bluuebunny/crossref_metadata_2025_split huggingface dataset:
Missed Critical Value Callbacks Due to Middleware Flaws
Authors: Altawallbeh Ghaith , Senn Christine , Rapp Michael , Karger Amy B 
Published: September 2019

Abstract
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

Abstract
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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract
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

Abstract

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

Abstract

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.