Management of a periductal stromal tumor in a young woman: Our breast unit experience.

Periductal stromal tumor (PDST) is a rare biphasic tumor of the breast that exhibits low-grade malignancy and intermediate behavior. It is characterized by proliferation of atypical spindle cells surrounding benign mammary ducts and infiltrating adjacent adipose tissue. PDST is distinguished from phyllodes tumor by its lack of leaf-like architecture; however, it is still unclear whether PDST is a separate entity or a certain spectrum of phyllodes tumor. Phyllodes tumors constitute a group of rare epithelial lesions of the breast which mainly develops at around 40-50 years. The histologic characteristics to be considered are many and often heterogeneous in the same lesion which makes interpretation in needle biopsy material difficult. Most phyllodes tumors have a benign nature, with a high rate of postsurgical recurrence. In the malignant form, metastases are described by distant hematogenous route; its indolent behavior implies a tight surgical management with precise excision of the lesion even if there is not, however, a unanimous consent on the parameters of accuracy of the margins.

Self-healing CD30- T-clonal proliferation of the tongue: report of an extremely rare case.

BACKGROUND: The etiology of traumatic ulcerative granulomas with stromal eosinophilia (TUGSE) is not clear, traumatic irritation having advocated as the most likely cause. TUGSEs are typically self-limiting slow-healing lesions of the oral mucosa with unclear pathogenesis, commonly manifesting as a rapidly developing, long-lasting ulcer. CASE PRESENTATION: Here we report a controversial case of a self-healing lesion of the tongue in a 57 year-old woman. A clonal T-cell proliferation and CD30 negative immunohistochemical (IHC) profile could be documented. DISCUSSION AND CONCLUSION: In view of the very peculiar clinical and histological features, a retrospective diagnosis of a TUGSE with scarce eosinophilic infiltrate (possibly in regression), displaying CD30- T-clonal proliferation was eventually rendered. The patient did not report signs of recurrence after a 3-year follow-up period.

Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target.

The importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell lines (HMCLs) are highly sensitive to Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) CD138(+) cells produced large amounts of ammonium in the presence of Gln. MM patients have lower BM plasma Gln with higher ammonium and glutamate than patients with indolent monoclonal gammopathies. Interestingly, HMCLs expressed glutaminase (GLS1) and were sensitive to its inhibition, whereas they exhibited negligible expression of glutamine synthetase (GS). High GLS1 and low GS expression were also observed in primary CD138(+) cells. Gln-free incubation or treatment with the glutaminolytic enzyme l-asparaginase depleted the cell contents of Gln, glutamate, and the anaplerotic substrate 2-oxoglutarate, inhibiting MM cell growth. Consistent with the dependence of MM cells on extracellular Gln, a gene expression profile analysis, on both proprietary and published datasets, showed an increased expression of the Gln transporters SNAT1, ASCT2, and LAT1 by CD138(+) cells across the progression of monoclonal gammopathies. Among these transporters, only ASCT2 inhibition in HMCLs caused a marked decrease in Gln uptake and a significant fall in cell growth. Consistently, stable ASCT2 downregulation by a lentiviral approach inhibited HMCL growth in vitro and in a murine model. In conclusion, MM cells strictly depend on extracellular Gln and show features of Gln addiction. Therefore, the inhibition of Gln uptake is a new attractive therapeutic strategy for MM.

Continuous positive airway pressure treatment of sleepy patients with milder obstructive sleep apnea: results of the CPAP Apnea Trial North American Program (CATNAP) randomized clinical trial.

RATIONALE: Twenty-eight percent of people with mild to moderate obstructive sleep apnea experience daytime sleepiness, which interferes with daily functioning. It remains unclear whether treatment with continuous positive airway pressure improves daytime function in these patients. OBJECTIVES: To evaluate the efficacy of continuous positive airway pressure treatment to improve functional status in sleepy patients with mild and moderate obstructive sleep apnea. METHODS: Patients with self-reported daytime sleepiness (Epworth Sleepiness Scale score >10) and an apnea-hypopnea index with 3% desaturation and from 5 to 30 events per hour were randomized to 8 weeks of active or sham continuous positive airway pressure treatment. After the 8-week intervention, participants in the sham arm received 8 weeks of active continuous positive airway pressure treatment. MEASUREMENTS AND MAIN RESULTS: The Total score on the Functional Outcomes of Sleep Questionnaire was the primary outcome measure. The adjusted mean change in the Total score after the first 8-week intervention was 0.89 for the active group (n = 113) and -0.06 for the placebo group (n = 110) (P = 0.006). The group difference in mean change corresponded to an effect size of 0.41 (95% confidence interval, 0.14-0.67). The mean (SD) improvement in Functional Outcomes of Sleep Questionnaire Total score from the beginning to the end of the crossover phase (n = 91) was 1.73 ± 2.50 (t[90] = 6.59; P < 0.00001) with an effect size of 0.69. CONCLUSIONS: Continuous positive airway pressure treatment improves the functional outcome of sleepy patients with mild and moderate obstructive sleep apnea.

[Covid-19 emergency and telemedicine: multifamily psychoeducational intervention in a forensic setting.] / Emergenza covid-19 e telemedicina: intervento psicoeducativo multifamiliare in contesto forense.

AIM: The aim is to describe remote multifamily psychoeducational intervention led by REMS "Castore" team (an Italian health care facility for offenders who suffer from mental disorders and socially dangerous) in ASL Roma 5, a local health authority, during covid-19 emergency. METHODS: The applied theoretical models have been the integrated psychoeducational intervention by I. Falloon and the multifamily psychoeducational intervention based on problem solving by F. Veltro. The multifamily psychoeducational intervention was attempted by inpatients' relatives from June to August 2020 with 8 weekly meetings of 90' each led by two psychiatric rehabilitation therapists and healthcare experts. Six families were involved in the study and its members were assessed by questionnaire on family problems, Brief-COPE and general health questionnaire tests. Users were assessed by Level of Expressed Emotion Scale test for their expressed emotion. RESULTS: Data analysis highlighted the general low level of subjective and objective burden for family members in association with a high perception of that support provided by REMS. Furthermore, the study has shown those coping approaches oriented to the research of practical solutions, acceptance of events and assertive communication. DISCUSSION: The low subjective and objective burden may be attributed to implicit security conditions in REMS and the absence of tasks mainly carried out by experts. Those coping styles oriented to more practical than emotional approaches suggest an emotional hyper control or stigma perception leading to isolation and loneliness. CONCLUSIONS: The multifamily psychoeducational intervention has allowed a trustworthy relationship with REMS. Considering that the families involved in the study have never benefited by other psychoeducational interventions before, their early involvement appears to be a potential tool for preventing and managing crisis as well as minimizing recidivism.

Advancing the PD-L1 CPS test in metastatic TNBC: Insights from pathologists and findings from a nationwide survey.

Pembrolizumab has received approval as a first-line treatment for unresectable/metastatic triple-negative breast cancer (mTNBC) with a PD-L1 combined positive score (CPS) of ≥ 10. However, assessing CPS in mTNBC poses challenges. Firstly, it represents a novel analysis for breast pathologists. Secondly, the heterogeneity of PD-L1 expression in mTNBC further complicates the assessment. Lastly, the lack of standardized assays and staining platforms adds to the complexity. In KEYNOTE trials, PD-L1 expression was evaluated using the IHC 22C3 pharmDx kit as a companion diagnostic test. However, both the 22C3 pharmDx and VENTANA PD-L1 (SP263) assays are validated for CPS assessment. Consequently, assay-platform choice, staining conditions, and scoring methods can significantly impact the testing outcomes. This consensus paper aims to discuss the intricacies of PD-L1 CPS testing in mTNBC and provide practical recommendations for pathologists. Additionally, we present findings from a nationwide Italian survey elucidating the state-of-the-art in PD-L1 CPS testing in mTNBC.

Tuberculosis in kindergarten and primary school, Italy, 2008-2009.

An outbreak of tuberculosis (TB) in Italy involved 19 schoolchildren with active TB and 43 with latent infection. The source of the outbreak was a school assistant born in Italy who had a family history of TB. This outbreak highlights the need for maintaining clinical and public health expertise in countries with low TB incidence.

Evaluation of sham-CPAP as a placebo in CPAP intervention studies.

STUDY OBJECTIVES: To evaluate the use of sham-continuous positive airway pressure (CPAP) treatment as a placebo intervention. DESIGN AND SETTING: Analysis of polysomnograms performed in fixed order without sham-CPAP and on the first night of the sham-CPAP intervention in participants in the CPAP Apnea Trial North American Program (CATNAP), a randomized, placebo controlled trial evaluating the effects of CPAP treatment on daytime function in adults with newly diagnosed mild to moderate obstructive sleep apnea (apnea hypopnea index (AHI) 5-30). PARTICIPANTS: The first 104 CATNAP participants randomized to the sham-CPAP intervention arm. MEASUREMENTS AND RESULTS: Compared to the polysomnographic measures without sham-CPAP, the study on the first night with sham-CPAP had statistically significant differences that suggested a decrease in sleep quality: decreased sleep efficiency, increased arousal index, increased time in stage 1 NREM sleep, and prolonged latency to REM sleep. However, all of these differences had a relatively small effect size. Compared to the polysomnogram without sham-CPAP, the number of hypopneas on the sham-CPAP polysomnogram was significantly increased and the number of apneas significantly decreased. Relatively minor differences in AHI with and without sham-CPAP were present and were dependent on the criteria used to score hypopneas. CONCLUSION: Comparison of polysomnograms with and without sham-CPAP revealed differences that, although statistically significant, were small in magnitude and had relatively low effect sizes suggesting minimal clinical significance. The results support the use of sham-CPAP as a placebo intervention in trials evaluating the effects of CPAP treatment in patients with obstructive sleep apnea. CLINICAL TRIAL INFORMATION: This paper was a secondary analysis of clinical trial data. CATNAP: CPAP Apnea Trial North American Program, the trial from which the data were obtained, is registered with clinicaltrial.gov. Registration #NCT00089752.

Clinicopathologic features of 2 new cases of uterine tumors resembling ovarian sex cord tumors.

Uterine neoplasms showing an exclusive sex cord-like differentiation or focal low-grade sarcoma differentiation, designated as uterine tumors resembling ovarian sex cord tumors (UTROSCTs), are rare, with only 48 cases described earlier in international literature. Generally, this entity is characterized by benign behavior. In this study, we report the clinical and pathologic features of 2 peculiar new cases of UTROSCTs. In these examples, the pathologic diagnosis of UTROSCT was made incidentally after the clinical diagnosis of a leiomyoma and endometrial polyp. On examination of small biopsies, the diagnosis was facilitated by specific immunohistochemical analysis using markers for the sex cord component. In 1 of these cases, the patient, because of her young age and her desire to preserve her fertility, was only treated by minimally invasive hysteroscopic surgery. In the other case, the neoplasm seemed to be the consequence of tamoxifen treatment for breast carcinoma. After diagnosis, in this second case, the woman underwent hysterectomy that showed a residue of the tumor and cervical metastasis from the earlier breast carcinoma. The differential diagnosis of UTROSCT and the role of immunohistochemistry in confirming a diagnosis are discussed.

Accuracy and relative value of bone marrow aspiration in the detection of lymphoid infiltration in non-Hodgkin lymphoma.

AIMS AND BACKGROUND: In hematologic malignancies, bone marrow aspiration is considered complementary to bone marrow biopsy for the detection of tumor infiltration. The present study evaluated the accuracy of bone marrow aspiration and the relative contributions of bone marrow aspiration and bone marrow biopsy in detecting bone marrow involvement by non-Hodgkin lymphomas. METHODS AND STUDY DESIGN: We compared 51 simultaneous marrow aspirates and core biopsies from non-Hodgkin lymphoma patients for sensitivity, specificity, concordance, quality and clinical relevance. RESULTS: The agreement level of bone marrow biopsy and bone marrow aspiration was 80%, and the overall sensitivity and specificity for bone marrow aspiration were 69% and 86%, respectively. When considering only the indolent non-Hodgkin lymphoma samples, the sensitivity of bone marrow aspiration was 82% and the specificity was 85%, whereas the sensitivity and specificity were 40% and 86%, respectively, in the aggressive non-Hodgkin lymphoma specimens. Five cases (10%) were reported in which bone marrow biopsy did not detect lymphoid infiltration even though the bone marrow aspiration was positive. In one of these, lymphoid infiltration was documented by a second bone marrow biopsy performed thereafter. CONCLUSIONS: The data from the current study show that bone marrow aspiration is a useful procedure with which to detect bone marrow infiltration by lymphoma. Although it cannot be a substitute for examination of the marrow by core biopsy, the utility of adding an aspirate to bone marrow biopsy is supported by its earlier and easier availability for bone marrow examination, the larger amounts of marrow that can be examined with both procedures, and the percentage, although small, of potentially true-positive bone marrow aspirates with negative biopsies.

Bovine pestivirus is a new alternative virus for multiple myeloma oncolytic virotherapy.

BACKGROUND: The oncolytic viruses have shown promising results for the treatment of multiple myeloma. However, the use of human viruses is limited by the patients' antiviral immune response. In this study, we investigated an alternative oncolytic strategy using non-human pathogen viruses as the bovine viral diarrhea virus (BVDV) that were able to interact with CD46. METHODS: We treated several human myeloma cell lines and non-myeloma cell lines with BVDV to evaluate the expression of CD46 and to study the effect on cell viability by flow cytometry. The possible synergistic effect of bortezomib in combination with BVDV was also tested. Moreover, we infected the bone marrow mononuclear cells obtained from myeloma patients and we checked the BVDV effect on different cell populations, defined by CD138, CD14, CD3, CD19, and CD56 expression evaluated by flow cytometry. Finally, the in vivo BVDV effect was tested in NOD-SCID mice injected subcutaneously with myeloma cell lines. RESULTS: Human myeloma cells were selectively sensitive to BVDV treatment with an increase of cell death and, consequently, of apoptotic markers. Consistently, bone marrow mononuclear cells isolated from myeloma patients treated with BVDV, showed a significant selective decrease of the percentage of viable CD138+ cells. Interestingly, bortezomib pre-treatment significantly increased the cytotoxic effect of BVDV in myeloma cell lines with a synergistic effect. Finally, the in vitro data were confirmed in an in vivo myeloma mouse model showing that BVDV treatment significantly reduced the tumoral burden compared to the vehicle. CONCLUSIONS: Overall, our data indicate, for the first time, a direct oncolytic effect of the BVDV in human myeloma cells suggesting its possible use as novel alternative anti-myeloma virotherapy strategy.

Myeloma Cells Deplete Bone Marrow Glutamine and Inhibit Osteoblast Differentiation Limiting Asparagine Availability.

Multiple myeloma (MM) cells consume huge amounts of glutamine and, as a consequence, the amino acid concentration is lower-than-normal in the bone marrow (BM) of MM patients. Here we show that MM-dependent glutamine depletion induces glutamine synthetase in stromal cells, as demonstrated in BM biopsies of MM patients, and reproduced in vitro by co-culturing human mesenchymal stromal cells (MSCs) with MM cells. Moreover, glutamine depletion hinders osteoblast differentiation of MSCs, which is also severely blunted by the spent, low-glutamine medium of MM cells, and rescued by glutamine restitution. Glutaminase and the concentrative glutamine transporter SNAT2 are induced during osteoblastogenesis in vivo and in vitro, and both needed for MSCs differentiation, pointing to enhanced the requirement for the amino acid. Osteoblastogenesis also triggers the induction of glutamine-dependent asparagine synthetase (ASNS), and, among non-essential amino acids, asparagine rescues differentiation of glutamine-starved MSCs, by restoring the transcriptional profiles of differentiating MSCs altered by glutamine starvation. Thus, reduced asparagine availability provides a mechanistic link between MM-dependent Gln depletion in BM and impairment of osteoblast differentiation. Inhibition of Gln metabolism in MM cells and supplementation of asparagine to stromal cells may, therefore, constitute novel approaches to prevent osteolytic lesions in MM.

Bone Marrow CX3CL1/Fractalkine is a New Player of the Pro-Angiogenic Microenvironment in Multiple Myeloma Patients.

C-X3-C motif chemokine ligand 1 (CX3CL1)/fractalkine is a chemokine released after cleavage by two metalloproteases, ADAM metallopeptidase domain 10 (ADAM10) and ADAM metallopeptidase domain 17 (ADAM17), involved in inflammation and angiogenesis in the cancer microenvironment. The role of the CX3CL1/ C-X3-C motif chemokine receptor 1(CX3CR1) axis in the multiple myeloma (MM) microenvironment is still unknown. Firstly, we analyzed bone marrow (BM) plasma levels of CX3CL1 in 111 patients with plasma cell disorders including 70 with active MM, 25 with smoldering myeloma (SMM), and 16 with monoclonal gammopathy of undetermined significance (MGUS). We found that BM CX3CL1 levels were significantly increased in MM patients compared to SMM and MGUS and correlated with BM microvessel density. Secondly, we explored the source of CX3CL1 in MM and BM microenvironment cells. Primary CD138⁺ cells did not express CXC3L1 but up-regulated its production by endothelial cells (ECs) through the involvement of tumor necrosis factor alpha (TNFα). Lastly, we demonstrated the presence of CX3CR1 on BM CD14⁺CD16⁺ monocytes of MM patients and on ECs, but not on MM cells. The role of CX3CL1 in MM-induced angiogenesis was finally demonstrated in both in vivo chick embryo chorioallantoic membrane and in vitro angiogenesis assays. Our data indicate that CX3CL1, present at a high level in the BM of MM patients, is a new player of the MM microenvironment involved in MM-induced angiogenesis.

Neurofibromatosis type I and multiple myeloma coexistence: A possible link?

The association between Neurofibromatosis type I (NF1) and multiple myeloma (MM), a plasma cell, dyscrasia is very rare. Here we put to the attention of the scientific community two new cases. The first one is a patient with active MM whereas the second with smoldering MM. Both patients present typical features of NF1 but skeletal alterations were present only in the second case including dysplasia, marked scoliosis and osteoporosis. MM osteolytic lesions were absent in both patients. In addition to the clinical diagnosis of NF1, a molecular testing for NF1 gene mutations has been performed finding that patient one was heterozygous for the c.6855C>A (Tyr2285Ter) mutation, while patient two was heterozygous for the c.7838dupC (Lys2614GlufsTer20) mutation. The two mutations were diagnosed both in genomic DNA from peripheral blood and from MM cells. The potential link between NF1 mutation and the increased risk of MM is discussed in the report.

A Rare Case of Systemic AL Amyloidosis with Muscle Involvement: A Misleading Diagnosis.

Muscle involvement in AL amyloidosis is a rare condition, and the diagnosis of amyloid myopathy is often delayed and underdiagnosed. Amyloid myopathy may be the initial manifestation and may precede the diagnosis of systemic AL amyloidosis. Here, we report the case of a 73-year-old man who was referred to our center for a monoclonal gammopathy of undetermined significance (MGUS) diagnosed since 1999. He reported a progressive weakness of proximal muscles of the legs with onset six months previously. Muscle biopsy showed mild histopathology featuring alterations of nonspecific type with a mixed myopathic and neurogenic involvement, and the diagnostic turning point was the demonstration of characteristic green birefringence under cross-polarized light following Congo red staining of perimysial vessels. Transmission electron microscopy (TEM) confirmed amyloid fibrils around perimysial vessels associated with collagen fibrils. A stepwise approach to diagnosis and staging of this disorder is critical and involves confirmation of amyloid deposition, identification of the fibril type, assessment of underlying amyloidogenic disorder, and evaluation of the extent and severity of amyloidotic organ involvement.