Initial Specimen Research Articles

Abstract P2-15-02: Using Oncotype DX Breast Recurrence Score® (RS) assay to define the role of neoadjuvant endocrine therapy (NET) in early-stage hormone receptor positive (HR+) breast cancer (BC)

Abstract Background:Adjuvant endocrine therapy remains the standard of care for patients (pts) with early stage, HR+ BC who can safely omit chemotherapy based on RS results; however, the role of NET remains unclear. There are limited data regarding the optimal duration of treatment with NET and the ideal patient (pt) population for NET in terms of age and RS result. This question rose to critical importance amidst the COVID-19 pandemic, during which NET was utilized more broadly in attempts to delay surgery or chemotherapy while preserving optimal pt outcomes. This study re-examines the use of NET among a cohort of pts with HR+ BC randomized to NET or neoadjuvant chemotherapy (NCT) based on RS (performed on initial core biopsy specimens).Methods:Data were pooled from two independent studies performed at Emory’s Winship Cancer Institute and Massey Cancer Center at Virginia Commonwealth University (VCU) from 2010-2012. These studies evaluated rates of clinical and pathologic complete response (pCR) among pts with early stage, HR+ BC assigned to treatment groups based on RS results. Pts with RS 0-10 received NET (Group (Grp) A), RS 11-24/25 (Emory 11-24 vs VCU 11-25) were randomized to NET (Grp B) or NCT (Grp C), and those with RS 25/26-100 received NCT (Grp D). Associations between RS result, neoadjuvant therapy and pCR in the breast, lymph nodes (LN) and breast plus LN were evaluated using Fisher’s exact test. Results:109 pts were included in this analysis. The Emory cohort was younger (median age 56 years (yrs) vs 63 yrs in VCU cohort) and more diverse (37.5% African American (AA) vs 18.6% AA in VCU cohort). The pts were predominantly post-menopausal (69.6% Emory vs 83.1% VCU). Nodal status among the Emory cohort was evenly divided with 50% N0 and 50% N+, while the majority of VCU pts were N0 (76.3% N0 vs 22.0% N+). Pts were grouped based on RS result: RS <11 (18% Emory vs 20.3% VCU), RS 11-24/25 (36% Emory vs 55.9% VCU) and RS 24/25 or higher (46% Emory vs 23.7% VCU). Pts with low RS result were older (median 64 yrs vs 59 yrs among RS > 24/25) with higher percentage of low-grade tumors (47.6% grade 1 vs 5.4% grade 1 among RS >24/25). With regard to pCR, there were no significant differences among pts with low or intermediate RS results, as no pts in these groups achieved pCR in the breast or breast + LN (Table). Pts with RS result 25/26-100 (Grp D) were the only pts shown to achieve pCR in breast + LN (18.9%, p= 0.0043 across groups). Notably, while pts on the Emory study received longer courses of NET (median 10 months vs 5.5 months), there were no significant differences in pCR across RS result subgroups noted between the two institutions. Conclusion:Our results demonstrate that the use of Oncotype DX Breast Recurrence Score® or other genomic assays in the neoadjuvant setting may help guide treatment decisions when considering the use of NET versus NCT. Pt age and length of endocrine therapy as well as pt preferences should be considered when determining neoadjuvant treatment plans. There are currently ongoing studies evaluating the use of NET with CDK4/6 inhibitors that will offer further insight into optimal neoadjuvant treatment strategies in HR+ BC. Subsequent phase III evaluation of the role of genomic assays in the neoadjuvant setting is feasible and may help determine whether NET + CDK 4/6 inhibitors could replace NCT for pts with higher RS values. Table: pCR according to treatment groups (All Eligible Patients)VariableGroup A (N=21)Group B (N=23)Group C (N=22)Group D (N=37)P value (a)pCR Breast0 (0.0%)0 (0.0%)0 (0.0%)8 (21.6%)0.0016pCR Nodes0 (0.0%)1 (4.3%)3 (13.6%)2 (5.6%)0.2977pCR Breast + Nodes0 (0.0%)0 (0.0%)0 (0.0%)7 (18.9%)0.0043(a) Fisher's exact test was used for categorical variables with cell counts <5.Note: Group A= Recurrence Score <11,Group B= Recurrence Score 11-24 (Emory study) or 11-25 (VCUstudy) receiving NET,Group C= Recurrence Score 11-24 (Emory study) or 11-25 (VCUstudy) receiving NCT,and Group D= Recurrence Score >24 (Emory study) or >25 (VCUstudy).Note: 1 patient did not receive SLNB(sentinel lymph node biopsy) or ALND (axillary lymph node dissection) and is excluded from the denominator for pCR Nodes. Citation Format: Caitlin Taylor, Aimee Foreman, Christy Russell, Dipankar Bandyopdhyay, Xiaoyan Deng, Lisa Floyd, Amelia Zelnak, Ruth O'Regan, Harry Bear, Jane Meisel. Using Oncotype DX Breast Recurrence Score® (RS) assay to define the role of neoadjuvant endocrine therapy (NET) in early-stage hormone receptor positive (HR+) breast cancer (BC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-15-02.

Experimental Investigations on Mechanical Properties of Consolidated Samples for Collapse Columns under Seepage-Stress Coupling Effects

Abstract Triaxial seepage tests were conducted on the consolidated collapse column specimens to investigate their mechanical properties under seepage-stress coupling effects using a triaxial multifield coupled mechanical test system for rocks. The effects of initial consolidation pressures and specimen components on mechanical properties and seepage characteristics of consolidated collapse column specimens were analyzed. Test results showed the following: (1) The stress–strain curves of consolidated collapse column specimens could be classified in three stages, namely, compaction stage, linear deformation stage, and creep-like deformation stage, while the permeability during loading showed an obvious four-stage evolution of gradual decrease, stable development, rapid increase, and slow decrease. (2) Under same sample components, the permeability characteristics of consolidated collapse column specimens showed an obvious initial consolidation pressure effect. The initial consolidation pressure changed the distribution of pores and fractures in the specimens, leading to a decreased peak permeability as the initial consolidation pressure increased. (3) At the initial stage of loading, the permeability of consolidated specimens was mainly affected by the initial consolidation pressure, and the corresponding permeability decreased with the increase of the consolidation pressure. When the consolidated specimens were gradually compacted, the main factor influencing the permeability changed to the specimen components. The peak permeability of consolidated specimens comprising grey mudstone and conglomerate was the largest, while the fuchsia mudstone would reduce the specimen permeability, and the peak permeability decreased with the fuchsia mudstone components.

Reticulated Porous Perovskite Structures for Thermochemical Solar Energy Storage

AbstractThe inherent capability of concentrated solar power (CSP) plants for sensible thermal energy storage ensures their continuous operation and is considered their most crucial competitive edge versus other renewable energy sources. The storage density of air‐operated CSP plants can be significantly increased by hybridizing sensible with thermochemical storage of solar heat, exploiting reversible air–solid oxide reduction–oxidation reactions. Thermochemical storage‐relevant‐protocols testing of in‐house manufactured lab‐scale reticulated porous ceramic foams made entirely of CaMnO3 perovskite reveals fully reversible reduction‐oxidation in up to 46 cycles between 300 and 1100 °C under air, without any deterioration of the foams’ structural integrity and exploitable endothermic/exothermic heat effects between 890 and 920 °C linked to an orthorhombic‐to‐cubic phase transition. Dilatometry experiments with CaMnO3 bars under identical cyclic conditions demonstrate the correlation of this phase transition to an increase in the thermal expansion coefficient but nevertheless, complete recovery of the initial specimen dimensions upon completion of a full heat‐up/cooldown redox cycle. The possibility of shaping into sturdy reticulated porous ceramic structures which exhibit complete dimensional reversibility upon cyclic redox operation, combined with the low cost, earth abundance and environmentally benign character of the constituting elements, render such perovskite compositions extremely attractive for the manufacture of large‐scale porous structured objects for exploitation in various thermochemical processes.

Cerebrospinal fluid flow cytometry and risk of central nervous system relapse after hyperCVAD in adults with acute lymphoblastic leukemia.

Potential involvement of the central nervous system (CNS) by acute lymphoblastic leukemia is typically evaluated by a conventional cytospin (CC) of cerebrospinal fluid (CSF). Multiparameter flow cytometry (MFC) is generally more sensitive and specific than morphology, but data to guide its use versus CC are limited. This study identified 92 patients who had MFC performed on their initial CSF specimen and received at least 4 cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine (hyperCVAD) as their initial treatment. Eighteen (20%) were CSF+ by MFC at the baseline, and only 6 of these patients were positive by CC. In contrast, 0 of 51 patients who were negative by MFC and had CC available were positive by CC. Despite the receipt of significantly more intra-CSF chemotherapy (P < .001), the cumulative incidence of CNS relapse by MFC was 22% among CSF+ patients versus 5% among those who were CSF- (P = .044). No such association was observed between CNS relapse and CC results (P = .42). None of the 74 CSF- patients became CSF+ during their initial treatment despite being tested a median of 5 times (range, 2-10). CSF positivity by MFC was the factor most strongly associated with CNS relapse in a series of univariate Cox models (hazard ratio, 3.7; P = .067). The initial CSF status by MFC had no significant impact on overall or event-free survival. MFC of CSF is superior to CC of CSF in identifying adults at high risk for CNS relapse after treatment with hyperCVAD. Surveillance of CSF by MFC has limited utility.

Proliferating CD8+ T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma

Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.36, p = 0.001) and CD20+ cells (HR 0.51, p = 0.008), as well as CD8+Tbet+ cells (HR 0.46, p = 0.004), and RORγt+ cells (HR 0.56, p = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, p = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.15, p < 0.001), and higher ratios of CD8+ cells to CD4+ cells (HR 0.31, p = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, p = 0.005) and higher mean intensities of IFNγ (HR 2.13, p = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8+ T cells and that approaches may be needed to promote CD8+ T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment.

The Alberta Newborn Screening Approach for Sickle Cell Disease: The Advantages of Molecular Testing.

Sickle cell disease (SCD), a group of inherited red blood cell (RBC) disorders caused by pathogenic variants in the beta-globin gene (HBB), can cause lifelong disabilities and/or early mortality. If diagnosed early, preventative measures significantly reduce adverse outcomes related to SCD. In Alberta, Canada, SCD was added to the newborn screening (NBS) panel in April 2019. The primary conditions screened for are sickle cell anemia (HbS/S), HbS/C disease, and HbS/β thalassemia. In this study, we retrospectively analyzed the first 19 months of SCD screening performance, as well as described our approach for screening of infants that have received a red blood cell transfusion prior to collection of NBS specimen. Hemoglobins eluted from dried blood spots were analyzed using the Bio-Rad™ VARIANT nbs analyzer (Bio-Rad Laboratories, Inc., Hercules, CA, USA). Targeted sequencing of HBB was performed concurrently in samples from all transfused infants. During the period of this study, 43 of 80,314 screened infants received a positive NBS result for SCD, and of these, 34 were confirmed by diagnostic testing, suggesting a local SCD incidence of 1:2400 births. There were 608 infants with sickle cell trait, resulting in a carrier frequency of 1:130. Over 98% of non-transfused infants received their NBS results within 10 days of age. Most of the 188 transfused infants and 2 infants who received intrauterine transfusions received their final SCD screen results within 21 ± 10 d of birth. Our SCD screening algorithm enables detection of affected newborns on the initial NBS specimen, independent of the reported blood transfusion status.

Ethmoidal silent sinus syndrome after nasal swab test.

This study reported the case of a healthy male in his 40s who presented with a 3-month history of frontal headache and post-nasal drip, which did not improve with oral antibiotics. One month prior to the onset of the symptoms, he underwent a nasopharyngeal swab testing for SARS-CoV-2 (which yielded a negative result) for a history of malaise and cough. The patient claimed that the swab insertion into the nasal cavity was particularly painful on the left side. Sinus computed tomography (CT) scan showed deformity of the left middle nasal turbinate with occlusion of the osteomeatal complex, resulting in ethmoid silent sinus syndrome. This study makes a significant contribution to the literature because nasopharyngeal, midturbinate and anterior nasal swabs have been recommended as initial diagnostic specimen collection methods by the US Centers for Disease Control and Prevention (CDC) for the coronavirus disease 2019. These methods require introducing an instrument into the nasal cavity, potentially leading to adverse effects due to the delicate and complex nasal anatomy. However, complications related to swab testing for respiratory pathogens have not yet been fully discussed in the literature.

Initial Specimen Diversion Device® reduces blood culture contamination and vancomycin use in academic medical centre

In suspected bloodstream infections, accurate blood culture results are critical to timely diagnoses and appropriate antibiotic administration. An Initial Specimen Diversion Device®, Steripath® (Magnolia Medical Technologies, Seattle, WA, USA) was evaluated for efficacy in reducing blood culture contamination at Brooke Army Medical Center (6.8% six-month contamination rate prior to intervention) in a six-month quality improvement project. Blood cultures in the emergency department were collected using either Steripath or the standard method. Blood samples of 20 mL were cultured into an aerobic and anaerobic medium and incubated for five days using an automated microbial detection system immediately after collection. Positive bottles were Gram-stained and plated. Rapid molecular polymerase chain reaction identification was performed on all first positive bottles within a blood culture set for each admission or ED visit. Speciation was deduced during antimicrobial sensitivity testing using the Vitek-2 instrument. Seven out of 1016 (0.69%) contamination events occurred when using Steripath vs 53 out of 800 (6.6%) contamination events when using the standard method. Steripath use was associated with a 90% lower incidence of blood culture contamination vs the standard method. Post study, Steripath use was implemented as standard practice hospital-wide, and a retrospective data analysis attributed a 31.4% decrease in vancomycin days of therapy to Steripath adoption. Using Steripath significantly decreased blood culture contamination events for bacterial bloodstream infections compared to the standard method. Subsequent adoption of Steripath reduced overall vancomycin usage. With widescale implementation Steripath could bolster antibiotic stewardship, mitigating antibiotic resistance caused by unnecessary antibacterial treatments.

Dermatofibrosarcoma Protuberans Presenting as a Subcutaneous Cystic Nodule

A 41-year-old African American male complains of a painful cyst located on his right shoulder and lasting 2 years. The specimen was excised and stained positive for CD34 and negative for SOX-10, confirming the diagnosis of Dermatofibrosarcoma Protuberans (DFSP). The initial specimen had positive extension at both the deep and lateral margins. Complete removal of the tumor required 3 stages of MMS resulting in a 10 cm x 7.6 cm final defect, extending to muscle. As demonstrated in this case, DFSP has an erratic growth pattern and requires meticulous histopathological examination to ensure clear margins. MMS is the preferred method of treatment. Cases of DFSP have high rates of recurrence and require regular follow-up for 3-5 years after treatment.

C3 Glomerulopathy and Related Disorders in Children: Etiology-Phenotype Correlation and Outcomes.

Membranoproliferative GN and C3 glomerulopathy are rare and overlapping disorders associated with dysregulation of the alternative complement pathway. Specific etiologic data for pediatric membranoproliferative GN/C3 glomerulopathy are lacking, and outcome data are based on retrospective studies without etiologic data. A total of 80 prevalent pediatric patients with membranoproliferative GN/C3 glomerulopathy underwent detailed phenotyping and long-term follow-up within the National Registry of Rare Kidney Diseases (RaDaR). Risk factors for kidney survival were determined using a Cox proportional hazards model. Kidney and transplant graft survival was determined using the Kaplan-Meier method. Central histology review determined 39 patients with C3 glomerulopathy, 31 with immune-complex membranoproliferative GN, and ten with immune-complex GN. Patients were aged 2-15 (median, 9; interquartile range, 7-11) years. Median complement C3 and C4 levels were 0.31 g/L and 0.14 g/L, respectively; acquired (anticomplement autoantibodies) or genetic alternative pathway abnormalities were detected in 46% and 9% of patients, respectively, across all groups, including those with immune-complex GN. Median follow-up was 5.18 (interquartile range, 2.13-8.08) years. Eleven patients (14%) progressed to kidney failure, with nine transplants performed in eight patients, two of which failed due to recurrent disease. Presence of >50% crescents on the initial biopsy specimen was the sole variable associated with kidney failure in multivariable analysis (hazard ratio, 6.2; 95% confidence interval, 1.05 to 36.6; P<0.05). Three distinct C3 glomerulopathy prognostic groups were identified according to presenting eGFR and >50% crescents on the initial biopsy specimen. Crescentic disease was a key risk factor associated with kidney failure in a national cohort of pediatric patients with membranoproliferative GN/C3 glomerulopathy and immune-complex GN. Presenting eGFR and crescentic disease help define prognostic groups in pediatric C3 glomerulopathy. Acquired abnormalities of the alternative pathway were commonly identified but not a risk factor for kidney failure.

Endoscopy biopsy is not efficiency enough for diagnosis of mucinous colorectal adenocarcinoma

BackgroundEndoscopy biopsy (EB) is the standard diagnostic method for colorectal cancer (CRC), whereas its accuracy and efficiency in mucinous adenocarcinoma (MAC) initial diagnosis is unclear.MethodsThe initial EB and postoperative specimen (PS) pathological diagnosis of MAC from two centers were retrospectively collected and analyzed. The accuracy and efficiency of initial EB compared with PS pathological diagnosis were analyzed. The potential factors which would affect the initial EB diagnosis of MAC were analyzed.Results280 and 78 eligible cases were enrolled in this study from two centers respectively. The initial EB diagnosis accuracy for MAC were 84.62% and 83.33%. However, among the cases of PS diagnosis with MAC, the diagnostic efficiency of initial EB was only 36.49% and 32.50% respectively. Lower tumor differentiation and more EB number were associated with an increased probability for the EB diagnosis of MAC, but only tumor differentiation was an independent diagnositic factor for EB in the two cohorts.ConclusionsThe accuracy of initial EB with MAC is high, but the diagnostic efficiency was extremely low. Tumor differentiation and EB number were associated with the diagnosis efficiency of MAC before surgery.

Mini-resectoscopy Endometrial Biopsy Accuracy Respect Dilatation and Curettage in Endometrial Cancer: A Retrospective Analysis

<h3>Study Objective</h3> Dilatation and curettage (D&C) biopsy is a "gold standard" to confirm the histology and grade of endometrial cancer but the concordance rate was only 70% between D&C and hysterectomy. <h3>Design</h3> We retrospectively reviewed 187 cases of endometrial cancer that were treated at our institution from January 2017 to June 2019. We analyzed all patients who underwent Trans Cervical mini-Resectoscopy (TCR) or D&C biopsy at our institution and received laparoscopic/laparotomic hysterectomy or staging as the treatment by our surgical team. <h3>Setting</h3> We categorized the patients into the TCR group or the D&C group. For each group, we compared the biopsy histological grade and histology with the final hysterectomy of all patients. <h3>Patients or Participants</h3> We analyzed 187 cases of endometrial cancer aged from 29 to 81 years. <h3>Interventions</h3> TCR was carried out, with lidocaine local cervical injection and awake sedation. Resectoscopy was performed with a 7mm bipolar resectoscope. D&C was carried out in general anesthesia and the cervix is dilated up to 10mm Hegar dilators. Two different pathologies analyzed the initial and hysterectomy specimens. <h3>Measurements and Main Results</h3> Endometrial biopsy was obtained by D&C in 103 (55%) cases and by TCR in 84 (45%) of cases. the median operative time was 17,5 for TCR and 17,41 for D&C without significant differences between the two methods (p<0,99). The second stage was preoperative detective only with the use of TCR biopsy 5 (100% of cases) respect none of D&C. Among 72 patients who underwent TCR biopsy, only 4 patients have been grading misdiagnosed in the final pathology, which gives a rate of 5,5% (K 0,918 IC 95% 0,958-0,878 p<0,001). In the D&C group of 87 patients, 17 (19,5%) patients have been grading misdiagnosed (K 0,699 IC 95% 0,764 - 0,634 p<0,001). <h3>Conclusion</h3> Our data, although retrospective, demonstrate that Trans cervical mini-resectoscopy provides a more accurate reflection of FIGO grade than D&C endometrial sampling.

Mantle cell lymphoma involving tonsils: a clinicopathologic study of 83 cases

We report 83 cases of mantle cell lymphoma (MCL) involving the tonsil as initial manifestation (IM). The median age at the time of tonsillar involvement was 58 years (range, 35-79 years). Most (85%) patients presented similar to acute tonsillitis. Lymphadenopathy (84%) and advanced stage of disease (81%) were frequent. With a median follow-up of 6.1 years (range, 0.5-18.4 years), the median overall survival (OS) was 11.3 years for all patients. Cases with classic MCL morphology demonstrated a superior OS (median OS: 11.7 years versus 7.8 years for aggressive morphology, P=0.0361). Approximately 20% of patients had limited stage of disease, and they had excellent outcomes (median OS: not reached versus 11.3 years for advanced-stage MCL, P=0.0479). All the patients were alive after a median follow-up of 6.6 years (range, 1-16.2 years). There were no differences in relapse-free survival in morphology and stage (P>0.05). When tonsils were involved by relapsed MCL, patients less commonly had acute tonsillitis-like symptoms, lymphadenopathy, and advanced stage of disease compared to MCL as IM. Patients in the relapse group had poorer OS than patients in the IM group from the time of tonsillar involvement by MCL to the date of death or last follow-up (7.8 versus 11.7 years, P=0.003). Compared with a group of 93 patients whose initial biopsy specimen was a lymph node, patients whose initial biopsy specimen was tonsil had similar OS (11.7 versus 8.8 years, P=0.1764). However, patients with tonsillar MCL more commonly had limited stage disease (19% versus 8%, P=0.0385) and a low-risk Mantle Cell Lymphoma International Prognostic Index score (71% versus 47%, P=0.0025).

DEK-AFF2 fusion-associated papillary squamous cell carcinoma of the sinonasal tract: clinicopathologic characterization of seven cases with deceptively bland morphology

A novel DEK-AFF2 fusion has been recently identified in four cases of basaloid to nonkeratinizing squamous cell carcinoma (SCC) in the sinonasal tract and middle ear with high-grade morphology. The exceptional response to immune checkpoint inhibitor in the first reported case highlights the potential clinical importance of identifying tumors with DEK-AFF2 fusions. We herein reported the first series of seven cases of DEK-AFF2 fusion-associated sinonasal SCC with deceptively bland morphology, including four cases of low-grade papillary Schneiderian carcinoma, which is a recently described tumor type with unknown molecular underpinnings. The DEK gene rearrangement was confirmed by DEK break-apart fluorescence in situ hybridization and DEK-AFF2 fusion transcripts were detected by reverse transcription polymerase chain reaction. In contrast to the previously reported DEK-AFF2 fusion-positive high-grade carcinomas, these tumors had a monotonous and bland morphology and were all initially diagnosed as sinonasal papilloma (SP) of various types, with or without dysplasia or carcinoma in situ. The tumor was characterized by mixed exophytic and inverted patterns, broad papillary fronds, acantholytic change, cellular monotony, dense neutrophilic infiltrates, and peripheral palisading. All tumors were diffusely positive for p40 or p63 and negative for NUT and p16. Molecular drivers associated with SP, including EGFR and KRAS mutations and both high and low-risk human papillomavirus infection, were negative in all cases. Although there was no overt stromal invasion or desmoplastic reaction in the initial specimens, these tumors tended to progress locoregionally through a prolonged clinical course and occasionally develop lymph node metastases, high-grade transformation, or extensively local destruction eventually leading to death. These justify more aggressive clinical management. Therefore, we propose the new terminology “DEK-AFF2 fusion-associated papillary SCC of the sinonasal tract” to better describe this clinicopathologically and molecularly distinct entity.

A CASE OF FATAL INVASIVE PULMONARY ASPERGILLOSIS IN A PATIENT WITH ANTI-MDA5 DERMATOMYOSITIS

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: Invasive pulmonary aspergillosis (IPA) is classically associated with solid/hematologic organ transplant, hematologic malignancy, and severe neutropenia. The presence of anti-melanoma differentiation-associated gene-5 (MDA-5) autoantibodies in dermatomyositis confers a higher risk of rapidly progressing interstitial lung disease (RP-ILD) resulting in high mortality. We present a case of a patient with a history of diagnosed anti-MDA5 dermatomyositis who developed acute fulminant IPA. CASE PRESENTATION: We report a case of a 65-year-old female with a history of MDA-5 positive dermatomyositis who presented to the hospital with symptoms of dyspnea, fever, and hypoxemia. A CT scan demonstrated bilateral peripheral patchy ground-glass opacities (image 1). The differential diagnosis was broad and included bacterial vs viral vs pneumocystis pneumonia. Upon presentation, she had been on 24 days of prednisone on a dose of 60mg for the first 14 days and 40mg daily for the last 10 for her recent diagnosis of dermatomyositis. Also on the differential was the possibility of RP-ILD. She was started on high-dose steroids at 60mg prednisone daily and broad-spectrum antibiotics. Given high clinical suspicion for RP-ILD, she was started on IVIG therapy. Bronchoscopy with bronchoalveolar lavage grew mold. A repeat CT days later demonstrated dramatically worsening bilateral pulmonary infiltrates with a consolidative pattern (image 2). The patient's clinical status worsened and required intubation for worsening respiratory failure. Eventually, galactomannan resulted positive on the initial and repeat BAL specimens (Ag Index 5.75, 3.62 respectively) with positive serum galactomannan (Ag index 3.33) making IPA the most likely diagnosis. She was started on voriconazole and micafungin with little clinical response and suffered from progressive respiratory decline leading to death. DISCUSSION: Our patient had anti-MDA-5 dermatomyositis with likely RP-ILD who experienced a rapid respiratory decline in the span of weeks. What makes this case interesting is the fulminant lung injury that occurred without a clear and early known diagnosis. Most notably the highest possibilities were RP-ILD and infection, now known to be from Aspergillus spp. The relationship between IPA in chronic respiratory diseases (CRD) particularly interstitial lung diseases is still unclear. There is some evidence to suggest even a short course of steroids may lead to substantial risk in those with underlying CRD such as dermatomyositis-related ILD. This may be the case in our patient who had been on high-dose prednisone before her presentation. CONCLUSIONS: There is the possibility that anti-MDA-5 positive dermatomyositis increases susceptibility to IPA, possibly through a mechanism related to RP-ILD. If characterized further, it may warrant more aggressive surveillance and treatment for invasive pulmonary fungal infections in these patients. REFERENCE #1: Naaraayan, A., Kavian, R., Lederman, J., Basak, P., & Jesmajian, S. (2015). Invasive pulmonary aspergillosis - case report and review of literature. Journal of community hospital internal medicine perspectives, 5(1), 26322. https://doi.org/10.3402/jchimp.v5.26322 REFERENCE #2: Sontheimer R. D. (2017). MDA5 autoantibody-another indicator of clinical diversity in dermatomyositis. Annals of translational medicine, 5(7), 160. https://doi.org/10.21037/atm.2017.03.94 DISCLOSURES: No relevant relationships by Merwise Baray, source=Web Response No relevant relationships by Deepa Lazarous, source=Web Response No relevant relationships by Robert Varipapa, source=Web Response No relevant relationships by Samuel Wopperer, source=Web Response

Spread Through Air Spaces (STAS) in Non-Small Cell Lung Carcinoma: Evidence Supportive of an In Vivo Phenomenon.

Tumor spread through air spaces (STAS) is associated with locoregional recurrence in patients undergoing limited resection (LR) for non-small cell lung carcinoma (NSCLC). We hypothesized that the observation of STAS in both the initial LR specimen and the additional resection specimen from the same patient, processed using different knives, would provide evidence that STAS is an in vivo phenomenon contributing to locoregional recurrence. We retrospectively identified patients with NSCLC (9 adenocarcinoma, 1 squamous cell carcinoma) who underwent LR, had STAS in the LR specimen, and underwent additional resection (lobectomy or LR). The LR and additional resection specimens from each patient were processed at different times using different tissue-processing knives. All specimens were analyzed for STAS. All 10 patients underwent LR with negative margins (R0). All additional resection specimens had STAS: 8 patients had STAS clusters in their completion lobectomy specimens, and 2 had STAS in their additional LR specimens. In 2 patients, STAS was found in the completion lobectomy specimen only after extensive sampling (>10 sections) from the staple line adjacent to the initial LR. The presence of STAS in both the LR and the additional resection specimen processed using different knives supports the concept that STAS is an in vivo phenomenon, rather than an artifact from tissue processing. This observation indicates that occult STAS tumor cells can be present in the lung tissue of the remaining unresected lobe after LR and supports the concept that STAS is a contributing factor for locoregional recurrence following LR.

Delayed time to surgery with hormonal treatment does not adversely impact outcomes in women with low-grade endometrioid endometrial cancer

<h3>Objectives:</h3> Longer wait times from diagnosis of low grade endometrioid endometrial cancer to treatment is associated with decreased overall survival. LNG-IUD therapy or systemic progesterone therapy can be reasonable options for conservative management of early-grade, uterus confined endometrial cancer in patients who wish to delay definitive surgical management. We sought to determine if delaying surgical treatment with progestin therapy adversely affected grade and stage of cancer at time of surgery. <h3>Methods:</h3> The Tumor Registries at a county and university hospital were used to perform a retrospective chart review of patients diagnosed with endometrial cancer from 2009 to 2017. Those with grade 1 or grade 2 endometrioid endometrial adenocarcinoma on EMB or D&C were included. Exclusion criteria included cervical involvement, imaging suggestive of metastatic disease, or completed surgical treatment prior to presentation for care. Patients were grouped into four cohorts: surgery within 42 days of diagnosis (S, n=65), surgery after 42 days (DS, n=52), delayed surgery after progestin therapy (DS+H, n=20), and progestin therapy alone (H, n=21). A one-way ANOVA test and two-tailed t-test were performed to determine whether cohorts differed demographically or in regard to grades and stages. <h3>Results:</h3> 158 patients met inclusion criteria. In total, average age at diagnosis was 55.30 years, average BMI was 39.22, and average Charlton Comorbidity Index (CCI) was 3.97. There was a difference in average age between the S v DS+H (p=0.002, 58.4 v 46.8) and DS v DS+H (p=0.009, 56.6 vs 46.8) cohorts. There was a difference in average BMI between the S vs DS+H (p=0.005, 35.9 vs 42.7) and S v H (p=0.01, 35.9 vs 46.4) cohorts. There were no differences in CCI scores between groups (p=0.25) (Figure 1). There were no differences between the cohorts in regard to initial grade (p=0.36), grade at surgery (p=0.75), grade change between initial diagnosis and surgical specimen (p=0.47), or surgical stage (p=0.52). <h3>Conclusions:</h3> Delayed time to surgery with progestin treatment does not result in stage progression or change in grade. Patients treated with hormones tended to be younger and with higher BMIs. Temporary progestin therapy should be considered if delaying surgical treatment for women with corpus confined low grade endometrioid endometrial cancer.

Effect of initial specimen height and solids concentration on the consolidation parameters of fine-grained coal tailings

ABSTRACT Proper understanding and analysis of the consolidation behaviour and parameters of tailings from a slurry-like to a soil-like state are vital for the design, management, and assessment of a tailings storage facility (TSF). Fine-grained coal tailings slurry can undergo relatively rapid and substantial settlement from a slurried state and can experience relatively slow and limited self-weight consolidation, remaining slurry-like and under-consolidated, rather than soil-like. A large purpose-built slurry consolidometer having a newly developed consolidometer cell, instrumented with load cells and pore water pressure transducers, is well-suited to test tailings from a slurry-like to a soil-like state and enables the constant rate of loading (CRL) to simulate the build-up of tailings. CRL is more representative of the rate of rise of tailings in a TSF than incremental step loading. By conducting consolidation tests on fine-grained coal tailings from a slurry-state under a loading rate of 0.12 kPa/min up to applied stress of 320 kPa, this research investigated the effect of initial specimen height (ISH) and initial solids concentration (ISC) on consolidation parameters and hydraulic conductivity. Using ISH and ISC as independent inputs, a statistical model has been proposed to estimate the consolidation settlement at the end of the slurry consolidation test.

The Truth about SARS-CoV-2 Cycle Threshold Values Is Rarely Pure and Never Simple.

Nucleic acid amplification tests (NAATs) are the reference standard methods for SARS-CoV-2 detection because of their high analytical sensitivity and specificity. Many NAATs, which use reverse-transcription real-time PCR (RT-PCR), are clinically validated, technically validated, and authorized by the U.S. Food & Drug Administration (FDA) to be interpreted qualitatively as "detected" (positive for SARS-CoV-2 RNA) or "not detected" (negative for SARS-CoV-2 RNA). As of this writing there are over 250 SARS-CoV-2 molecular diagnostic tests that have obtained emergency use authorization from the FDA. The primary results generated by RT-PCR are fluorescent light emissions; serial detection of this fluorescence is plotted and the amplification curves visualized. Positive or negative interpretation depends on whether or not the curve exceeds a specified signal threshold. Part of the resulting process includes determination of the number of cycles needed before the fluorescent signal crosses this threshold (Ct value). In general, the more viral RNA in the initial specimen, the fewer the number of amplification cycles required to generate a positive signal; thus, the lower the Ct value, the higher the viral burden in the primary sample. Though all current SARS-CoV-2 NAATs are authorized only for qualitative interpretation, as of 10 December 2020, the FDA explicitly states that the Ct value results may be reported by the clinical laboratory in addition to the qualitative interpretation. Throughout the pandemic, many scientists, physicians, politicians, and public citizens have attempted to emphasize the importance (or unimportance) of certain pandemic-related interventions, mitigation strategies, the disease itself, and testing approaches. Some have advocated that a specific variable is most important in a testing approach and should be maximized to the potential detriment of the others: analytical sensitivity and specificity, cost, turnaround time, sample type, or accessibility of collection. If the truth was obvious, then there would be little debate, but the debate has been important and earnest. As Oscar Wilde wrote, "The truth is rarely pure and never simple." We suggest that this quote describes the current situation on the debate over the relevance of Ct values, and we will explore the clinical utility of quantitative SARS-CoV-2 testing here.

Paired sensitivity analysis of four SARS-CoV-2 serological immunoassays in a longitudinal cohort of convalescent hospital staff.

SARS-CoV-2 serological testing has seen extensive academic and clinical use from investigating correlates of immunity to seroprevalence, convalescent plasma and vaccine trials. Interpretation of these studies will depend on robust validation of the longitudinal sensitivities of these assays, especially in the context of mild disease which makes up the majority of the Coronavirus Disease 2019 (COVID-19) caseload. Hospital staff (n = 94) returning to work following polymerase chain reaction confirmed COVID-19 were offered antibody testing to assist with laboratory verification. Initial specimens were collected at median 29 days post-symptom onset and run on the Roche, Abbott, Siemens and DiaSorin platforms. Re-sampling occurred at median 142 days from a subset of the initial cohort (n = 62) that had volunteered to provide further serum samples to assist in longitudinal sensitivity analysis. Samples that were not run across all four platforms were excluded from analysis. Comparative sensitivity analysis was conducted on 89/94 of the initial specimens and 55/62 of the repeat specimens. Sensitivity at initial sampling ranged from 78 to 87% across platforms. At re-sampling, sensitivities were: 100% (Roche), 45% (Abbott), 100% (Siemens), and 80% (DiaSorin). Paired analysis using the longitudinal cohort (n = 55) demonstrated stable or increasing median assay values on three platforms, with a clear reduction seen only on the Abbott platform (4.78 to 1.34) with corresponding sensitivity drop-off (81.8% to 45.4%). The Abbott assay demonstrated sensitivity drop-off and decrease in median assay signal below detection threshold at four to five months. This has implications on the interpretation and design of future studies.