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We describe a 78-year-old initially presenting with left breast cancer, status post mastectomy and bilateral dual-lumen breast implant placement, subsequently developed lung cancer years later status post lobectomy, who later developed FDG-avid pleural nodularity and thickening. The differential diagnosis of pleural thickening and nodularity can be broad, including metastatic cancer, asbestos-related pleural disease, loculated fluid (including simple pleural effusion, hemothorax, or chylothorax), and pleural infection. However, in the setting of two different primary malignancies, our patient's FGD-avid pleural thickening was concerning for metastatic disease. Further workup with a core-needle biopsy of the pleural nodule revealed “droplets of foreign material and foreign body giant cell reaction consistent with contents of ruptured medical device”, without evidence of malignancy. Prior imaging did not indicate breast implant compromise. A subsequent mammogram suggested findings of bilateral implant rupture, however, no further clinical workup was performed. A screening mammogram a decade later indicated possible extracapsular silicone within the right breast and left mastectomy site and an MRI was recommended for further workup. Subsequent MRI showed bilateral extracapsular silicone implant rupture with a thick layer of silicone signal within the left pleura in a similar distribution to her pleural thickening and nodularity. Her breast MRI findings, in conjunction with her pleural biopsy result, are concordant with pleural silicone granulomas from extracapsular breast implant rupture via radio-occult tract from prior left lobectomy procedure.

The purpose of this article is to explore the amount of work, quantitated by flexion and extension cycles, that is needed to obtain a positive Elson test following a central slip injury.Thirteen frozen cadaveric fingers from individuals with an average age of 79.6 years were used. Testing was performed by imposing sinusoidal displacement of the 2 tendons, with loads ranging from 30 N to 2 N at 1 Hz. Following transection to the central slip, each finger was cycled 1,000 times using the same protocol adopted for the control. Following 100, 200, 300, and 1,000 cycles, we measured the extension angles of the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints from the flexed position and the distance between landmarks of the extensor apparatus and simulated an Elson test.In both the fingers, the range of motion of the metacarpophalangeal and distal interphalangeal joints measured in the controls remained unchanged, whereas the range of motion of the proximal interphalangeal joint was significantly reduced immediately after central slip transection. Combining both ring and middle fingers, for a displacement of 5 mm, the force measured in the control (1.05 ± 0.69 N) increased to the value of 2.36 ± 0.97 N at the 1,000th cycle. Although the middle finger has shown a significant difference in force at 100 cycles following central slip transection, 200 cycles were needed to observe a difference on the ring finger.In controlled conditions, there is a variation in resistance to flexion of the distal interphalangeal joint. However, the amplitude of the forces is so small that they are likely imperceptible clinically. Delayed testing should be considered to increase the sensitivity of the test or in patients experiencing pain.Diagnostic V.

Purpose New federal legislation in the United States grants patients expanded access to their medical records, making it critical that medical records information is understandable to patients. Provision of informational summaries significantly increase patient perceptions of patient-centered care and reduce feelings of uncertainty, yet their use for cancer pathology is limited. Methods Our team developed and piloted patient-centered versions of pathology reports (PCPRs) for four cancer organ sites: prostate, bladder, breast, and colorectal polyp. The objective of this analysis was to identify common barriers and facilitators to support dissemination of PCPRs in care delivery settings. We analyzed quantitative and qualitative data from pilot PCPR implementations, guided by the RE-AIM framework to explore constructs of reach, effectiveness, adoption, implementation, and maintenance. Results We present two case studies of PCPR implementation – breast cancer and colorectal polyps — that showcase diverse workflows for pathology reporting. Cross-pilot learnings emphasize the potential for PCPRs to improve patient satisfaction, knowledge, quality of shared decision-making activities, yet several barriers to dissemination exist. Conclusion While there is promise in expanding patient-centered cancer communication tools, more work is needed to expand the technological capacity for PCPRs and connect PCPRs to opportunities to reduce costs, improve quality, and reduce waste in care delivery systems.

Background Conventional HER2-targeting therapies improve outcomes for patients with HER2-positive breast cancer (BC), defined as tumors showing HER2 protein overexpression by immunohistochemistry and/or ERBB2 gene amplification determined by in situ hybridization (ISH). Emerging HER2-targeting compounds show benefit in some patients with neither HER2 protein overexpression nor ERBB2 gene amplification, creating a need for new assays to select HER2-low tumors for treatment with these compounds. We evaluated the analytical performance of a targeted mass spectrometry-based assay for quantifying HER2 protein in formalin-fixed paraffin-embedded (FFPE) and frozen BC biopsies. Methods We used immunoaffinity-enrichment coupled to multiple reaction monitoring-mass spectrometry (immuno-MRM-MS) to quantify HER2 protein (as peptide GLQSLPTHDPSPLQR) in 96 frozen and 119 FFPE BC biopsies. We characterized linearity, lower limit of quantification (LLOQ), and intra- and inter-day variation of the assay in frozen and FFPE tissue matrices. We determined concordance between HER2 immuno-MRM-MS and predicate immunohistochemistry and ISH assays and examined the benefit of multiplexing the assay to include proteins expressed in tumor subcompartments (e.g., stroma, adipose, lymphocytes, epithelium) to account for tissue heterogeneity. Results HER2 immuno-MRM-MS assay linearity was ≥103, assay coefficient of variation was 7.8% (FFPE) and 5.9% (frozen) for spiked-in analyte, and 7.7% (FFPE) and 7.9% (frozen) for endogenous measurements. Immuno-MRM-MS-based HER2 measurements strongly correlated with predicate assay HER2 determinations, and concordance was improved by normalizing to glyceraldehyde-3-phosphate dehydrogenase. HER2 was quantified above the LLOQ in all tumors. Conclusions Immuno-MRM-MS can be used to quantify HER2 in FFPE and frozen BC biopsies, even at low HER2 expression levels.

While heart disease remains a common cause of mortality, cerebrovascular disease also increases with age, and has been implicated in Alzheimer's disease and related dementias (ADRD). We have described hydrogen sulfide (H2S), a signaling molecule important in vascular homeostasis, as a biomarker of cardiovascular disease. We hypothesize that plasma H2S and its metabolites also relate to vascular and cognitive dysfunction in ADRD. We used analytical biochemical methods to measure plasma H2S metabolites and MRI to evaluate indicators of microvascular disease in ADRD. Levels of total H2S and specific metabolites were increased in ADRD versus controls. Cognition and microvascular disease indices were correlated with H2S levels. Total plasma sulfide was the strongest indicator of ADRD, and partially drove the relationship between cognitive dysfunction and white matter lesion volume, an indicator of microvascular disease. Our findings show that H2S is dysregulated in dementia, providing a potential biomarker for diagnosis and intervention., Scheme for sulfide dysregulation in ADRD. In ADRD, increased accumulation of sulfides, measured in plasma, may reflect increased formation of H2S metabolites produced in the vascular compartment. Several sulfide species are known to impair blood brain barrier leading to persistent excitotoxic stress and subsequent destructive changes in brain microvascular structure and cognitive function seen in ADRD.

OBJECTIVES: Mutations in the TP53 tumor suppressor gene are common in ovarian carcinoma (OC) but their impact on outcomes is controversial. We sought to define the relationship of TP53 mutations to cancer outcomes and their interactions with co-occurrent BRCA1 or BRCA2 (BRCA) mutations, comparing three different TP53 mutation classification schemes. METHODS: We performed next generation sequencing on 393 cases of OC prospectively followed for survival. TP53 mutations were classified according to three schemes termed Structural, Functional, and Hotspot. Mutation distribution was compared between cases with and without BRCA mutations. In a subset of 281 cases of high grade serous carcinoma (HGSC), overall survival was compared using Kaplan-Meier curves, logrank testing, and multivariate Cox regression analysis, both stratified and adjusted for BRCA mutation status. Multivariate logistic regression was used to analyze the effects of TP53 mutation type on platinum resistance. RESULTS: TP53 mutations were identified in 76.8% of the total cohort (n=302/393) and 87.9% of HGSC (n=247/281). Cases with BRCA mutations demonstrated significantly higher TP53 mutation frequency overall (n=84/91, 92.3% vs. n=218/302, 72.2%, p

Objective: Community of Hope Health Clinic (CHHC), a free and charitable clinic in Shelby County, Alabama, developed a screening protocol to identify patients with asymptomatic COVID-19 with the goal of minimizing infection risk for other patients, health care providers, and staff. We sought to determine whether the use of the CHHC screening protocol identified asymptomatic carriers of SARS-CoV-2 before their scheduled clinic visits. Methods: The CHHC screening protocol included the use of an adapted Centers for Disease Control and Prevention questionnaire via telephone 48-72 hours before a scheduled clinic appointment, coupled with a second administration of the questionnaire and a temperature check immediately before the patient’s scheduled visit. Patients with positive responses to any questions or whose temperatures were greater than 100.4 °F were refused entry to the clinic, their appointments were rescheduled, and a SARS-CoV-2 test was recommended. SARS-CoV-2 laboratory testing was conducted on all patients with an appointment from October 26, 2020, through February 18, 2021, to verify whether the screening protocol was effective. Results: Of 298 patient encounters, 20 patients screened positive on the SARS-CoV-2 patient screen. Another 278 patients screened negative, were seen for patient care, and received a SARS-CoV-2 test via nasal swab; 274 (98.6%) patients received a negative test result, and 4 (1.4%) patients received a positive test result. Conclusions: The CHHC SARS-CoV-2 screening protocol, as validated by SARS-CoV-2 assay, was effective in screening out asymptomatic patients infected with SARS-CoV-2 before they were seen in clinic. As clinics and office practices return to prepandemic volumes, the use of such a screening protocol can help mitigate the risk of serious COVID-19 infection, especially for unvaccinated patients, health care providers, and staff.

Lactating adenomas are benign breast lesions that occur in pregnant, lactating, and postpartum women. These lesions have no associated malignant potential; their origin is disputed with no consensus on whether they represent hyperplastic or neoplastic processes. On ultrasound, lactating adenomas are classically described as solid, circumscribed, parallel masses with iso/hypoechoic internal echotexture and posterior enhancement. Histologically, lactating adenomas appear as circumscribed nodules of tightly packed lobular acini with extensive lactational change during pregnancy or the postpartum period. Masses in pregnant and lactating women with probably benign imaging characteristics—oval, circumscribed, parallel, iso/hypoechoic—can be managed with short interval follow-up (BI-RADS 3) rather than biopsy. However, lactating adenomas can also demonstrate characteristics that overlap with pregnancy-associated breast cancer, such as margins that are not circumscribed, prompting biopsy to exclude pregnancy-associated carcinoma. Breast imaging radiologists must be aware of the variable appearances of lactating adenomas to appropriately manage pregnant and lactating women presenting with palpable lumps.

Background. Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remains common, and severe complications are associated with ERCP. There is no previous study detailing the effect of race and gender in a US-based population on risk of PEP. Methods. Data were collected on 269 “first-performed” consecutive ERCPs followed by division by race (White vs. African-American) and sex (Female vs. Male). A total of 53 probable risk factors were evaluated by uni- and multivariate analysis followed by outcomes expressed as an odds ratio (OR) (with a 95% confidence interval, 95% CI). Finally, a principal component analysis was performed to construct a risk prediction model for PEP, which can be used by clinicians at bedside. Results. After analyzing the risk factors based on race and gender-based groups, Caucasian males with PEP are more likely to have prior history of pancreatitis (p = 0.009), lower hemoglobin (p = 0.02)/blood urea nitrogen (BUN) (p = 0.01)/creatinine before ERCP (p = 0.07) and lower BUN (p = 0.01)/creatinine after ERCP (p = 0.07), while Caucasian females with PEP are more likely to have higher white blood cell (WBC) count before ERCP (p = 0.08) and lower amylase (p = 0.10)/bilirubin (p = 0.09)/aspartate aminotransferase (AST) after ERCP (p = 0.08). African-American males with PEP are more likely to have lower weight (p = 0.001)/smaller height (p = 0.0005)/lower alkaline phosphatase (p = 0.002)/AST (p = 0.04)/alanine transaminase (ALT) (p = 0.03) before ERCP and lower alkaline phosphatase (p = 0.002)/AST (p = 0.01)/ALT (p = 0.004) after ERCP, while African-American females with PEP are more likely to have prior history of pancreatitis (p = 0.004)/higher lipase before (p = 0.0001) and after (p = 0.05) ERCP along with increased risk with pancreatic duct cannulation (p = 0.0001) and injection (p = 0.0001)/biliary sphincterotomy (p = 0.0001). Importantly, prior history of ERCP, elevated AST after ERCP, and BUN prior to ERCP were found to be important clinical features predicting post-ERCP pancreatitis. To our knowledge, this is a first known attempt at developing a risk scoring system for PEP in a US population with decision tree learning. Conclusions. It is very evident that both patient and procedure-related risk factors vary by race and gender in the US population, leading to the development of a new risk assessment tool for PEP that can be used in clinical practice. We need to follow up with a larger prospective study to validate this novel race and gender-based risk scoring system for PEP.

Granulomatous inflammation is an uncommon inflammatory condition of the breast that includes both infectious (bacterial, fungal, parasitic) and noninfectious (autoimmune, sarcoidosis, idiopathic granulomatous mastitis [IGM], reaction to foreign materials) etiologies. IGM is the most common subset of granulomatous inflammation where no underlying etiology is established. Infectious causes of granulomatous inflammation should be excluded, as these have established treatments that can significantly improve patient outcomes. IGM should be considered in the differential when mastitis is refractory to antibiotics. Patients usually present with an erythematous, tender, palpable unilateral breast mass. The most common mammographic presentation is a focal or global asymmetry. The imaging appearance mimics breast cancer, therefore diagnosis usually requires tissue sampling with histopathologic analysis and cultures to exclude infection. When patients are diagnosed with IGM, this poses a clinical dilemma as there are a variety of treatment options available, including oral and intralesional steroids. The time course of the disease is often prolonged by multiple recurrences, and specific treatment remains an area of ongoing research. The purpose of this article is to review the range of clinical features, imaging manifestations, associated histopathology, and management of IGM.

Interest in mutually exclusive pairs of bioorthogonal labeling reagents continues to drive the design of new compounds that are capable of fast and predictable reactions. The ability to easily modify S-, N-, and O-containing cyclooctynes (SNO-OCTs) enables electronic tuning of various SNO-OCTs to influence their cycloaddition rates with Type I-III dipoles. As opposed to optimizations based on just one specific dipole class, the electrophilicity of the alkynes in SNO-OCTs can be manipulated to achieve divergent reactivities and furnish mutually orthogonal dual ligation systems. Significant reaction rate enhancements of a difluorinated SNO-OCT derivative, as compared to the parent scaffold, were noted, with the second-order rate constant in cycloadditions with diazoacetamides exceeding 5.13 M-1 s-1. Computational and experimental studies were employed to inform the design of triple ligation systems that encompass three orthogonal reactivities. Finally, polar SNO-OCTs are rapidly internalized by mammalian cells and remain functional in the cytosol for live-cell labeling, highlighting their potential for diverse in vitro and in vivo applications.

Women with fallopian tube carcinoma (FTC) are reported to have a higher frequency of inherited BRCA mutations than those with ovarian carcinoma (OC) or primary peritoneal carcinoma (PPC). We hypothesized that routine serial sectioning of fallopian tubes would increase the proportion of cases designated as FTC and change the frequency of inherited mutations between carcinoma types.Eight hundred and sixty-seven women diagnosed from 1998 to 2018 were enrolled at diagnosis into an institutional tissue bank. Germline DNA, available from 700 women with FTC (N = 124), OC (N = 511) and PPC (N = 65), was assessed using targeted capture and massively parallel sequencing for mutations in ovarian carcinoma susceptibility genes. Cases were divided between those prior to routine serial sectioning (1998-2008) and after (2009-2019), and the frequency of FTC and inherited mutations was assessed.The proportion of carcinomas attributed as FTC after 2009 was 28% (128/465), significantly higher than before 2009 [5% (21/402), p .0001, OR 6.9, 95% CI 4.3-11.2], with subsequent decreases in OC and PPC. In the sequenced group, overall inherited mutation frequency in FTC (24/124, 19%), OC (106/511, 21%, p = .42), and PPC (16/65, 25%, p = .25) were similar. Germline mutation rates in FTC were lower after 2009,16/107 cases (15%), compared to 8/17 cases (47.1%) before 2009 (p = .005, OR 0.20, 95% CI 0.06-0.64).The prevalence of inherited mutations is similar in FTC compared to OC or PPC when using modern pathological assignment. Complete serial sectioning of fallopian tubes has significantly increased the diagnosis of FTC, and subsequently decreased the frequency of inherited mutations within this group.

Intraepithelial fallopian tube neoplasia is thought to be a precursor lesion to high-grade serous carcinoma of the Müllerian adnexae, particularly in women with BRCA1 or BRCA2 mutations. This association has led to recommendations to assess fallopian tubes for intraepithelial atypia. However, the diagnostic reproducibility of a diagnosis of intraepithelial neoplasia is unclear. In this study, 2 gynecologic pathologists independently evaluated sections of fallopian tubes from a sample of women (N=198, 623 slides) undergoing salpingectomy. A total of 101 (54%) women were undergoing risk-reducing salpingo-oophorectomy. Pathologists were blinded to patient histories and prior diagnoses. Pathologists rendered one of three diagnoses for each slide: "negative for fallopian tube intraepithelial neoplasia (FTIN)," "indeterminate for FTIN," or "definite for FTIN." Cases that were considered by histology definite for FTIN or suspicious for FTIN were stained with p53 and Ki67. Pathologists agreed on the diagnosis of "definite for FTIN" 61.5% of the time. There was no agreement on any cases for the diagnosis of "indeterminate for FTIN." Fifteen "indeterminate for FTIN" and 12 "definite for FTIN" cases were stained with p53 and Ki67. Two of the "indeterminate" cases (13%) had p53-positive foci. Five of the "definite" cases had p53-positive foci. In 3 of the other 8 "definite" cases, there was obvious carcinoma present, but the carcinoma did not stain with p53, suggesting a possible null phenotype. We propose that immunostains should only be used to aid in the diagnosis of FTIN in cases with indeterminate histology. The use of p53 immunohistochemistry in cases that were considered "definite for FTIN" by histology was minimally helpful, and in fact often served to further confuse the diagnosis.

Errors in anatomic pathology can result in patients receiving inappropriate treatment and poor patient outcomes. Policies and procedures are necessary to decrease error and improve diagnostic concordance. Breast pathology may be more prone to diagnostic errors than other surgical pathology subspecialties due to inherit borderline diagnostic categories such as atypical ductal hyperplasia and low-grade ductal carcinoma in situ. Mandatory secondary review of internal and outside referral cases before treatment is effective in reducing diagnostic errors and improving concordance. Assessment of error through amendment/addendum tracking, implementing an incident reporting system, and multidisciplinary tumor boards can establish procedures to prevent future error.

Tumor data from the ABCSG 5 trial of chemotherapy versus endocrine therapy for premenopausal ER+ breast cancer supports molecular subtyping by Ki-67 IHC as a prognostic marker. But while this tissue was handled uniformly, Ki-67 testing overall is unstandardized, complicating clinical utility. Increasing potential biomarkers herald more challenges in biomarker validation. See related article by Bago-Horvath et al., p. 5682

Immunohistochemistry (IHC) is often critical for distinction between metastatic carcinomas of Mullerian organ and breast origin. Paired box family protein 8 (PAX8) has been described as a transcription factor highly specific to neoplasms derived from Mullerian organs, thyroid, and kidney. PAX8 IHC with polyclonal and monoclonal antibody reagents was performed on 27 primary and 22 metastatic breast carcinomas. Eight of 27 primary breast carcinomas (30%) were positive for PAX8 with the monoclonal antibody reagent only; 0 of 22 were polyclonal anti-PAX8 immunoreactive. Substantial numbers of metastases had positive immunoreactivity for polyclonal anti-PAX8 (23%). Each of these metastases and additional cases (45% total) also had positive immunoreactivity for monoclonal anti-PAX8, including 5 of 7 brain metastases. IHC with monoclonal anti-PAX8 was positive on 6 of 7 primary breast carcinomas corresponding to PAX8-positive metastases. Together, these results indicate a significant fraction of breast carcinoma metastases and corresponding primary neoplasms have immunoreactivity for PAX8, and positivity rates depend on the antibody used. Diagnoses of metastatic breast carcinoma were achieved with the aid of clinical history and additional IHC in cases of PAX8 immunoreactivity. Contextual interpretation is imperative for PAX8 IHC, particularly when the differential diagnosis includes metastatic breast carcinoma with limited diagnostic material available.

The pathogenesis of inflammatory bowel disease (IBD) has been linked with lymphostasis, but whether and how lymphatic obstruction might disturb the intestinal microbiome in the setting of Crohn's Disease (CD) is currently unknown. We employed a new model of CD in African Green monkeys, termed 'ATLAS' (African green monkey truncation of lymphatics with obstruction and sclerosis), to evaluate how gut lymphatic obstruction alters the intestinal microbiome at 7, 21 and 61 days. Remarkable changes in several microbial sub- groupings within the gut microbiome were observed at 7 days post-ATLAS compared to controls including increased abundance of Prevotellaceae and Bacteroidetes-Prevotella-Porphyromonas (BPP), which may contribute to disease activity in this model of gut injury. To the best of our knowledge, these findings represent the first report linking lymphatic structural/gut functional changes with alterations in the gut microbiome as they may relate to the pathophysiology of CD.

Biomolecular condensates compartmentalize and regulate assemblies of biomolecules engaged in vital physiological processes in cells. Specific proteins and nucleic acids engaged in shared functions occur in any one kind of condensate, suggesting that these compartments have distinct chemical specificities. Indeed, some small molecule drugs concentrate in specific condensates due to chemical properties engendered by particular amino acids in the proteins in those condensates. Here we argue that the chemical properties that govern molecular interactions between a small molecule and biomolecules within a condensate can be ascertained for both the small molecule and the biomolecules. We propose that learning this chemical grammar, the rules describing the chemical features of small molecules that engender attraction or repulsion by the physicochemical environment of a specific condensate, should enable design of drugs that with improved efficacy and reduced toxicity.

SUMMARYDuctal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We have performed the first multiscale, integrated profiling of DCIS with clinical outcomes by analyzing 677 DCIS samples from 481 patients with 7.1 years median follow-up from the Translational Breast Cancer Research Consortium (TBCRC) 038 study and the Resource of Archival Breast Tissue (RAHBT) cohorts. We identified 812 genes associated with ipsilateral recurrence within 5 years from treatment and developed a classifier that was predictive of DCIS or IBC recurrence in both cohorts. Pathways associated with recurrence include proliferation, immune response, and metabolism. Distinct stromal expression patterns and immune cell compositions were identified. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.HIGHLIGHTS⍰ Development of a new classifier for DCIS recurrence or progression⍰ Outcome associated pathways identified across multiple data types and compartments⍰ Four stroma-specific signatures identified⍰ CNAs characterize DCIS subgroups associated with high risk invasive cancers

Ductal carcinoma in situ (DCIS) is the most commonly diagnosed precursor of invasive breast cancer (IBC), with variable propensity for progression. We have performed the first multiscale, integrated profiling of DCIS with clinical outcomes to identify predictors of subsequent ipsilateral breast events. We analyzed 677 DCIS samples from 481 patients with 7.1 years median follow-up from two independent cohorts. We made observations on DNA, RNA, and protein expression, and generated a de novo clustering scheme for DCIS that represents the fundamental transcriptomic organization at this early stage of breast neoplasia. Distinct DCIS stromal expression patterns and immune cell compositions were identified. We also found RNA expression patterns that correlate with later events in both cohorts. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.

Objective To determine whether invasive lobular carcinoma (ILC) extent is more accurately depicted with preoperative MRI (pMRI) than conventional imaging (mammography and/or ultrasound). Methods After IRB approval, we retrospectively identified women with pMRIs (February 2005 to January 2014) to evaluate pure ILC excluding those with ipsilateral pMRI BI-RADS 4 or 5 findings or who had neoadjuvant chemotherapy. Agreement between imaging and pathology sizes was summarized using Bland-Altman plots, absolute and percent differences, and the intraclass correlation coefficient (ICC). Rates of underestimation and overestimation were evaluated and their associations with clinical features were explored. Results Among the 56 women included, pMRI demonstrated better agreement with pathology than conventional imaging by mean absolute difference (1.6 mm versus −7.8 mm, P < 0.001), percent difference (10.3% versus −16.4%, P < 0.001), and ICC (0.88 versus 0.61, P = 0.019). Conventional imaging more frequently underestimated ILC span than pMRI using a 5 mm difference threshold (24/56 (43%) versus 10/56 (18%), P < 0.001), a 25% threshold (19/53 (36%) versus 10/53 (19%), P = 0.035), and T category change (17/56 (30%) versus 7/56 (13%), P = 0.006). Imaging–pathology size concordance was greater for MRI-described solitary masses than other lesions for both MRI and conventional imaging (P < 0.05). Variability of conventional imaging was lower for patients ≥ the median age of 62 years than for younger patients (SD: 12 mm versus 22 mm, P = 0.012). Conclusion MRI depicts pure ILC more accurately than conventional imaging and may have particular value for younger women.

Kohonen’s self-organizing map is an unsupervised machine learning method designed to preserve the topology of its input space. Although this method has been used to efficiently summarize multidimensional data, the visualization of its constituent data has received less attention. We propose a method of addressing the visualization problem by augmenting a classical self-organizing map visualization to include an embedded histogram and evaluate its utility in depicting the self-organizing maps’s constituents categorized by a discrete variable.

Purpose Lobular neoplasia (LN) detected on breast core needle biopsy is frequently managed with surgical excision because of concern for undersampled malignancy. The authors performed a systematic review and meta-analysis to estimate the risk for upgrade to malignancy in the setting of imaging-concordant classic LN diagnosed on core biopsy. Methods PubMed and Embase were searched for original articles published from 1998 to 2020 that reported rates of upgrade to malignancy for classic LN, including atypical lobular hyperplasia (ALH) and classic lobular carcinoma in situ (LCIS). Two reviewers extracted study data and assessed the following quality criteria: exclusion of variant LCIS, exclusion of imaging-discordant lesions, and outcome reporting for ≥70% of lesions. For studies meeting all criteria, pooled risks for upgrade to any malignancy (invasive carcinoma or ductal carcinoma in situ) and invasive malignancy for all LN, ALH, and LCIS were estimated using random-effects models. Results For 65 full-text articles included in the review, the risk for upgrade to any malignancy ranged from 0% to 45%. Among the 16 studies that met all quality criteria for the meta-analysis, pooled risks for upgrade to any malignancy were 3.1% (95% confidence interval [CI], 1.8%-5.2%) for all LN, 2.5% (95% CI, 1.6%-3.9%) for ALH, and 5.8% (95% CI, 2.9%-11.3%) for LCIS. Risks for upgrade to invasive malignancy were 1.3% (95% CI, 0.7%-2.4%) for all LN, 0.4% (95% CI, 0.0%-4.2%) for ALH, and 3.5% (95% CI, 2.0%-5.9%) for LCIS. Conclusions The risk for upgrade to malignancy for LN found on breast biopsy is low. Imaging surveillance can likely be offered as an alternative to surgical management for LN, particularly for ALH.

Lung cancer (LC) represents the topmost mortality-causing cancer in the U.S. LC patients have overall poor survival rate with limited available treatment options. Dysregulation of the mesenchymal epithelial transition factor (c-MET) and cyclooxygenase 2 (COX2) initiates aggressive LC profile in a subset of patients. The Mediterranean extra-virgin olive oil (EVOO)-rich diet already documented to reduce multiple malignancies incidence. (-)-Oleocanthal (OC) is a naturally occurring phenolic secoiridoid exclusively occurring in EVOO and showed documented anti-breast and other cancer activities via targeting c-MET. This study shows the novel ability of OC to suppress LC progression and metastasis through dual targeting of c-MET and COX-2. Western blot analysis and COX enzymatic assay showed significant reduction in the total and activated c-MET levels and inhibition of COX1/2 activity in the lung adenocarcinoma cells A549 and NCI-H322M, in vitro. In addition, OC treatment caused a dose-dependent inhibition of the HGF-induced LC cells migration. Daily oral treatment with 10 mg/kg OC for 8 weeks significantly suppressed the LC A549-Luc progression and prevented metastasis to brain and other organs in a nude mouse tail vein injection model. Further, microarray data of OC-treated lung tumors showed a distinct gene signature that confirmed the dual targeting of c-MET and COX2. Thus, the EVOO-based OC is an effective lead with translational potential for use as a prospective nutraceutical to control LC progression and metastasis.

Bonds between sulfur atoms are prevalent in natural products, peptides, and proteins. Disulfide bonds have a distinct chromophore. The wavelength of their maximal absorbance varies widely, from 250 to 500 nm. Here, we demonstrate that this wavelength derives from stereoelectronic effects and is predictable using quantum chemistry. We also provide a sinusoidal equation, analogous to the Karplus equation, that relates the absorbance maximum and the C-S-S-C dihedral angle. These insights provide a facile means to characterize important attributes of disulfide bonds and to design disulfides with specified photophysical properties.

Dextrans are a versatile class of polysaccharides with applications that span medicine, cell biology, food science, and consumer goods. Here, we report on a new type of large monofunctionalized dextran that exhibits unusual properties: efficient cytosolic and nuclear uptake. This dextran permeates various human cell types without the use of transfection agents, electroporation, or membrane perturbation. Cellular uptake occurs primarily through active transport via receptor-mediated processes. These monofunctionalized dextrans could serve as intracellular delivery platforms for drugs or other cargos.

Objectives: To assess implementation of a novel microsatellite instability (MSI) screen using next generation sequencing (NGS) in endometrial cancer (EC) through comparison to prior Lynch syndrome screening strategies, as well as to compare characteristics of patients with microsatellite stable (MSS) and microsatellite unstable endometrial cancer. Methods: Retrospective review was performed of patients with newly diagnosed endometrial cancer at a single academic institution during three time periods and using different screening strategies: 1) 01/2010 - 01/2013 with provider-directed mismatch repair immunohistochemistry (MMR IHC) in women ≤60, 2) 01/2013 - 01/2016 with universal MMR IHC in all women ≤60, and 3) 10/2018 - 10/2019 with universal screening for MSI using NGS regardless of age. In cohorts 1 and 2, women with abnormal MMR IHC were referred to a genetic counselor who ordered MLH1 promoter methylation or germline genetic testing as indicated. In cohort 3, reflexive MLH1 promoter methylation was performed for patients with MSI and no MMR germline or somatic mutations, with referral to genetic counseling for suspected germline MMR mutation or unexplained MSI. Statistical analysis was performed using a t-test for continuous variables and Fisher's exact test for categorical variables. ≤60, 2) 01/2013 - 01/2016 with universal MMR IHC in all women ≤60, and 3) 10/2018 - 10/2019 with universal screening for MSI using NGS regardless of age. In cohorts 1 and 2, women with abnormal MMR IHC were referred to a genetic counselor who ordered MLH1 promoter methylation or germline genetic testing as indicated. In cohort 3, reflexive MLH1 promoter methylation was performed for patients with MSI and no MMR germline or somatic mutations, with referral to genetic counseling for suspected germline MMR mutation or unexplained MSI. Statistical analysis was performed using a t-test for continuous variables and Fisher's exact test for categorical variables. Results: There were 133 subjects in cohort 1, 135 subjects in cohort 2, and 140 subjects in cohort 3. The proportion of patients screened for Lynch syndrome increased over time (39%, 94%, and 100% of intended screening population). The proportion of positive screens was similar between the 3 cohorts (27%, 21%, and 27%). The proportion with positive screens who underwent confirmatory testing with germline genetic testing or MLH1 promoter methylation was 50% in cohort 1 and 59% in cohort 2. Following implementation of reflexive MLH1 promoter methylation testing when indicated, the proportion increased to 89% (p=0.001). Attendance at genetic counseling appointments following referral was 50%, 59%, and 61% in each cohort. Eleven patients were diagnosed with Lynch syndrome across the 3 cohorts (4%, 3%, and 1% respectively). In cohort 3, subjects with MSI EC had similar clinicopathologic characteristics compared with MSS cancers, and over half of MSI cancers were identified in subjects over the age of 60 (71%). Eight subjects had incidental somatic mutations identified through NGS, including 6 POLE mutations, 1 BRIP1 mutation, and a subject with mutations in TP53, AKT1, and FBXW7. At our institution, MSI testing by NGS was billed at $905 versus $1200 for MMR IHC screening. Download : Download high-res image (108KB) Download : Download full-size image Conclusions: Transition to universal screening using NGS with reflexive MLH1 promoter methylation testing increased the number of subjects completing genetic assessment for Lynch syndrome after a positive screen, likely as somatic causes of MSI were ruled out, allowing more focused genetics referrals. Similar characteristics between subjects with MSI and MSS EC supports universal screening regardless of clinical characteristics. In addition to identifying Lynch syndrome, detection of MSI through NGS can identify somatic alterations with therapeutic implications, and can be performed at a lower cost than MMR IHC.

Copyright © 2020 American Chemical Society. Epithiodiketopiperazines (ETPs) are a structurally complex class of fungal natural products with potent anticancer activity. In ETPs, the diketopiperazine ring is spanned by a disulfide bond that is constrained in a high-energy eclipsed conformation. We employed computational, synthetic, and spectroscopic methods to investigate the physicochemical attributes of this atypical disulfide bond. We find that the disulfide bond is stabilized by two n→π∗ interactions, each with large energies (3-5 kcal/mol). The n→π∗ interactions in ETPs make disulfide reduction much more difficult, endowing stability in physiological environments in a manner that could impact their biological activity. These data reveal a previously unappreciated means to stabilize a disulfide bond and highlight the utility of the n→π∗ interaction in molecular design.

Copyright © 2020 American Chemical Society. Glycosylation is a common modification that can endow proteins with altered physical and biological properties. Ribonuclease 1 (RNase 1), which is the human homologue of the archetypal enzyme RNase A, undergoes N-linked glycosylation at asparagine residues 34, 76, and 88. We have produced the three individual glycoforms that display the core heptasaccharide, Man5GlcNAc2, and analyzed the structure of each glycoform by using small-angle X-ray scattering along with molecular dynamics simulations. The glycan on Asn34 is relatively compact and rigid, donates hydrogen bonds that "cap"the carbonyl groups at the C-terminus of an α-helix, and enhances protein thermostability. In contrast, the glycan on Asn88 is flexible and can even enter the enzymic active site, hindering catalysis. The N-glycosylation of Asn76 has less pronounced consequences. These data highlight the diverse behaviors of Man5GlcNAc2 pendants and provide a structural underpinning to the functional consequences of protein glycosylation.