bluuebunny/crossref_metadata_2025 huggingface dataset:
Global mobility of microfinance policies
Authors: Oikawa Cordeiro Beatriz
Published: September 2019

Throughout the 1970s in South Asia and Latin America, there was a surge of experiences of offering small loans through innovative practices. Following these successes, the dissemination of microfinance institutions is seen all over the globe. Brazil stands out for being a pioneer in this field, having developed a microcredit program even before Grameen Bank, from Bangladesh, the main institution responsible for the spread of microfinance worldwide. This paper aims to understand the social practices, power relations and institutional infrastructure surrounding microfinance, taking the Global South as a starting point and focusing on Brazil. In so doing, it looks at the policy mobility of microfinance, shining light on how policy diffusion and transfer are entangled in the practices and processes of different institutions, actors and networks. It identifies two approaches within the formulation and practice of microfinance historically. Four illustrative cases are discussed in order to present the mobility of microfinance policies in Brazil drawing from the international scenario. The paper’s point of departure for the analysis of the mobility of microfinance is that policy trajectories are fraught with ambivalence and contradiction. They are part of a complex universe permeated by hybridism over time and space.
Conduction through a narrow inward-rectifier K+ channel pore
Authors: Bernsteiner Harald , Zangerl-Plessl Eva-Maria , Chen Xingyu , Stary-Weinzinger Anna
Published: September 2019

Inwardly rectifying potassium (Kir) channels play a key role in controlling membrane potentials in excitable and unexcitable cells, thereby regulating a plethora of physiological processes. G-protein–gated Kir channels control heart rate and neuronal excitability via small hyperpolarizing outward K+ currents near the resting membrane potential. Despite recent breakthroughs in x-ray crystallography and cryo-EM, the gating and conduction mechanisms of these channels are poorly understood. MD simulations have provided unprecedented details concerning the gating and conduction mechanisms of voltage-gated K+ and Na+ channels. Here, we use multi-microsecond–timescale MD simulations based on the crystal structures of GIRK2 (Kir3.2) bound to phosphatidylinositol-4,5-bisphosphate to provide detailed insights into the channel’s gating dynamics, including insights into the behavior of the G-loop gate. The simulations also elucidate the elementary steps that underlie the movement of K+ ions through an inward-rectifier K+ channel under an applied electric field. Our simulations suggest that K+ permeation might occur via direct knock-on, similar to the mechanism recently shown for Kv channels.
Effect of the surface nanocrystallization on tribological behavior of the Cu based bimetallic materials (CuPbSn)
Authors: Gençer Gökçe Mehmet , Yolcu Coşkun , Kahraman Fatih , Saklakoğlu Nurşen
Published: September 2019

In this study, ultrasonic impact treatment was used to improve the tribological behavior of copper-based bimetallic materials that are used in internal combustion engine bearings and bushes. Bimetallic materials were obtained by coating three different CuPbSn alloys by sintering on the material surfaces of carbon steel substrate. After the sintering process, bimetallic materials were treated by ultrasonic impact process. As a result of the metallographic examination, sintered layers have uniform structure along the cross-section of the bimetallic materials. In addition, it was determined that the porosity of sintered materials decreased after the ultrasonic impact treatment. Due to the grain refinement and work hardening, higher hardness was obtained in the fine-grained layer. The hardness of the ultrasonic impact treated samples always higher than the untreated material. Because of the high surface hardness, ultrasonic impact treated samples showed higher wear resistance. The highest wear resistance was detected in the samples with the highest Sn content. Because Sn and Cu combine to form Cu3Sn intermetallic phase in Cu-Pb alloys and Cu3Sn increases the strength of the Cu-Pb alloys. Thus, increasing the Sn content in the Cu-Pb alloy resulted in the wear resistance increase. Furthermore, the formation of the SnO2 intermetallic phase on the sample surface has a significant effect on the wear resistance increase by preventing adhesion.
Inhibition of spindle extension through the yeast S phase checkpoint is coupled to replication fork stability and the integrity of centromeric DNA
Authors: Julius Jeff , Peng Jie , McCulley Andrew , Caridi Chris , Arnak Remigiusz , See Colby , Nugent Constance I. , Feng Wenyi , Bachant Jeff
Published: September 2019

Budding yeast treated with hydroxyurea (HU) activate the S phase checkpoint kinase Rad53, which prevents DNA replication forks from undergoing aberrant structural transitions and nuclease processing. Rad53 is also required to prevent premature extension of the mitotic spindle that assembles during a HU-extended S phase. Here we present evidence that checkpoint restraint of spindle extension is directly coupled to Rad53 control of replication fork stability. In budding yeast, centromeres are flanked by replication origins that fire in early S phase. Mutations affecting the Zn2+-finger of Dbf4, an origin activator, preferentially reduce centromere-proximal origin firing in HU, corresponding with suppression of rad53 spindle extension. Inactivating Exo1 nuclease or displacing centromeres from origins provides a similar suppression. Conversely, short-circuiting Rad53 targeting of Dbf4, Sld3, and Dun1, substrates contributing to fork stability, induces spindle extension. These results reveal spindle extension in HU-treated rad53 mutants is a consequence of replication fork catastrophes at centromeres. When such catastrophes occur, centromeres become susceptible to nucleases, disrupting kinetochore function and spindle force balancing mechanisms. At the same time, our data indicate centromere duplication is not required to stabilize S phase spindle structure, leading us to propose a model for how monopolar kinetochore-spindle attachments may contribute to spindle force balance in HU.
Imaging endogenous synaptic proteins in primary neurons at single-cell resolution using CRISPR/Cas9
Authors: Matsuda Takahiko , Oinuma Izumi
Published: September 2019

Fluorescence imaging at single-cell resolution is a crucial approach to analyzing the spatiotemporal regulation of proteins within individual cells of complex neural networks. Here we present a nonviral strategy that enables the tagging of endogenous loci by CRISPR/Cas9-mediated genome editing combined with a nucleofection technique. The method allowed expression of fluorescently tagged proteins at endogenous levels, and we successfully achieved tagging of a presynaptic protein, synaptophysin (Syp), and a postsynaptic protein, PSD-95, in cultured postmitotic neurons. Superresolution fluorescence microscopy of fixed neurons confirmed the identical localization patterns of the tagged proteins to those of endogenous ones verified by immunohistochemistry. The system is also applicable for multiplexed labeling and live-cell imaging. Live imaging with total internal reflection fluorescence microscopy of a single dendritic process of a neuron double-labeled with Syp-mCherry and PSD-95-EGFP revealed the previously undescribed dynamic localization of the proteins synchronously moving along dendritic shafts. Our convenient and versatile strategy is potent for analysis of proteins whose ectopic expressions perturb cellular functions.
The intrinsically disordered region of the cytokinetic F-BAR protein Cdc15 performs a unique essential function in maintenance of cytokinetic ring integrity
Authors: Mangione MariaSanta C. , Snider Chloe E. , Gould Kathleen L.
Published: September 2019

Successful separation of two daughter cells (i.e., cytokinesis) is essential for life. Many eukaryotic cells divide using a contractile apparatus called the cytokinetic ring (CR) that associates dynamically with the plasma membrane (PM) and generates force that contributes to PM ingression between daughter cells. In Schizosaccharomyces pombe, important membrane–CR scaffolds include the paralogous F-BAR proteins Cdc15 and Imp2. Their conserved protein structure consists of the archetypal F-BAR domain linked to an SH3 domain by an intrinsically disordered region (IDR). Functions have been assigned to the F-BAR and SH3 domains. In this study we probed the function of the central IDR. We found that the IDR of Cdc15 is essential for viability and cannot be replaced by that of Imp2, whereas the F-BAR domain of Cdc15 can be swapped with several different F-BAR domains, including that of Imp2. Deleting part of the IDR results in CR defects and abolishes calcineurin phosphatase localization to the CR. Together these results indicate that Cdc15’s IDR has a nonredundant essential function that coordinates regulation of CR architecture.
Cytotoxicity of 1-deoxysphingolipid unraveled by genome-wide genetic screens and lipidomics in Saccharomyces cerevisiae
Authors: Haribowo A. Galih , Hannich J. Thomas , Michel Agnès H. , Megyeri Márton , Schuldiner Maya , Kornmann Benoît , Riezman Howard
Published: September 2019

Hereditary sensory and autonomic neuropathy (HSAN) types IA and IC (IA/C) are caused by elevated levels of an atypical class of lipid named 1-deoxysphingolipid (DoxSL). How elevated levels of DoxSL perturb the physiology of the cell and how the perturbations lead to HSAN IA/C are largely unknown. In this study, we show that C26-1-deoxydihydroceramide (C26-DoxDHCer) is highly toxic to the cell, while C16- and C18-DoxDHCer are less toxic. Genome-wide genetic screens and lipidomics revealed the dynamics of DoxSL accumulation and DoxSL species responsible for the toxicity over the course of DoxSL accumulation. Moreover, we show that disruption of F-actin organization, alteration of mitochondrial shape, and accumulation of hydrophobic bodies by DoxSL are not sufficient to cause complete cellular failure. We found that cell death coincides with collapsed ER membrane, although we cannot rule out other possible causes of cell death. Thus, we have unraveled key principles of DoxSL cytotoxicity that may help to explain the clinical features of HSAN IA/C.
Diagnostic Management Team: Platelet Refractory Algorithm and Consult
Authors: Wade Jenna , Dean Christina L , Roback John D , Sullivan Harold C
Published: September 2019

Platelet refractoriness occurs when a patient fails to achieve appropriate platelet count increment following platelet (plt) transfusion. Approximately 30% to 40% of cases are due to human leukocyte antigen (HLA) alloantibodies and 2% to 10% are due to human platelet antigen (HPA) alloantibodies, which can be detected by various assays. The results of these tests are then used to guide selection of appropriate units, such as crossmatch-compatible (XM) and HLA-matched (HLAm) plts. Given the various steps and tests involved in diagnosing and managing plt refractoriness, clinicians may order unnecessary tests resulting in delays in patient care. In April 2018, our institution formed a diagnostic management team (DMT) to establish an algorithmic approach to testing, diagnosing, and transfusing plt refractory patients.

We performed a retrospective review of clinician requests for XM or HLAm plts over a 9-month period prior to the launch of the DMT and compared that to requests placed during the initial 9-month period following the launch of the DMT. We collected the date transfusion medicine (TM) service was notified and the time to complete the following: 1-hour corrected count increment (CCI), ELISA indirect antibody screen, HLA flow cytometry PRA screen, HLA single antigen bead (SAB), and obtain the first XM or HLAm plt unit for the patient. There were 12 and 20 patients evaluated for plt refractoriness pre- and post-DMT, respectively. The median time to complete the ELISA indirect antibody screen was 2 days pre- and post-DMT, respectively. Eight percent of patients never had an ELISA screen performed pre-DMT. All patients meeting plt refractory criteria had ELISA screens performed post-DMT. Median time to complete HLA testing decreased from 4 days to 2 days and all patients who had positive FlowPRAs had subsequent SABs performed post-DMT compared to only 40% of patients pre-DMT. The median times to obtain the first XM unit were 6 and 5 days and the first HLAm unit was 5 and 6 days pre- and post-DMT, respectively. One patient had a CCI above 7,500 and four patients had negative screening ELISA and FlowPRA tests after the launch of the DMT. No further testing was performed and they continued to receive ABO-compatible (ABOc) plt units. Since the launch of the DMT, there is improved consistency regarding what tests are performed and standardization of the sequence in which the appropriate tests are ordered. We have reduced unnecessary testing by identifying patients with nonimmune-mediated etiologies of plt refractoriness. Divergence from the algorithm is the main issue encountered during the initial 9-month period following implementation of the DMT. This divergence stemmed from lack of consistent education about plt refractoriness and the DMT. We believe better adherence to the algorithm will lead to decreased product acquisition time and further improve efficiency.
Performance Evaluation of CEA Assay on Beckman Coulter UniCel DxI 800
Authors: Wei Qing , Hardy Robert , Cao Liyun
Published: September 2019

Carcinoembryonic antigen (CEA) is a glycoprotein normally found in embryonic entodermal epithelium. Increased levels may be found in patients with primary colorectal cancer or other malignancies. CEA levels are not useful in screening the general population for undetected cancers. However, CEA levels provide important information about patient prognosis, recurrence of tumors after surgical removal, and effectiveness of therapy. The aim of this study was to assess the analytical performance of CEA assay on a Beckman Coulter UniCel DxI 800. The linearity, sensitivity, reference range, precision, and accuracy were evaluated following CLSI guidelines. The within-run and between-run precisions were assessed by analyzing QC material at low and high levels of concentrations. The accuracy was assessed by comparison of 152 patient serum CEA on DXI with CEA on a previously established ADVIA Centaur System. The analytical measurement range was determined to be linear between 0.00 and 951.3 ng/mL with a slope of 0.976 and intercept of 0.075. The limit of blank (LOB) was determined as 0.03 ng/mL and the limit of detection (LOD) was 0.1 ng/mL. The reference range was verified as 0.0 to 3.0 ng/mL (nonsmokers) and 0.0 to 5.0 ng/mL (smokers). The within-run CVs for CEA were 4.4% at the low level of 2.239 ng/mL and 2.5% at the high level of 38.1 ng/mL. The between-run CVs at low and high levels were 4.4%, and 4.0%, respectively. Comparison of CEA on the Beckman Coulter UniCel DxI 800 with CEA on the ADVIA Centaur System of 152 patient samples showed the slope was 1.541 (95% CI, 1.515-1.567) with an intercept of 0.17 and a correlation coefficient of 0.9943 (Deming). The mean bias between Beckman and ADVIA was 6.49 (41.71%). In summary, our data demonstrate that CEA assay on the Beckman Coulter UniCel DxI 800 has good linearity and precision. There is also good correlation between CEA tested on the Beckman Coulter UniCel DxI 800 and on the ADVIA Centaur System with a positive bias.
Missed Critical Value Callbacks Due to Middleware Flaws
Authors: Altawallbeh Ghaith , Senn Christine , Rapp Michael , Karger Amy B
Published: September 2019

A provider notified the laboratory of a missed sodium critical value notification on a patient; during further investigation, it was noted that the laboratory had missed a second sodium critical value notification several hours later on the same patient. The two missed critical callbacks occurred on different shifts with different technologists, pointing to a systematic issue. A thorough investigation was undertaken involving review of critical callback procedures, staff interviews, and retrospective data review to determine the etiology. It was confirmed that the middleware, Siemens Centralink, had captured and displayed the critical values for review. The Centralink display highlights rows with critical results in red for easy visual identification by the laboratory technologist, and a numerical code of “8” appears in the Normal Severity (NS) column as an additional cue. Upon discussion with involved laboratory staff, a supervisor noted that sodium consistently appears in the top row of the Siemens Centralink result screen when held for review. Our Siemens Centralink display was noted to have a blue bar that by default appears in the top row and was noted to obscure the red highlight and NS Flag that provides a visual cue to staff that it is a critical value. Therefore, we hypothesized that the sodium critical values were missed due to being obscured by the default blue bar, and hypothesized that they could be preferentially affected relative to other analytes due to sodium’s default position in the top row when displayed. To investigate further, we pulled retrospective critical value callback data from our university hospitals for 2018. Our overall critical callback failure rates were ~2.0%. When broken down by individual analyte, we found that 7.2% of sodium critical values were not called back to providers, whereas only 1.0% of potassium critical values were missed. Additionally, critical callback failure rates for hemoglobin were 0.1%; our hematology analyzer has a hard stop for all critical values, whereas the chemistry analyzer does not. In conclusion, we discovered that the default display on our Siemens Centralink middleware screen places a blue bar in the top row that obscures the visual cues associated with a critical value. Because sodium results are placed in the top row on the display screen, missed sodium critical callbacks occurred seven times more often than missed potassium callbacks. To remedy the issue, a blank row has been added to the display as the top row so that no clinical data are obscured by the default blue bar. Additionally, the very low critical callback failure rate on the hematology analyzer points to a need for a hard stop on the chemistry analyzer. We will prospectively monitor critical callback data for sodium to determine whether the display change improves sodium callback rates.
Whole-Exome Sequencing in Evaluation of Thrombophilia: Characterization of Novel Genetic Variants
Authors: Gu Sean , Shevell Lauren , Tormey Christopher , Rinder Henry , Lee Alfred
Published: September 2019

Venous thromboembolism (VTE), defined as deep venous thrombosis and pulmonary embolism, is a cause of significant morbidity and mortality worldwide, with an overall incidence of about 10,000,000 cases per year. The majority of VTE is attributable to genetic factors, yet the five major heritable thrombophilias of factor V Leiden, prothrombin gene mutation, antithrombin deficiency, protein C deficiency, and protein S deficiency comprise only a minority of VTE cases, suggesting that further genetic factors must contribute to VTE risk. We performed whole-exome sequencing (WES) in 106 patients with VTE, focusing our analysis on a 55-gene extended thrombophilia panel comprising genes previously reported in next-generation sequencing studies to be associated with VTE. In our cohort, we identified a probable disease-causing genetic variant or variant of unknown significance (VUS) in approximately 60% of study patients. We then selected several novel VUS involving genes with known roles in hemostasis for further characterization to determine their biological and pathological significance in thrombophilia. Multiple sequence alignment analysis showed that several nonsynonymous variants produced amino acid substitutions in highly conserved regions of proteins relevant to hemostasis and thrombosis, including thrombomodulin (TM), heparin cofactor II, ADAMTS13, and von Willebrand factor (vWF). To evaluate the theoretical effects of selected VUS on thrombosis susceptibility, we visualized proteins using PyMol and performed in silico mutagenesis modeling to evaluate for structural alterations that can predict functional and physiological consequences. Our analyses showed that several variants caused conformational changes predicted to either result in a deleterious effect on enzymatic activity or prevent substrate binding to the active site. For example, variants in TM (P401L and V454A) are predicted to decrease thrombin binding and protein C activation, whereas a C668R variant in the spacer domain of ADAMTS13 is predicted to prevent binding to vWF, resulting in ultra-large vWF multimers. We plan to use these results in combination with clinical laboratory-based coagulation testing and family studies to determine pathogenicity of specific variants in thrombosis and thrombophilia. Overall, these findings indicate that WES is a potentially useful tool for inherited thrombophilia and can provide insight into the genetic factors contributing to VTE.
High Expression of Trophoblast Cell Surface Antigen 2 in Triple-negative Breast Cancer Identifies a Novel Therapeutic Target
Authors: Makhoul Elias , Dadmanesh Farnaz
Published: September 2019

Objectives

Patients with triple-negative breast cancer (TNBC) respond poorly to current therapeutic modalities. The newly FDA-approved drug conjugate, Sacituzumab Govitecan, targeting antitrophoblastic cell surface antigen 2 (Trop-2), offers a new modality to treat these subtypes of breast carcinoma (BC). Our study examines expression of Trop-2 by immunohistochemistry (IHC) in TNBC.

Methods

Forty cases of TNBC were selected from our files (34 ductal, 4 pleomorphic lobular, 1 metaplastic, and 1 mixed ductal and lobular carcinoma). A control group included 11 luminal A-like, 11 luminal B-like, and 8 HER2-like BC. Immunostaining for Trop-2 was performed on 4-micron-thick tissue sections using goat polyclonal antibody (R&D Systems). Three pathologists individually scored the % and intensity of membranous staining. The % of staining was defined as <10%, 10%-50%, and >50%. The intensity of staining was scored as 3+ (crisp circumferential membranous staining), 2+ (medium membranous staining), 1+ (patchy weak membranous staining), and 0 (no staining). A Kruskal-Wallis H-test and pairwise comparison with Bonferroni correction was performed to compare % and intensity of staining in TNBC to control group.

Results

TNBC exhibited stronger Trop-2 staining in both intensity and extent when compared to the control. The result was significantly different, χ2 (4) = 17.427, P = .001. A pairwise comparison with Bonferroni correction found significant difference between TNBC (42.55) and luminal A (16.65) (P < .001). There was significant agreement (P < .001) among 3 independent pathologists for assessing % and intensity of staining.

Conclusion

The extent and intensity of staining for Trop-2 is higher in TNBC than in other molecular subtypes of BC. These findings suggest that patients with TNBC may potentially benefit from this targeted therapy. Furthermore, identification of Trop-2 in other molecular subtypes may expand the therapeutic potential of this new drug. Further studies are needed to determine the efficacy of this marker.
Complex Dysembryoplastic Neuroepithelial Tumor With Pilocytic Astrocytoma Component
Authors: Dasaraju Sandhyarani , Patel Krutika , Akbar Shalla , Elkadi Osama
Published: September 2019

Objectives

Dysembryoplastic neuroepithelial tumor (DNET) is an uncommon mixed glioneuronal tumor. DNET is classified as WHO grade I neoplasm and commonly seen in the temporal lobe of children and young adults with features of pharmacoresistant seizures. The term complex DNET defines those tumors associated with additional features, including a pilocytic astrocytoma (PA) component, a finding that is rarely described in the literature.

Methods

Here we report a 16-year-old male who presented with seizures. On imaging, a 5.5 × 2.2 × 2.1-cm multiloculated mass was centered in the left frontoparietal gray matter with solid and cystic components and focal areas of contrast enhancement.

Results

Microscopic examination revealed a noninfiltrative glioneuronal neoplasm composed of a bland population of round to oval cells arranged around pools of mucinous material. Occasional large neuronal cells were noted. Focal areas composed of elongated astrocytic cells demonstrating piloid morphology were also present. No high-grade features were demonstrated. The findings are consistent with DNET, complex form in addition to a second component with piloid features resembling pilocytic astrocytoma.

Conclusion

The early recognition of DNET is important as it has an excellent prognosis on complete surgical excision without use of adjunct therapies. Unresected or incompletely removed DNET and secondary radiochemotherapy may give rise to recurrence and malignancy. The development of the secondary neoplasm challenges the stability in terms of biological behavior and highlights the importance of complete surgical excision and close follow-up. Our patient had neither undergone previous surgery nor received any adjuvant therapy, and hence this case is a de novo development of PA in a DNET. The association of contrast enhancement with DNET is an unusual finding in this case.
Bilateral Cystic Neutrophilic Granulomatous Mastitis Due to Corynebacterium tuberculostearicum
Authors: Ibarra Alvaro , Donaire Juan , Behnke Carolina , Salas Alberto , Sanhueza Camila
Published: September 2019

Introduction

Cystic neutrophilic granulomatous mastitis (CNGM) is a form of breast lobulocentric granulomatous inflammation characterized by cystic spaces of dissolved lipid, surrounded by neutrophils. Corynebacterium is frequently the etiological agent, specially C kroppenstedtii. It is often painful and can simulate malignancy by clinical and imaging features.

Clinical Case

A 36-year-old woman, three pregnancies with puerperal mastitis in all. Consults by increase in left breast volume, painful, 1-month evolution, with erythema and not quantified fever. With antibiotherapy, erythema resolved, but the mass persisted. Ultrasound showed a 28-mm right nodule and extensive left architecture distortion, hypoechogenic, poorly delimited, which compromised superior quadrants, both BIRADS 4. Bilateral core biopsies had typical findings of CNGM, with bacteria inside cysts, identified with HE, which were Gram positive. The cultures gave Corynebacterium, typified as tuberculostearicum by MALDI-TOF methodology, with antibiotic multisensitivity. After 6 weeks of evolution, the last two with ciprofloxacin, on the left the mass had decreased, with 3-cm periareolar collection. Right lesion fistulized on the biopsy path.

Conclusions

We present a case of bilateral cystic neutrophilic granulomatous mastitis with clinical and imaging features suspected of malignancy. After 6 weeks of evolution, the last two with ciprofloxacin therapy, she had reduction of volume of the larger lesion and fistulization contralateral. She would probably require in its management, in addition to surgery to resolve the fistula, use of lipophilic antibiotics and corticosteroids.
B-Cell lymphoma 2 Protein Expression and Established Clinicopathologic Features in Breast Cancers
Authors: Xiang Yan , Li Li , Zarella Mark , Brzezinska Katarzyna , Hosny Kareem , Hou Steve , Garcia Fernando
Published: September 2019

Objectives

B-cell lymphoma 2 (Bcl-2) proto-oncogene alterations are involved in tumor genesis and play a vital role in regulating cell apoptosis. The objective of this research is to determine the prognostic value of quantitative expression of the Bcl-2 protein in breast cancer.

Methods

This study investigated a series of 158 primary breast cancers for Bcl-2 protein expression. Results were correlated with clinicopathologic features (age, tumor size, tubule formation, nuclear pleomorphism, mitotic count, and Nottingham prognostic index: NPI) and a panel of markers of established or presumed predictive values.

Results

Bcl-2 H-score (multiplied by staining intensity and percentage of positive cells) was observed to have a significant reversed correlation with the Magee Equation 1, 2, 3 (P1 < .001, P2 < .001, P3 < .001, r1 = –0.36, r2 = –0.34, r3 = –0.34). High proliferative activity as assessed by Ki-67 (>25%) staining negatively associated with Bcl-2 H-score (P = .03). Low Bcl-2 H-score was associated with old age (age >63, P = .039). Bcl-2 cytoplasm percent positive score was negatively associated (P = .02, n = 92) with overexpression of p53 (positive percentage >1.5). High Bcl-2 H-score was also associated with tumor size (T >1.5 cm, P = .034), but there was no significant correlation observed between Bcl-2 expression and the NPI calculated using the size of the lesion, the number of involved lymph nodes, and the grade of the tumor (NPI >3.4, P = .317).

Conclusion

(1) This study reports a correlation between Bcl-2 H-score and all three Magee equation values. (2) Bcl-2 H-score provides prognostic value better than percentage of positive cells. (3) This study further reports a correlation between Bcl-2 H-score and age, tumor size, Ki-67, and p53, irrespective of the type of adjuvant therapy received and across molecular subtypes. Collectively, these results establish the rationale for introduction of semiquantitative expression of the Bcl-2 protein to improve prognostic stratification of breast cancer patients.
Morphologic Clues Identify Muscularis Propria at Colonic Biopsy and Warn of Potential Perforation
Authors: Arain Hafsah , Wu Mark
Published: September 2019

Objectives

Perforation is currently believed to be a rare but potentially serious complication of colonic biopsies performed with cold forceps. Most reported cases have occurred in the setting of colitis. The presence of muscularis propria in specimens from colonic biopsies might portend increased risk of perforation. However, identifying muscularis propria at time of biopsy is difficult for many reasons, including histologic overlap with muscularis mucosa. Incidental muscularis propria obtained in this manner has yet to be studied. We hypothesized that differences in nuclear density could distinguish muscularis propria from muscularis mucosa.

Methods

We retrospectively reviewed 3 specimens from colonic biopsies performed with cold forceps for which muscularis propria was presumed to be visualized based on the presence of smooth muscle with lower nuclear density compared to areas known to be muscularis mucosa. All patients were adults clinically suspected to have colitis. These specimens were then compared to a full-thickness section from normal colonic tissue obtained via colectomy that served as control to confirm whether nuclear density or other features could distinguish muscularis propria from muscularis mucosa.

Results

Muscularis propria in the control tissue had lower nuclear density, more cytoplasmic pallor, greater maximal thickness, and smoother texture than the corresponding muscularis mucosa in the control tissue. The constellation of these features was consistently seen in all three specimens obtained via biopsy and therefore confirmed the presence of muscularis propria in all three specimens, although all patients lacked perforation clinically. Surprisingly, all three specimens had histologically normal mucosa.

Conclusion

We showed that several morphologic features, including low nuclear density, identify muscularis propria at time of colonic biopsy and alert endoscopists to the possibility of perforation, and we showed that muscularis propria can accompany normal mucosa obtained via biopsy with cold forceps. Additional studies are necessary to further validate these findings.
Adenosquamous Carcinoma of the Proximal Colon: Case Report and Literature Review of a Rare, Aggressive Entity
Authors: Beversdorf Walter , Rinker Elizabeth
Published: September 2019

Primary adenosquamous carcinoma of the colon is exceedingly rare and accounts for a clinically aggressive minority of colonic epithelial malignancies, with metastatic disease identified in 36% to 49% of cases at the time of diagnosis or resection, compared to 14% of conventional adenocarcinoma cases. Reported median overall survival time is less than half of that for conventional colonic adenocarcinoma, supporting inclusion of squamous differentiation as an adverse prognostic factor. Due to its rarity, optimal treatment protocols have yet to be standardized. We present the case of a 61-year-old female who underwent emergent right hemicolectomy due to bowel obstruction secondary to an ileocecal mass discovered on imaging. Gross examination revealed a 7.3-cm, primarily submucosal cecal mass involving the appendix with associated ileocolic adhesion. Histologic examination showed carcinoma with distinct areas of glandular and squamous differentiation, exhibiting the anticipated differential expression patterns of CK5/6, p63, CK20, CDX2, and mucicarmine. Immunohistochemistry for p16 was negative in both components. The adenocarcinoma component was continuous with a small focus of dysplastic colonic surface epithelium, supportive of cecal origin. Eight of 19 lymph nodes were positive for squamous and adenocarcinomatous metastasis, and a concurrent liver biopsy was also positive for metastasis. There was no evidence of mismatch repair protein deficiency by immunohistochemistry, which was performed on tissue containing both glandular and squamous components. We share this case to highlight a rare and uniquely aggressive subtype of a routinely encountered malignancy, reinforcing the importance of identifying and reporting squamous differentiation within cases of colonic adenocarcinoma.
Prostate Cystadenocarcinoma: A Rare Cystic Epithelial Lesion in an Unusual Clinical Setting
Authors: Ahmed Sunjida , Deng Fang-Ming , Melamed Jonathan
Published: September 2019

Introduction

Cystic tumors of prostate are rare and their clinicopathologic significance remains to be defined. The tumors present with either obstructive urinary symptoms or elevated serum prostate-specific antigen (PSA). Here we report a multilocular cystadenocarcinoma in a patient without significant urologic symptoms.

Case Report

A 71-year-old male with prior abnormal prostate biopsy, 6 years previously (unknown pathology), was referred for prekidney transplant workup. His symptom of oliguria and proteinuria was associated with end-stage renal disease without any obstructive urinary symptoms. Serum PSA detected 5.5 ng/mL. Magnetic resonance imaging (MRI) of the pelvis demonstrated a multilocular cystic lesion measuring 6.2 × 4.6 cm, arising from the right peripheral zone of prostate. The patient underwent MRI-guided prostate needle biopsy. Histology of prostate biopsy revealed glands and cystic structures lined by cuboidal to columnar epithelial cells with basally located hyperchromatic nuclei, pseudostratification, and focal papillary architecture. The cyst wall was immunoreactive for Cam 5.2, NKX 3.1, and AMACR, while negative for PAX8 and 34BE12 and p63, suggesting a diagnosis of primary prostate cystadenocarcinoma.

The patient underwent robotic prostatectomy. The resected specimen showed a soft periprostatic mass, 6.8 × 5.0 cm at the right posterolateral aspect. Cut sections showed multiple multilocular cysts, with papillary projections, involving the right posterior-lateral surfaces with extensive extraprostatic extension. Histology showed multilocular cysts with papillary lining. Immunohistochemical studies showed strong reactivity of the cyst lining for NKX3.1, AMACR, weak CDX-2, and absent 34be12, p63, and ERG reactivity. The microscopic and immunohistochemical evidence supported a diagnosis of prostate cystadenocarcinoma, stage pT3a with free resection margin.

Conclusion

Cystadenocarcinoma is a variant of prostate carcinoma associated with obstructive urinary symptoms and potential for locally advanced growth. This case and other published reports of prostate cystadenocarcinoma show histologic features similar to the ductal variant of prostate adenocarcinoma, and therefore we suggest to grade it as Gleason pattern 4. The current case of prostate cystadenocarcinoma was an incidental diagnosis in an asymptomatic patient with mildly elevated PSA (T1c).
Malignant Perivascular Epithelioid Cell Tumor Mimicking Renal Cell Carcinoma: A Diagnostic Pitfall
Authors: Hakim Natalya , Chornenkyy Yevgen , Qasem Shadi
Published: September 2019

Introduction

Perivascular epithelioid cell tumors (PEComas) are defined by the World Health Organization (WHO) as mesenchymal tumors arising from perivascular epithelioid cells with myomelanocytic immunophenotype. In the kidney, they are often referred to as epithelioid angimyolipoma (AML). Most are benign but some can be malignant. Their rarity and wide differential render diagnosis challenging.

Case Presentation

A 56-year-old male presented with a 3-month history of flank pain. Computed tomography (CT) identified bilateral necrotic heterogeneous enhancing kidney masses, with right significantly larger than left. Initially, the patient underwent a right radical nephrectomy. On gross examination, no tumor infiltration was observed. Histology demonstrated sheets of highly atypical cells with clear cytoplasm and easily identifiable nucleoli. Areas of spindle and rhabdoid differentiation were present. The initial diagnosis was renal clear cell (RCC) carcinoma, Fuhrman grade 4, with extensive rhabdoid and focal sarcomatoid features.

A follow-up CT demonstrated a hypodense area within the right hepatic lobe. Status post liver resection and histomorphological examination, the lesion was identical to the renal mass except for focal areas of prominent epithelioid cells with eosinophilic cytoplasm. Immunohistochemical (IHC) stains of both masses were positive for Melan-A, HMB-45, and EMA but negative for PAX8, SOX10, S100, SMA, desmin, and cytokeratin. The initial diagnosis was amended to malignant AML with hepatic metastasis.

Discussion and Conclusion

Renal PEComa (epithelioid AML) is a rare tumor with a prevalence of 0.44%. While most are benign, some are malignant with metastatic potential. The differential diagnosis for PEComa is broad and includes more common tumors like RCC, melanoma, clear cell sarcoma, and liposarcoma. The presence of spindle and epithelioid histology with eosinophilic cytoplasm in RCC should prompt additional IHC workup (HMB45, Melan-A, SMA, and EMA) in order to exclude PEComa/AML.
The Many Faces of Cardiac Sarcoidosis
Authors: Serei Virian , Fyfe-Kirschner Billie
Published: September 2019

Introduction

Cardiac involvement by sarcoidosis, a disease characterized by nonnecrotizing granulomas of unknown etiology, is rare and affects up to 7% of sarcoidosis patients clinically, but with an autopsy prevalence of 15% to 90%. The clinical presentation, as well as macroscopic and microscopic findings in cardiac sarcoidosis patients, varies.

Methods

Retrospective clinical chart review and gross and microscopic examination of surgical specimen from two adult cardiac sarcoidosis patients with literature review were performed.

Results

Case 1: A 23-year-old woman with no past medical history presented with 2 months of heart failure symptoms following a viral gastrointestinal infection. Endomyocardial biopsy showed a dense chronic inflammatory infiltrate, without giant cells. Anterior mediastinal lymph node biopsy and left apical core showed effacement by nonnecrotizing granulomas with giant cells and multifocal calcification, supporting cardiac sarcoidosis. Twelve months later, she underwent cardiac transplantation. The explanted heart showed concentric ventricular scarring, which microscopically corresponded to myocardial fibrosis with scattered lymphocytic inflammation with no residual granulomas.

Case 2: A 52-year-old man with a medical history significant for ischemic cardiomyopathy and cutaneous sarcoidosis with lung involvement presented with congestive heart failure. Endomyocardial biopsy and left apical core showed myocyte hypertrophy and scattered interstitial inflammation. Mediastinal lymph node showed nonnecrotizing granulomas, consistent with sarcoidosis. Eighteen months later, he underwent cardiac transplantation. The explanted heart showed biventricular dilatation with interstitial fibrosis. There was also mild diffuse inflammation and occasional granulomas with rare focal necrosis.

Conclusion

Though the gold standard for diagnosing cardiac sarcoidosis is demonstration of myocardial nonnecrotizing granulomas, the sensitivity of endomyocardial biopsy is low. This is due to sampling error and stage of disease. Chronic end-stage disease can lead to fibrous encasement of granulomas and end-stage heart failure, necessitating cardiac transplantation. Current guidelines employ a combination of clinical, radiologic, and histologic criteria for diagnosing cardiac sarcoidosis.
Unusual Left Atrium and Pulmonary Vein Mass: Correlation of Imaging and Immunohistochemical Stains
Authors: Nowroozizadeh Behdokht , Ibe Ifegwu , Nowroozizadeh Sara , Bosemani Thangavijayan , Sun Jack , Wang Beverly
Published: September 2019

Introduction

Intimal sarcoma derived from the pulmonary vein and left atrium is an extremely rare and highly aggressive soft tissue neoplasm. We report a 21-year-old woman with a large filling defect in the pulmonary vein. The lesion extended into the left atrium mimicking a thrombus or a myxoma.

Case History

A 21-year-old woman presented with progressively worsening weakness, orthopnea, and exertional dyspnea of 2 weeks’ duration. Chest CT scan revealed a large left atrial mass, measuring 8.6 × 4.9 cm, which invaded the right lower lobe of lung and inferior pulmonary vein. Patient underwent right lower lobectomy and surgical resection of the left atrial mass and pulmonary vein.

Result

Histologic examination showed a highly cellular, cytologically malignant spindle cell neoplasm in a fascicular pattern. The lesional cells had hyperchromatic tapering nuclei and indistinct cytoplasm. There were numerous mitoses, focal necrosis, and predominantly myxoid stroma. The histologic features suggested the possibility of a myxofibrosarcoma or an intimal sarcoma. The lesional cells were immunoreactive for MDM2 and CDK4, consistent with amplification of the genes on the long arm of chromosome 12. Additionally, the lesional cells were vimentin, CD99, and BCL2 positive while nonimmunoreactive for S100, AE1/3, CD31, CD34, desmin, SMA, MyoD1, myogenin, MPO, and calretinin. Immunohistochemical staining for H3K27me3 was retained. These immunohistochemical findings supported the diagnosis of an intimal sarcoma.

Conclusion

Intimal sarcoma commonly involves the aorta and rarely presents as a pulmonary vein or atrial mass. Correlation of imaging and pathologic findings is critical, as intimal sarcoma can mimic a thrombus. Application of immunostains and cytogenetic studies are useful to distinguish intimal sarcoma from other cardiac sarcomas and myxoma of atrium.
Metastatic Malignant Paraganglioma: A Case Report
Authors: Sahni Suhalika , Mehta Vikas
Published: September 2019

Objectives

Paragangliomas are rare neuroendocrine tumors that arise from chromaffin cells with the ability to secrete catecholamines. The estimated combined prevalence is between 1:6,500 and 1:2,500. Paragangliomas can have a benign or a malignant course with incidence of malignant paraganglioma estimated to be 93/400 million. The majority of paragangliomas are sporadic but may be related to syndromes like multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and neurofibromatosis type 1.

Methods

We present a unique case of a 25-year-old female who presented with a hepatic mass. Further workup showed an enhancing hypervascular mass along with lesions within the bilateral lungs, liver, spleen, and sclerotic osseous metastatic disease at cervical thoracic lumbar and sacral spine. A liver biopsy was performed, which was consistent with the diagnosis of a metastatic paraganglioma.

Results

The liver biopsy showed a tumor consisting of epithelioid and polygonal tumor cells with eosinophilic cytoplasm present in a vascularized fibrous stroma in a sinusoidal pattern. In certain areas, the tumor cells show marked pleomorphism with large cells with macronuclei and bizarre shapes. On immunohistochemistry (IHC), the tumor cells were strongly and diffusely positive for CD56 and vimentin and focally positive for synaptophysin and chromogranin. S100 highlighted sustentacular cells. Ki-67 was very low, staining less than 2%. In addition, the tumor cells showed loss of expression of SDHB by IHC.

Conclusion

Metastatic malignant nonsecretory paraganglioma is an extremely rare disease. The most unique pathological aspect of paragangliomas is that tissue acquired from different organ appears the same histologically and yet different in terms of prognosis. Metastatic hepatic paraganglioma in our patient offers interesting insights to appreciate the rare metastatic nature of paraganglioma to the liver. The elusive nature of the metastatic disease in paraganglioma poses a challenge to clinicians since the diagnosis of metastatic hepatic paraganglioma is usually clinically undiagnosed.
Perplexing Gastrointestinal Pathology: A Case Report on Ectopic Gastric Tissue Presenting as Rectal Mass
Authors: Sahni Suhalika , Mehta Vikas
Published: September 2019

Objectives

Gastric heterotopia (GHT) is a commonly reported epithelial heterotopia and has been described as heteroplasia (congenital) during organogenesis or metaplasia (acquired) during process of damaged epithelial repair. GHT can occur along the GI tract from nose to anus; it is predominantly seen in esophagus, duodenum, and Meckel’s diverticulum. It is the most common subtype of epithelial heterotopia. However, the presence of gastric mucosa in the rectum is a very uncommon entity. The endoscopic prevalence of GHT can reach up to 11% in foregut and midgut with a lesser prevalence in hindgut.

Methods

We present an interesting case of heterotopic gastric mucosa presenting as a rectal mass. A 27-year-old female patient presented with lower abdominal pain and episodic bloody diarrhea. After initial workup, a colonoscopy was done, which showed a 3-cm mass in the rectum. Features of inflammatory bowel disease were not identified.

Results

At the first rectal biopsy, multiple fragments of gastric mucosa, with some minimally attached rectal crypts, were identified and a diagnosis of gastric heterotopia was made. Subsequently, the mass was resected and similar findings were identified, confirming the diagnosis. Our case showed mixed oxyntic and antral mucosa comingling with rectal-type mucosa. Immunohistochemical studies were performed, which showed CDX2 and CK20 being positive in rectal and CK7 in gastric mucosa.

Conclusion

Gastric heterotopia is a rare entity that can present as a solitary lesion. The clinical signs and symptoms can mimic those of inflammatory bowel disease. Floater or contamination is an important pitfall in this entity and can lead to an erroneously diagnose. Due to high frequency of having floater in some histology laboratories, we recommend ordering multiple deeper recuts on cases when the pathologist sees closeness or attachment of gastric tissue to the rectal tissue.