glioma (pLGG) treated with vemurafenib, an oral BRAF-inhibitor: a 12-year-old girl with involvement of basal ganglia, hypothalamus, and diencephalic junction; a 3-year-old boy, with an optic pathway/hypothalamic glioma extending along the left optic tract and basal ganglia. Both received a biopsy and molecular analysis was performed in the girl’s tumor, showing BRAF V600E mutation. Therefore, instead of surgical removal planned by neurosurgeons, first-line treatment with vemurafenib was started: after one month 45% reduction of the mass according to RANO criteria was found, as well as better balance control and strong reduction of the right arm paresis; five months later, a 70% shrinkage was detected, stabilized to 76% after a year. The young boy first started chemotherapy with vincristine and carboplatin, but at the end of the induction phase the tumor had increased and ascites, hydrocephalus, and visual impairment occurred. Molecular testing showing BRAF V600E mutation on the initial tumor biopsy was obtained; therefore, the surgical option was postponed and therapy with vemurafenib started. After only three days, visual acuity and muscle tone improved; brain MRI showed a 34% reduction of the mass after one week, increased up to 65% after six months. Therefore, no ulterior surgery was necessary. In pLGG, the neurosurgical biopsy is essential to let an early and rapid molecular diagnosis of BRAF mutations and guide subsequent targeted therapies. Our cases demonstrate how a prompt radiological response to vemurafenib and the related clinical improvement can influence both therapeutic and surgical decisions, hopefully reducing the occurrence of second neurosurgery with associated risks of neurological sequelae. To our knowledge, this is the first report assessing such a quick shrinkage in pLGG treated with vemurafenib, highlighting the importance of an early investigation of BRAF status in all cases of LGG in children.

The targeted therapies for brain tumors are innovative and promising oncological treatments and as a result their use has expanded widely. BRAF inhibitors (BRAFi) in recent years have played a central role in disease control of unresectable BRAF-mutated pediatric low-grade gliomas (LGG). Understanding the side effects of these drugs is crucial for clinical practice. The aim of the study was to investigate retrospectively the acute and long-term effects of vemurafenib on lipid metabolism in children treated for an LGG. Children (n=6) treated with vemurafenib at the mean age of 8.41±6.1 exhibited early alterations in plasma lipid profile as demonstrated after 1 month (n=4) by high plasma levels of Low-Density Lipoprotein (LDL 139.5±51.5,mg/dL), Total Cholesterol (TC 221.5±42.1,mg/dL) and Triglycerides (TG 107.8±44.4,mg/dL). Despite dietary recommendations, dyslipidemia persisted 3 months later (LDL 148.8±40.2,mg/dL; TC 238±36.5,mg/dL; TG 115±45.6,mg/dL; n=4) and at long distance follow-up (38±23,months) after treatment with vemurafenib: LDL 139.2±49.1,mg/dL; TC 216.5±38.4,mg/dL; TG 129.7±83.4 mg/dL. This potential side effect suddenly resolved itself in the only patient in which a change of therapy was made (to the combination of dabrafenib and trametinib). BMI was compatible with overweight/obesity at baseline (mean BMI-SDS 0.9±1.8) in 2 patient and normal in 4 patients: during follow-up BMI remained stable in 5 patients and increased in 1 patient. Our findings highlight that Vemurafenib could be associated with an increased risk of dyslipidemia independently of weight. This risk should be anticipated by the identification of high-risk patients and managed by close monitoring of metabolic parameters during routinely follow-up. The association of dabrafenib with trametinib seem not be associated to dyslipidemia, yet more data are needed to explore the hypothesis about the possible role to reduce the risk of dyslipidemia.

Bone skeletal alterations are no longer considered a rare event in chronic lymphocytic leukemia (CLL), especially at more advanced stages of the disease. This study is aimed at elucidating the mechanisms underlying this phenomenon. Bone marrow stromal cells, induced to differentiate toward osteoblasts in osteogenic medium, appeared unable to complete their maturation upon co-culture with CLL cells, CLL-cell-derived conditioned media (CLL-cm) or CLL-sera (CLL-sr). Inhibition of osteoblast differentiation was documented by decreased levels of RUNX2 and osteocalcin mRNA expression, by increased osteopontin and DKK-1 mRNA levels, and by a marked reduction of mineralized matrix deposition. The addition of neutralizing TNFα, IL-11 or anti-IL-6R monoclonal antibodies to these cocultures resulted in restoration of bone mineralization, indicating the involvement of these cytokines. These findings were further supported by silencing TNFα, IL-11 and IL-6 in leukemic cells. We also demonstrated that the addition of CLL-cm to monocytes, previously stimulated with MCSF and RANKL, significantly amplified the formation of large, mature osteoclasts as well as their bone resorption activity. Moreover, enhanced osteoclastogenesis, induced by CLL-cm, was significantly reduced by treating cultures with the anti-TNFα monoclonal antibody infliximab. An analogous effect was observed with the use of the BTK inhibitor, ibrutinib. Interestingly, CLL cells co-cultured with mature osteoclasts were protected from apoptosis and upregulated Ki-67. These experimental results parallel the direct correlation between amounts of TNFα in CLL-sr and the degree of compact bone erosion that we previously described, further strengthening the indication of a reciprocal influence between leukemic cell expansion and bone structure derangement.

Membranous nephropathy (MN) is one of the most common causes of adult-onset nephrotic syndrome. We describe the cases of 2 young women in their 20s presenting with nephrotic syndrome due to antiphospholipase A2 receptor (anti-PLA2R)–negative MN, that was found to be associated with benign tumors. Both women had no extrarenal symptoms of a connective tissue disease, infection, or malignancy. They both had been previously healthy and were not receiving treatment with any drugs. Both had MN on kidney biopsy. Biopsies were negative for PLA2R antigen, and their serum did not demonstrate the presence of anti-PLA2R antibodies. Both were investigated for a secondary cause on the basis of negative anti-PLA2R serology and biopsy features supportive of secondary MN and were found to have benign tumors on radioimaging: a uterine leiomyoma and mesenteric fibromatosis, respectively. In both instances, the nephrotic syndrome remitted following resection of the tumors. To our knowledge, uterine leiomyoma and mesenteric fibromatosis have not previously been described in association with MN. These cases highlight the importance of pursuing a secondary cause of MN in patients without anti-PLA2R antibodies in serum or PLA2R antigen on kidney biopsy.

e16545 Background: The Meet-URO 18 study is ongoing to assess the prognostic role of I-TME in advanced RCC patients treated with ≥second line nivolumab divided into two cohorts according to clinical benefit [progression-free survival ≥ 12 and ≤ 3 months]. We primarily assessed the feasibility of multiple antibody testing related to I-TME on matched metastases and primary tumor. Methods: Immunohistochemical analyses were used for the TME assessment of T-lineage (CD3, CD4, CD8), FOXP-3, granulocytes (CD15), macrophage-lineage (CD68), natural killer (NK)-cells (CD56), tumor cells (TCs) (CD56), B-lineage (CD20) and phosphorylated mTOR (phmTOR). TCs were quantitatively assessed for CD15, CD56 and phmTOR positivity. For T-, B- and CD68 cells within TC nests, the number of immunoreactive cells were counted with a microscopic field of x200 (0.933 mm2). Results: Overall, 42 tumor tissue samples (primary tumors, metastases) were available and for 17 patients both metastatic and primary tumor tissues were assessable for matched analyses. Among these patients, 12 had clear cell, 1 papillary and 4 mucinous tubular and spindle cell histotype according to WHO 2016 classification. Intratumoral T/CD8 cells ranged from 32 to >400 spots (mean 240; >400 in 7 samples) and intratumoral T/CD4 cells from 4 to >400 spots (mean 168; >400 in 5 samples). Nine samples showed absence of phmTOR expression, while 8 ranged from 10% to 90% of positive TCs. We did not observe countable NK-cells, whereas CD56 was visible in 5 samples (mean 55% of positive TCs). Intratumoral CD68 cells ranged from 34 to >400 spots (mean 175, >400 in 3 patients). Agreement of CD15 method of reporting granulocytic presence was high, thus only CD15 neoplastic expression was reported and ranged from 12% to 55% (mean 30%) in 15 patients. TME multiple analysis resulted equally clustered in 8 patients (

Backgroundto investigate endometrial carcinoma prognostic value of some histopathological and immunohistochemical factors, fairly easily accessible in every routinely pathology lab set.Methodswe considered patients affected by endometrial carcinoma with available clinical and radiological follow-up data after radical hysterectomy (S. Martino Polyclinic Hospital, Genoa, Italy, period 1/1/2013 - 1/7/2016). We analyzed the following histopathological items: histotype, stage (FIGO), type of infiltration (infiltrative/espansive), desmoplasia, intratumoral necrosis, tumor infiltrating lymphocytes and lymph vascular spaces invasion. Moreover, each case has been investigated with a panel of immunohistochemistry including estrogen receptor α, progesteron receptor, Ki67, p53, β-catenin, e-cadherin, bcl-2 and cyclin D1. Primary endpoints were disease free survival and overall survival.Resultsout of 99 cases eligible for our purpose, we found 69 low-grade endometrioid, 8 high-grade endometrioid and 22 other high-grade endometrial carcinomas. Disease free survival multivariate analysis showed a strong significant correlation between poor prognosis and advanced stage (p=0.0042). Advanced stage (p=0.0003) and presence of desmoplasia (p=0.04) resulted significantly correlated to a worse prognosis in overall survival multivariate analysis. In univariate model, the non-endometrioid histotype was significantly correlated with an unfavorable prognosis when compared to the endometriod type. Same for progesteron receptor low expression.Conclusionthe multivariate analysis confirmed the central prognostic role of stage in endometrial carcinoma. Moreover, other immunohistochemical markers in univariate analysis, have confirmed their easily reproducible usefulness, well integrating the recent TGCA molecular classification.

There is no specific therapy for polyoma BK virus nephropathy (BKVN) in kidney transplant recipients, a condition associated with poor outcomes. Everolimus showed promising antiviral effects, but data from prospective studies are limited. Therefore, we converted ten consecutive kidney transplant recipients with biopsy-proven BKVN from standard exposure Calcineurin inhibitors and Mycophenolate to Everolimus and reduced exposure Calcineurin inhibitors. Ten patients not administered Everolimus, on reduced exposure Calcineurin inhibitor and halved MPA doses served as controls. All kidney transplant recipients continued steroid therapy. Each patient underwent kidney graft biopsy, BKV replication by PCR, and de novo DSA determination. During a 3-year follow-up no graft loss occurred in kidney transplant recipients on Everolimus but it was observed in 5/10 controls (P = 0.032). eGFR improved on Everolimus and worsened in controls (between group difference + 25.6 ml/min/1.73 m2, 95% CI 10.5–40.7, P = 0.002). BKV replication declined in the Everolimus group alone (from 6.4 ± 0.8 to 3.6 ± 1.6 Log 10 genomic copies, P = 0.0001), and we found a significant inverse relationship between eGFR and BKV genomic copy changes (P = 0.022). Average Calcineurin inhibitors trough levels did not differ between the two study groups during follow-up. By multivariable Cox regression analysis, Everolimus treatment resulted the only significant predictor of survival free of a combined endpoint of graft loss and 57% eGFR reduction (P = 0.02). Kidney transplant recipients on Everolimus had a higher survival free of adverse graft outcome (log-rank test, P = 0.009). In conclusion an Everolimus-based immunosuppressive protocol with minimization of Calcineurin inhibitors and antimetabolite discontinuation effectively treated BKVN in kidney transplant recipients.

e16565 Background: Grading tissue signatures in ccRCC is a potential tool to improve patients’ selection for anti-angiogenic drugs and immunotherapies. After the molecular audit to the TCGA public platforms, we aimed to grade angiogenic and immune signatures in ccRCC using a new 3D next-generation gross sampling method to overcome intratumoral heterogeneity. Methods: 100 consecutive advanced ccRCCs (≥pT3a) were sampled. Paraffin-embedded blocks were obtained after mapping the position of each sample to the whole tumor, to allow the reconstruction of the entire 3D tumor mass ( fusion 3D). Multisite tumor sampling was performed to analyze the whole tumor. TCGA platforms were assessed for angiogenic and immune molecular signatures: CD31 and CD34 to evaluate the absolute count and density of vessels, while E1L3N and sp263 clones for PD-L1 expression in tumor cells (TCs). The digital analysis was performed with image processing: comparing each tissue block to whole 3D assessment, the coefficient of variation (CV) was the statistical measure of the dispersion of data points in the data series around the mean. CV < 0.2 defined the homogeneity of the assessment. Results: 656 gross photographs representative of the 3D tumoral masses were collected and 4231 paraffin blocks and tissue sections were stored. Matching gross photographs with tissue samples was performed. 6324 tissue cores were evaluated after combining standard routine sampling plus the 3D multisite sampling and tissue microarray cores. Only 18% of cores displayed homogeneous profile of angiogenesis (CV < 0.2) with two distinct patterns: homogeneous high level of angiogenesis (pattern A) (10% of cases) or homogeneous low level of angiogenesis (pattern B) (8% of cases). The heterogeneous profile of angiogenesis was more frequent than the homogeneous one and was characterized by zones with high and low density of angiogenesis (82% of cases) (pattern C). On the other hand, the homogeneity of PD-L1 expression was more frequently observed both as diffuse absence ( < 1% of TCs, grade 0) or high expression (≥50% of TCs, grade 2) compared to low PD-L1 expression (1-49% of TCs, grade 1) (60% plus 7% versus 33% of cases, respectively). After the comparison of grading angiogenic versus immune signatures, we observed that cases with low PD-L1 expression (grade 0/1) usually expressed high density of angiogenesis (pattern A). Conclusions: Grading angiogenic (pattern A, B and C) versus immune (grade 0, 1 and 2) signatures in ccRCCs can be performed using commonly available tissue vascular (CD31 or CD34) and immune (PD-L1) antibodies. We promoted a simple assay to perform fusion 3D gross sampling to reduce at minimum the bias of heterogeneity in RCCs analyses. Both angiogenic versus immune signature by using the grading systems may help treatment decision-making and response assessment in ccRCC patients.

Macrophage infiltration is associated with unfavorable kidney graft outcome in protocol biopsies, but few studies have evaluated its impact on clinical practice. We therefore prospectively evaluated 37 kidney transplant recipients (KTRs) who underwent kidney biopsy due to slight increases in serum creatinine, or mild proteinuria (>0.3 g/24 hr), in the first post-transplant year. Banff score, CD68+ count (score 0-3) by immunohistochemistry, and 1-year DSA were assessed. DGF was reported in 10 (27%) patients, 6 (16%) had normal biopsy, 7 (19%) borderline lesions, 13 (35%) IFTA, and 11 (30%) other lesions. Fifteen KTRs had grade 3 CD68+ infiltration, and 47% developed de novo DSA. During a 6.2 ± 2.7 year follow-up, four patients (11%) suffered from biopsy-proven T-cell rejection, 17 KTRs (46%) lost their graft (12 in the grade 3 CD68+ group). Graft survival was lower in KTRs with grade 3 CD68+ infiltration (P = 0.0074; log-rank test). Grade 3 CD68+ infiltrate was an independent predictor of graft loss (HR 5.41, 95% CI 1.74-16.8; P = 0.003), together with more severe graft dysfunction at biopsy (HR 6.41, 95% CI 2.57-16; P

Leiomyosarcoma represents a rather uncommon malignancy, and reports of cases characterized by a renal genesis are particularly rare.We describe 2 cases of leiomyosarcoma of the kidney, in a 63-year-old woman and in a 53-year-old man, respectively. Both tumors share a common immunohistochemical profile with a strong positivity for smooth muscle actin, a focal positivity for desmin, and negativity for cytokeratins and other markers.We provide a comparison between our findings and the data available in the literature, and we note an interesting relatively long survival in our patients (10 months for the first case and 20 months for the second case).

Primary cardiac tumours are very uncommon lesions with an estimated incidence of less than 0.03% during autoptic examination. Among these, about 75% are benign, mainly myxomas. The intracardiac tumours occur over a wide range of ages and can progress silently or have many clinical presentations, such as valvular dysfunction, cardiac compression and embolic accidents, mostly in case of atrial localization. Primary atrial tumours often progress asymptomatically. Sudden death could represent the "first symptom" of these pathological findings. Indeed, cardiac neoplasms may cause disorders of atrioventricular or intraventricular conduction, which are manifested by fatal arrhythmias. Two cases of sudden death due to atrial tumours are reported. A complete autoptic examination, with histologic and immunohistochemical study of cardiac lesions, confirmed that these neoplasms were primary. Very few cases of sudden death due to right atrial tumours have been described in forensic literature, a fact which emphasizes their rarity.

Primary cardiac tumors are rare. Of all primary heart neoplasms, sarcomas account for around 10%, and of these, rhabdomyosarcomas (RMS) constitute a minority. A case of primary left atrial RMS, reminiscent of leiomyosarcoma, is reported herein. Histologically, the tumor was composed of tightly-packed spindle-shaped cells arranged in long fascicles. At immunohistochemistry, the tumor cells stained strongly and diffusely with vimentin, muscle-specific actin, desmin and myogenin, and focally with fast-myosin and sarcomeric actin. WT-1 showed diffuse and intense cytoplasmic staining. Staining for calponin was weak. Staining for alpha-SMA, H-caldesmon, CD34, epithelial membrane antigen (EMA), keratin wide-spectrum (CK w.s.), and S100 protein was negative. Electron microscopy revealed poorly differentiated spindle cells, containing contractile filaments with a "Z-band-like" appearance. The final diagnosis was embryonal RMS, spindle cell variant. Conclusively, spindle cell RMS is a well-recognized variant of embryonal RMS, typically occurring in soft tissue, with only rare cases described in visceral organs. This is the first case of primary cardiac spindle cell RMS ever described.

Mesenchymal stem cells (MSCs) may be of value in regeneration of renal tissue after damage; however, lack of biological knowledge and variability of results in animal models limit their utilization. We studied the effects of MSCs on podocytes in vitro and in vivo utilizing adriamycin (ADR) as a model of renal toxicity. The in vivo experimental approach was carried out in male Sprague-Dawley rats (overall 60 animals) treated with different ADR schemes to induce acute and chronic nephrosis. MSCs were given a) concomitantly to ADR in tail vein or b) in aorta and c) in tail vein 60 days after ADR. Homing was assessed with PKH26-MSCs. MSCs rescued podocytes from apoptosis induced by ADR in vitro. The maximal effect (80% rescue) was obtained with MSCs/podocytes coculture ratio of 1:1 for 72 h. All rats treated with ADR developed nephrosis. MSCs did not modify the clinical parameters (i.e., proteinuria, serum creatinine, lipids) but protected the kidney from severe glomerulosclerosis when given concomitantly to ADR. Rats given MSCs 60 days after ADR developed the same severe renal damage. Only a few MSCs were found in renal tubule-interstitial areas 1–24 h after injection and no MSCs were detected in glomeruli. MSCs reduced apoptosis of podocytes treated with ADR in vitro. Early and repeated MSCs infusion blunted glomerular damage in chronic ADR-induced nephropathy. MSCs did not modify proteinuria and progression to renal failure, which implies lack of regenerative potential in this model.