Can core biopsy be used instead of surgical biopsy in the diagnosis and prognostic factor analysis of breast carcinoma?

PURPOSE: The aim of this article was to investigate the efficacy of ultrasonography-guided core needle biopsy and prognostic factor analysis of breast cancer to plan overall treatment strategy. PATIENTS AND METHODS: A consecutive series of nonpalpable and palpable breast cancers constituted our study group (n= 201 lesions; mean size, 20.4 mm) Mean number of core samples was 3.4. Malignant lesions diagnosed with core biopsy underwent therapeutic surgical excision. Core biopsy and surgical excisions were compared for histologic type, grade, estrogen receptors (ERs), progesterone receptors (PgRs), and c-erbB2 levels. Cutoff values for ER, PgR, and c-erbB2 affecting the management strategy were selected as 10%, 10%, and 50%, respectively. RESULTS: Eighty-five lesions (42.3%) were malignant in core biopsy (mean size, 18.4 mm). Among these, 11 were inoperable and 13 were surgically excised at other institutions. In 61 lesions, core and surgical excision specimens were evaluated in the same institution (mean tumor size, 18.6 mm; range 6-60 mm). Concordance between the 2 biopsy methods was 85.2% (52 of 61) for histologic type of tumor, 68.8% (33 of 48) for tumor grade, 90% (27 of 30) for ER, 86.7% (26 of 30) for PgR, and 79.3% (23 of 29) for c-erbB2 levels. Appropriate site selection for sampling was indicated to be of paramount importance, especially in determining reliable ER, PgR, and c-erbB2 levels. CONCLUSION: Core needle biopsy of breast cancer is equally effective compared with surgical biopsy and can be used in overall treatment planning. However, appropriate site selection for sampling should be guaranteed using ultrasonographic guidance.     

Inguinal keratotic Basal cell carcinoma mimicking giant solitary trichoepithelioma

Keratotic basal cell carcinoma may not only clinically but also histologically share more or less the same features with giant solitary trichoepithelioma. It can be difficult to distinguish these two entities from each other, even for an experienced dermatopathologist. We present an unusual case of inguinal keratotic basal cell carcinoma mimicking giant solitary trichoepithelioma in a 56-year-old woman with a finger-like tumor of 20 years duration. The patient presented with an asymptomatic, skin colored, firm, nonulcerative, nodular lesion. Scanty mitotic activity and apoptotic cells were the histopathologic findings against basal cell carcinoma, whereas absence of papillary mesenchymal bodies, presence of peritumoral lacunae detected only around the solid areas, and accumulation of amyloid-like hyalinized material were the findings in favor of basal cell carcinoma. This case illustrates that keratotic basal cell carcinoma must be taken into account in the differential diagnosis of inguinally located solitary, polypoid masses, especially giant solitary trichoepithelioma.     

The protective effect of ethyl pyruvate on lung injury after burn in rats

OBJECTIVE: To investigate the effects of administered ethyl pyruvate (EP), a novel anti-inflammatory agent, on oxidoinflammatory and apoptotic pathways in the lung tissue of rats in a full-thickness burn model. METHODS: The study took place in Ankara Research and Training Hospital Animal Laboratory, Turkey in June 2006. Thirty-two rats were randomly divided into 4 groups in equal numbers as sham, burn, sham+EP, and burn+EP. The burn model, used produced a full thickness burn of the 30-35% of the total body surface area. Ethyl pyruvate was administered as 40 mg/kg intraperitoneally. Rats were sacrificed after 24 hours, acute lung injury (ALI) was evaluated by direct light microscopy and apoptosis was evaluated by caspase-3 staining. Oxidoinflammatory events were evaluated by determining the tissue levels of myeloperoxidase (MPO), lipid peroxidation products, and nitrite. RESULTS: No significant difference was observed in lung tissue nitrite and malondialdehyde levels among the study groups. Histopathological results revealed that ALI and apoptosis were significantly higher in the burn group and EP prevented this effect. Similar results were obtained in tissue MPO levels. CONCLUSION: Ethyl pyruvate is a novel, potent anti-inflammatory agent. This agent prevented leukocyte infiltration, ALI, and apoptotic loss of the lung tissue in thermal injury.     

Comparison of stepwise vs single-step advancement with the Functional Mandibular Advancer in Class II division 1 treatment

Objective:To compare two groups of subjects at the peak of the pubertal growth period treated with the Functional Mandibular Advancer (FMA; Forestadent, Pforzheim, Germany) appliance using either single-step or stepwise mandibular advancement.Materials and Methods:This study was conducted on 34 Class II division 1 malocclusion subjects at or just before the peak phase of pubertal growth as assessed by hand-wrist radiographs. Subjects were assigned to two groups of mandibular advancement, using matched randomization. Both groups were treated with the FMA. While the mandible was advanced to a super Class I molar relation in the single-step advancement group (SSG), patients in the stepwise mandibular advancement group (SWG) had a 4-mm initial bite advancement and subsequent 2-mm advancements at bimonthly intervals. The material consisted of lateral cephalograms taken before treatment and after 10 months of FMA treatment. Data were analyzed by means paired t-tests and an independent t-test.Results:There were statistically significant changes in SNB, Pg horizontal, ANB, Co-Gn, and Co-Go measurements in both groups (P < .001); these changes were greater in the SWG with the exception of Co-Go (P < .05). While significant differences were found in U1-SN, IMPA, L6 horizontal, overjet, and overbite appraisals in each group (P < .001), these changes were comparable (P > .05).Conclusion:Because of the higher rates of sagittal mandibular skeletal changes, FMA using stepwise advancement of the mandible might be the appliance of choice for treating Class II division 1 malocclusions.     

Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K

Class IA phosphatidylinositol 3-kinases (PI3K), which generate PIP₃ as a signal for cell growth and proliferation, exist as an intracellular complex of a catalytic subunit bound to a regulatory subunit. We and others have previously reported that heterozygous mutations in PIK3CD encoding the p110δ catalytic PI3K subunit cause a unique disorder termed p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI) disease. We report four patients from three families with a similar disease who harbor a recently reported heterozygous splice site mutation in PIK3R1, which encodes the p85α, p55α, and p50α regulatory PI3K subunits. These patients suffer from recurrent sinopulmonary infections and lymphoproliferation, exhibit hyperactive PI3K signaling, and have prominent expansion and skewing of peripheral blood CD8⁺ T cells toward terminally differentiated senescent effector cells with short telomeres. The PIK3R1 splice site mutation causes skipping of an exon, corresponding to loss of amino acid residues 434–475 in the inter-SH2 domain. The mutant p85α protein is expressed at low levels in patient cells and activates PI3K signaling when overexpressed in T cells from healthy subjects due to qualitative and quantitative binding changes in the p85α–p110δ complex and failure of the C-terminal region to properly inhibit p110δ catalytic activity.Primary human immunodeficiency diseases offer insights into genes and pathways critical for host defense and healthy immune homeostasis. We and others have recently described a unique immune disorder featuring recurrent sinopulmonary infections, predisposition to chronic EBV and CMV viremia, lymphoproliferation, and increased lymphoma susceptibility (Angulo et al., 2013; Crank et al., 2014; Kracker et al., 2014; Lucas et al., 2014). Heterozygous gain-of-function mutations in the PIK3CD gene encoding the leukocyte-restricted p110δ catalytic subunit of phosphatidylinositol 3-kinase (PI3K) are responsible for this disorder, which we have termed p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI) disease (Lucas et al., 2014). PASLI disease is caused by mutation of at least four different sites in PIK3CD that drive hyperactivation of PI3K signaling in immune cells (Crank et al., 2014; Lucas et al., 2014). Some of the disease-causing amino acid substitutions in p110δ are identical to those occurring in tumor cells at homologous sites in PIK3CA encoding p110α, suggesting a similar molecular mode of action. Indeed, PASLI patients exhibit increased lymphoma risk that is further compounded by immunodeficiency leading to poor control of EBV viral loads (Crank et al., 2014; Kracker et al., 2014). We are now aware of ∼80 PASLI patients worldwide, and the number of patients diagnosed with this disorder is expected to increase. Our previous work clearly established that hyperactivation of the PI3K signaling pathway causes immune dysregulation and raised the question of whether or not mutations in other PI3K genes would cause similar clinical manifestations by augmenting this pathway.The phosphoinositide 3-kinase (PI3K) pathway transduces cell growth and proliferation signals through generation of the PIP₃ second messenger, which is important for recruitment and activation of pleckstrin homology (PH) domain–containing signaling proteins. The class IA PI3K family members include the catalytic p110α, p110β, and p110δ proteins and the regulatory p85α, p55α, p50α, p85β, and p55γ proteins. The complex becomes activated upon recruitment to tyrosine-phosphorylated YXXM motifs with major signaling roles downstream of the insulin receptor, insulin-like growth factor-1 receptor, cytokine receptors, T cell receptor, and others. The class IA PI3Ks exist as a dimer of a catalytic and a regulatory subunit. The major roles of the regulatory subunit are to bind and stabilize p110 (Conley et al., 2012), inhibit p110 kinase activity (Burke et al., 2011), and recruit the PI3K complex to phosphotyrosine where binding of the SH2 domains to phosphotyrosine relieves the inhibitory (but not dimerizing) contacts with the catalytic subunit (Yu et al., 1998). There is debate about the existence and potential roles for free monomeric p85α that is not bound to p110 and its possible function in regulating PI3K activity (Geering et al., 2007b). Evidence against roles for free p85α includes the observation that monomeric p85α is relatively unstable (Brachmann et al., 2005; Zhao et al., 2006) and that p85α and p110 are obligate heterodimers normally present in the cell at 1:1 ratio (Geering et al., 2007a). Whether or not p85α can exist unbound to p110 and whether or not free p85α exerts biological or pathological effects remain open questions.Studies in animal models have revealed a complex relationship between p110 and p85α (Vanhaesebroeck et al., 2005). The total PIK3R1 knockout mouse dies in the perinatal period and shows secondary loss of p110 catalytic protein (Fruman et al., 2000). Mice heterozygous for p85α have normal levels of p110 and show greater insulin-stimulated PI3K activity than WT counterparts but display no overt immunological phenotypes (Ueki et al., 2002, 2003; Vanhaesebroeck et al., 2005). Two inherited human diseases have been associated with mutations in the PIK3R1 gene: (1) SHORT syndrome, a disease of short stature, hyperextensible joints, Rieger anomaly of the eye, teething delay, lipoatrophy, and often insulin resistance, caused by heterozygous PIK3R1 mutations (Chudasama et al., 2013; Dyment et al., 2013; Thauvin-Robinet et al., 2013; Bárcena et al., 2014); and (2) agammaglobulinemia due to absent B cells caused by a homozygous PIK3R1 mutation that leads to loss of p85α with secondary loss of p110 (Conley et al., 2012). Somatic, heterozygous mutations in PIK3R1 have also been found in human glioblastoma (Cancer Genome Atlas Research Network, 2008; Parsons et al., 2008) and colon cancer (Jaiswal et al., 2009). These mutations reduce inhibition of p110 by p85α, leading to hyperactive PI3K signaling and tumorigenesis (Jaiswal et al., 2009; Sun et al., 2010). More recently, somatic PIK3R1 mutations in endometrial carcinoma were discovered that cluster mostly within amino acid residues 434–475 in the inter-SH2 domain of p85α and augment PI3K signaling (Urick et al., 2011). These findings in mice and previously described human diseases shed light on the various physiological roles of PIK3R1 gene products and support the hypothesis that cancer-related PIK3R1 gene mutations could be a driver of PASLI-like disease.We have now discovered heterozygous PIK3R1 splice site mutations in patients with PASLI-like disease characteristics and striking hyperactivation of PI3K signaling in immune cells. An independent report has also recently described similar patients with the same splice site mutation (Deau et al., 2014). Here, we not only describe the clinical findings and gene defect in these patients but also provide biochemical evidence that the mutant p85α protein is expressed in patient cells, associates abnormally with p110δ, and dominantly drives constitutive PI3K signaling due to loss of inhibitory contacts, which results in cellular derangements that contribute to immunodeficiency in this patient population. These findings further provide a possible treatment option for these patients using approved or investigational drugs that target PI3K or its downstream effectors (i.e., mTOR inhibition with rapamycin).     

Metastases of renal cell carcinoma to the larynx and thyroid: Two case reports on metastasis developing years after nephrectomy

Renal cell carcinoma (RCC) has a high metastatic potential due to its hematogen and vascular features. It metastasizes frequently to the lungs, the bones, the liver, the lymph nodes and the brain. Metastasis of RCC to the head and neck region is quite rare. In this case report, two RCC patients with head and neck metastases are presented: one occurring after 5 years and the other occurring 17 years after diagnosis.