Comparative genomic analysis of PIK3R1-mutated and wild-type breast cancers.

PURPOSE: The PIK3R1 gene encodes the regulatory subunit-p85a-of the PI3K signaling complex. Prior studies have found that pathogenic somatic alterations in PIK3R1 are enriched in human breast cancers but the genomic landscape of breast cancer patients harboring PIK3R1 mutations has not been extensively characterized. METHODS: We retrospectively analyzed 6,009 patient records that underwent next-generation sequencing (NGS) using the Tempus xT solid tumor assay. All patients had breast cancer with known HER2 (+/-) and hormone receptor (HR; +/-) status and were classified according to the presence of PIK3R1 mutations including short variants and copy number alterations. RESULTS: The frequency of PIK3R1 mutations varied according to subtype: 6% in triple negative (TNBC, 89/1,475), 2% in HER2-/HR+ (80/3,893) and 2.3% in HER2+ (15/641) (p < 0.001). Co-mutations in PTEN, TP53 and NF1 were significantly enriched, co-mutations in PIK3CA were significantly less prevalent, and tumor mutational burden was significantly higher in PIK3R1-mutated HER2- samples relative to PIK3R1 wild-type. At the transcriptional-level, PIK3R1 RNA expression in HER2- disease was significantly higher in PIK3R1-mutated (excluding copy number loss) samples, regardless of subtype. CONCLUSION: This is the largest investigation of the PIK3R1 mutational landscape in breast cancer patients (n = 6,009). PIK3R1 mutations were more common in triple-negative breast cancer (~ 6%) than in HER2 + or HER2-/HR + disease (approximately 2%). While alterations in the PI3K/AKT pathway are often actionable in HER2-/HR + breast cancer, our study suggests that PIK3R1 could be an important target in TNBC as well.

Artificial intelligence-augmented histopathologic review using image analysis to optimize DNA yield from formalin-fixed paraffin-embedded slides.

To achieve minimum DNA input requirements for next-generation sequencing (NGS), pathologists visually estimate macrodissection and slide count decisions. Unfortunately, misestimation may cause tissue waste and increased laboratory costs. We developed an artificial intelligence (AI)-augmented smart pathology review system (SmartPath) to empower pathologists with quantitative metrics for accurately determining tissue extraction parameters. SmartPath uses two deep learning architectures, a U-Net based network for cell segmentation and a multi-field-of-view convolutional network for tumor area segmentation, to extract features from digitized H&E-stained formalin-fixed paraffin-embedded slides. From the segmented tumor area, SmartPath suggests a macrodissection area. To predict DNA yield per slide, the extracted features from within the macrodissection area are correlated with known DNA yields to fit a regularized linear model (R = 0.85). Then, a pathologist-defined target yield divided by the predicted DNA yield per slide gives the number of slides to scrape. Following model development, an internal validation trial was conducted within the Tempus Labs molecular sequencing laboratory. We evaluated our system on 501 clinical colorectal cancer slides, where half received SmartPath-augmented review and half traditional pathologist review. The SmartPath cohort had 25% more DNA yields within a desired target range of 100-2000 ng. The number of extraction attempts was statistically unchanged between cohorts. The SmartPath system recommended fewer slides to scrape for large tissue sections, saving tissue in these cases. Conversely, SmartPath recommended more slides to scrape for samples with scant tissue sections, especially those with degraded DNA, helping prevent costly re-extraction due to insufficient extraction yield. A statistical analysis was performed to measure the impact of covariates on the results, offering insights on how to improve future applications of SmartPath. With these improvements, AI-augmented histopathologic review has the potential to decrease tissue waste, sequencing time, and laboratory costs by optimizing DNA yields, especially for samples with scant tissue and/or degraded DNA.

Somatic Tumor Profile Analysis in a Patient with Germline PMS2 Mutation and Synchronous Ovarian and Uterine Carcinomas.

Lynch syndrome patients with synchronous endometrial and ovarian cancer (SEOC) are rare. When these cases occur, they are most often endometrioid histology and early grade. Early-grade tumors are not often sent for somatic tumor profiling. We present a 39 year old SEOC patient with germline PMS2 Lynch syndrome and clinical tumor analysis leading to insight regarding the origin and cause of these tumors, with potential therapy options. PMS2-related SEOC is less common due to lower risks for these cancers associated with germline PMS2 mutation compared to other Lynch genes. While synchronous cancers are not common, they are more likely to occur with Lynch syndrome. Tumor profiling with next-generation sequencing of 648 genes identified sixteen shared somatic actionable and biologically relevant mutations. This case is a rare example of a patient with PMS2 germline Lynch syndrome with shared somatic variants that demonstrate clonality of the two tumors arising from one common site.

Plasmablastic Lymphoma Associated with Adjacent Mature Plasma Cell Population Exhibiting Opposite Light Chain Restriction.

Plasmablastic lymphoma (PBL) is an aggressive high-grade B cell lymphoma, considered a variant of diffuse large B cell lymphoma with approximately 75% mortality within 6-7 months. We describe an unusual case of PBL arising as a maxillary mass in an HIV-negative, nontransplanted 78-year-old female. Histologic examination revealed a diffuse infiltrate of anaplastic appearing cells exhibiting plasmablastic morphology with an adjacent contiguous infiltrate of mature appearing plasma cells. The PBL and mature plasma cell components both demonstrated an immunophenotype of CD20(-), CD38(+), and CD138(+). The two populations differed by the PBL featuring a high proliferation rate by Ki-67 (~95%) with coexpression of both c-MYC and EBV, while the mature plasma cell component featured a low proliferation rate by Ki-67 (~5%) without coexpression of c-MYC or EBV. Kappa/lambda staining demonstrated lambda light chain restriction involving the PBL, while the mature plasma cell infiltrate revealed kappa light chain restriction. Our findings describe the rare association of PBL with a synchronous distinct population of mature plasma cells exhibiting opposite light chain restriction.

Multi-Field-of-View Deep Learning Model Predicts Nonsmall Cell Lung Cancer Programmed Death-Ligand 1 Status from Whole-Slide Hematoxylin and Eosin Images.

BACKGROUND: Tumor programmed death-ligand 1 (PD-L1) status is useful in determining which patients may benefit from programmed death-1 (PD-1)/PD-L1 inhibitors. However, little is known about the association between PD-L1 status and tumor histopathological patterns. Using deep learning, we predicted PD-L1 status from hematoxylin and eosin (H and E) whole-slide images (WSIs) of nonsmall cell lung cancer (NSCLC) tumor samples. MATERIALS AND METHODS: One hundred and thirty NSCLC patients were randomly assigned to training (n = 48) or test (n = 82) cohorts. A pair of H and E and PD-L1-immunostained WSIs was obtained for each patient. A pathologist annotated PD-L1 positive and negative tumor regions on the training samples using immunostained WSIs for reference. From the H and E WSIs, over 145,000 training tiles were generated and used to train a multi-field-of-view deep learning model with a residual neural network backbone. RESULTS: The trained model accurately predicted tumor PD-L1 status on the held-out test cohort of H and E WSIs, which was balanced for PD-L1 status (area under the receiver operating characteristic curve [AUC] =0.80, P << 0.01). The model remained effective over a range of PD-L1 cutoff thresholds (AUC = 0.67-0.81, P ≤ 0.01) and when different proportions of the labels were randomly shuffled to simulate interpathologist disagreement (AUC = 0.63-0.77, P ≤ 0.03). CONCLUSIONS: A robust deep learning model was developed to predict tumor PD-L1 status from H and E WSIs in NSCLC. These results suggest that PD-L1 expression is correlated with the morphological features of the tumor microenvironment.

Clinical validation of the tempus xT next-generation targeted oncology sequencing assay.

We developed and clinically validated a hybrid capture next generation sequencing assay to detect somatic alterations and microsatellite instability in solid tumors and hematologic malignancies. This targeted oncology assay utilizes tumor-normal matched samples for highly accurate somatic alteration calling and whole transcriptome RNA sequencing for unbiased identification of gene fusion events. The assay was validated with a combination of clinical specimens and cell lines, and recorded a sensitivity of 99.1% for single nucleotide variants, 98.1% for indels, 99.9% for gene rearrangements, 98.4% for copy number variations, and 99.9% for microsatellite instability detection. This assay presents a wide array of data for clinical management and clinical trial enrollment while conserving limited tissue.

Effective Use of Sirolimus and Zoledronic Acid for Multiosteotic Pseudomyogenic Hemangioendothelioma of the Bone in a Child: Case Report and Review of Literature.

Pseudomyogenic hemangioendothelioma (PMH) is a rare neoplasm with vascular and sarcomatous elements, unpredictable course, and uncommon metastatic or fatal potential. Although systemic chemotherapy has been reported with variable success, generally accepted treatment is aggressive surgery with wide margins. Evidence-based treatment options are lacking, and lack of clear prognostic features poses a risk of undertreatment or overtreatment with associated morbidity and mortality. We report the use of initial systemic therapy with oral sirolimus (SIR) and IV zoledronic acid (ZA) to induce a sustained clinical response and avoidance of amputation in a 6-year-old boy. At 37 months after diagnosis, our patient remains in sustained clinical remission as documented by x-ray, MRI, and PET-CT with return of normal mobility/activity and resolution of swelling and pain. Literature review identified 20 cases of pediatric and young adult patients with PMH, of which 7 received some form of systemic therapy. To the best of our knowledge, our patient represents the youngest reported case of PMH and the first successful and limb-sparing utilization of systemic chemotherapy as primary treatment for PMH.

Durable Response to Venetoclax Monotherapy in Richter's Syndrome: A Case Report and Review of Literature.

In 2017, 20,110 people in the United States were diagnosed with chronic lymphocytic leukemia (CLL). Of these patients, 5-15% will ultimately undergo Richter's syndrome (RS), a transformation to a more aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL) type. Particularly when the transformation is clonally related, prognosis is poor in these individuals with a median survival of only 5 - 14 months. This is an area of unmet need, and as such, the benefits of novel approaches with targeted therapies should be explored. Our patient is a 70-year-old female who was diagnosed with CLL in 2010. In 2016, she presented to her general practitioner with new B symptoms and leukocytosis. Cytogenetics on peripheral blood was notable for known trisomy 12 (52.8% of cells) and new 17p deletion (93.4% of cells). She received five cycles of ofatumumab with complete resolution of systemic symptoms but mixed response on interim computed tomography (CT) scan with ensuing rise in her white blood cell (WBC) and lactic acid dehydrogenase (LDH). A positron emission tomography (PET) scan had disproportionate uptake in the porta hepatis lymph nodes and subsequent lymph node biopsy confirmed transformation. She was started on R-CHOP chemotherapy but tolerated it very poorly. She was transitioned to venetoclax monotherapy in April 2017 and achieved a partial response by CT and bone marrow biopsy. This has been maintained over the last 12 months allowing the patient to travel and maintain a high quality of life. While the pathogenesis to RS is poorly understood, there have been several studies to identify tumor genetic changes predisposing to transformation. Of the proposed factors, a review of the literature consistently suggests p53 tumor suppressor gene mutation and/or 17p deletion to be associated with RS. Venetoclax is a selective BCL-2 inhibitor that is now approved for CLL patients with 17p deletion. This case serves as an example encouraging the use and study of novel agents such as venetoclax alone or in combination with traditional regimens or other novel agents to mitigate the poor prognosis of 17p deletion associated RS. Further research, however, is required to clarify the pathogenesis of RS and identify optimal treatment strategies.

Depth of Muscularis Propria Invasion Does Not Prognosticate Survival in T2 Esophageal Adenocarcinoma.

AIM: Although tumor depth of invasion is strongly associated with risk of lymph node metastasis and long-term survival in patients with esophageal adenocarcinoma, the significance of differential T2 invasion (inner circular layer versus outer longitudinal layer) is unknown. The current study was undertaken to explore the hypothesis that greater T2-specific depth of invasion is associated with inferior long-term outcomes in patients with esophageal adenocarcinoma treated with esophagectomy. PATIENTS AND METHODS: Demographic, treatment, and outcome data were collected for patients with resected pT2N0-3M0 esophageal adenocarcinoma treated between 2005 and 2015 pooled from four U.S. academic medical centers. Two blinded pathologists evaluated depth of muscularis propria tumor invasion. Univariate and Cox proportional hazard regression analyses were performed to identify prognostic factors for overall (OS) and disease-free (DFS) survival, and Kaplan-Meier analysis to compare survival differences specific to prognostic factors. RESULTS: A total of 84 patients were identified for analysis (53 with circular invasion; 31 with longitudinal invasion), with a median age of 66 years. Sixty percent of patients (50/84) received induction therapy prior to esophagectomy. The median OS and DFS was 58 months (95% confidence interval(CI)=42 months-not reached) and 27 months (95% CI=13.7-66 months) respectively. Depth of muscularis propria invasion did not correlate with OS or DFS on univariate (p=0.42; and p=0.34, respectively) or multivariate (p=0.15 and p=0.21, respectively) analysis after adjustment for age, nodal status, perineural invasion, and tumor grade. These findings did not vary by induction therapy status. CONCLUSION: Depth of muscularis propria invasion does not appear to correlate with survival in patients with esophageal adenocarcinoma.

Patients with small and diminutive proximal hyperplastic polyps have higher rates of synchronous advanced neoplasia compared with patients without serrated lesions.

BACKGROUND AND AIMS: The association of proximal small and diminutive hyperplastic polyps (HPs) with synchronous advanced neoplasia is not well-defined. However, sessile serrated polyps (SSPs), even when small, are known to portend a risk of synchronous neoplasia. Currently, the U.S. Multi-Society Task Force on Colorectal Cancer does not recommend a change in the surveillance interval when proximal small HPs are detected. We aimed to compare the rates of synchronous advanced neoplasia in a screening colonoscopy cohort of patients with small and then diminutive proximal HPs in comparison, first to a cohort absent any serrated or proximal HPs and then in comparison with a cohort with small proximal SSPs. METHODS: Consecutive screening colonoscopies were recorded between 2005 and 2010 at an academic medical center. Patients were divided into 3 mutually exclusive groups. Group 1 consisted of patients with at least 1 HP that was proximal to the sigmoid colon, <1 cm in endoscopic size, and up to 3 total HPs in number. Group 2 included patients without any proximal HPs or SSPs. Group 3 consisted of patients with 1 to 2 SSPs, with at least 1 being proximal to the sigmoid colon, that were <1 cm in endoscopic size and without dysplasia. Rates of synchronous advanced neoplasia in patients with small (<1 cm) and diminutive (≤5 mm) proximal HPs were compared with the rates for the other 2 groups. RESULTS: There were 482 of 2569 patients (18.8%) with a small proximal HP who met the criteria for Group 1. The rate of synchronous advanced neoplasia in patients with a small proximal HP (61/482, 12.7%) was significantly greater compared with the average risk in the non-serrated cohort (Group 2, 133/1878, 7.1%; P < .001). There was no significant difference in the rate of synchronous advanced neoplasia when the small proximal HP group was subdivided by size (≤5 mm, 51/404, 12.6% vs 6-9 mm, 10/78, 12.8%; P = 1.00). The rate of synchronous advanced neoplasia in patients with diminutive (≤5 mm) proximal HPs (51/404, 12.6%) was not significantly different from the rate observed with proximal SSPs of similar size (17/113, 15.0%; P = .529). CONCLUSION: Patients with small and diminutive proximal HPs tend to harbor higher rates of synchronous advanced neoplasia compared with those without any serrated lesions detected on screening colonoscopy. Surveillance outcomes for metachronous advanced neoplasia for patients with small proximal HPs deserves further study. The synchronous advanced neoplasia rate in patients with proximal diminutive HPs is similar to that of proximal diminutive SSPs and could have implications in a resect and discard strategy.

Breast implant-associated anaplastic large-cell lymphoma and the role of brentuximab vedotin (SGN-35) therapy: A case report and review of the literature.

Breast implant-associated (BIA) anaplastic large-cell lymphoma (ALCL) is a rare disease, comprising a small percentage of all non-Hodgkin lymphomas (NHLs), reportedly 2-3%. There is currently no established standard approach to the treatment of BIA ALCL. The first case on the development of ALCL in the presence of a breast implant was reported in 1997 and the association was first identified by the Food and Drug Administration in 2011. We herein describe a case of BIA ALCL in a patient with a previous history of breast cancer and breast reconstruction who presented with hardening of her breast implant. The patient underwent capsulectomy and the findings of the pathological examination were consistent with ALCL. The patient completed three cycles of combination chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP regimen) followed by radiation consolidation therapy, and has maintained a complete remission ever since. The aim of the present study was to review the treatment options for BIA ALCL and suggest an investigation of the CD30-directed antibody-drug conjugate, brentuximab vedotin, as a potential treatment option for BIA ALCL.

Bendamustine and Rituximab: Complete Response in a 62-Year-Old Female with an Aggressive Lymphoma and an Ejection Fraction of 20.

The treatment of diffuse large B-cell lymphoma in the presence of cardiac comorbidities can be challenging considering that the standard treatment regimen used for this aggressive subtype of non-Hodgkin lymphoma (NHL) consists of a combination of rituximab, cyclophosphamide, doxorubicin hydrochloride, Oncovin (vincristine), and prednisone (R-CHOP). The use of the anthracycline doxorubicin has been associated with arrhythmias and cardiomyopathy, making patients with cardiac dysfunction poor candidates for R-CHOP. As such, it is imperative to find alternative regimens that omit cardiac toxicity without compromising efficacy for this patient population. We report a case of composite NHL in a patient who received frontline bendamustine with rituximab with encouraging results. Our patient had a left ventricular ejection fraction of 20%, making her a poor candidate for anthracycline-based therapy. We opted to administer bendamustine with rituximab for a total of 6 cycles. She remains disease free 18 months after the completion of therapy.

Plasma lipidomics profiling identified lipid biomarkers in distinguishing early-stage breast cancer from benign lesions.

BACKGROUND: Breast cancer is very common and highly fatal in women. Current non-invasive detection methods like mammograms are unsatisfactory. Lipidomics, a promising detection method, may serve as a novel prognostic approach for breast cancer in high-risk patients. RESULTS: According the predictive model, the combination of 15 lipid species had high diagnostic value. In the training set, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the combination of these 15 lipid species were 83.3%, 92.7%, 89.7%, and 87.9%, respectively. The AUC in the training set was 0.926 (95% CI 0.869-0.982). Similar results were found in the validation set, with the sensitivity, specificity, PPV and NPV at 81.0%, 94.5%, 91.9%, and 86.7%, respectively. The AUC was 0.938 (95% CI 0.889-0.986) in the validation set. METHODS: Using triple quadrupole liquid chromatography electrospray ionization tandem mass spectrometry, this study was to detect global lipid profiling of a total of 194 plasma samples from 84 patients with early-stage breast cancer (stage 0-II) and 110 patients with benign breast disease included in a training set and a validation set. A binary logistic regression was used to build a predictive model for evaluating the lipid species as potential biomarkers in the diagnosis of breast cancer. CONCLUSIONS: The combination of these 15 lipid species as a panel could be used as plasma biomarkers for the diagnosis of breast cancer.

Irreversible Electroporation as an Effective Technique for Ablating Human Metastatic Osteosarcoma.

Irreversible electroporation (IRE) induces apoptosis in tumor cells with electric energy, allowing treatment of unresectable tumors. One potential application is metastatic osteosarcoma (OS) in the pediatric population. A 12-year-old underwent thoracotomy with resection of metastatic OS. IRE was applied to 1 resected tumor section. Using 2 probes, 100 pulses with width of 90 ms were delivered. Efficacy was measured by increase in current draw during treatment. The treated sample was analyzed with hematoxylin and eosin and transmission electron microscopy. Default voltage of 1800 kV was ineffective. Voltage of 2700 kV caused excessive current draw and was aborted to prevent thermal injury. At 2200 kV, current draw rise was 9 amps, signifying successful treatment. Untreated specimen showed viable OS, normal surrounding lung tissue. Treated tumor had edema within the tumor and in surrounding lung tissue, with intra-alveolar hemorrhage and cellular architecture destruction. There was also evidence for cellular destruction such as disruption of lipid bilayer and release of intracellular fluid. Optimal voltage for treatment was 2200 kV, likely higher due to electrical conduction variation in the aerated lung. IRE may be an option for pediatric patients with unresectable metastatic OS.

Presence of small sessile serrated polyps increases rate of advanced neoplasia upon surveillance compared with isolated low-risk tubular adenomas.

BACKGROUND AND AIMS: The U.S. Multi-Society Task Force (USMSTF) stratifies patients with sessile serrated polyps (SSPs) without cytologic dysplasia of <10 mm in size as at low risk for metachronous advanced neoplasia and recommends management similar to low-risk conventional tubular adenomas. Evidence supporting the recommended surveillance interval for these low-risk SSPs is limited. We aimed to assess rates of metachronous advanced neoplasia based on the presence of an initial low-risk SSP compared with isolated low-risk tubular adenomas. METHODS: Colonoscopy data were retrieved for 2260 patients found to have an adenoma or SSP on pathology records between 2005 and 2011 at an academic medical center. The 788 patients who met study design criteria were stratified into 4 groups based on the presence of a high- or low-risk adenoma (HRA or LRA) and of a synchronous SSP on initial colonoscopy. The rates of advanced neoplasia at surveillance colonoscopy were then compared between groups. RESULTS: The rate of advanced neoplasia at surveillance in the LRA inclusive of SSP group (12/66, 18.2%) was greater than in the LRA without any SSP group (29/370, 7.8%; P = .019). The rate of advanced neoplasia at surveillance in patients with isolated low-risk SSP (10/56, 17.9%) remained significantly greater than those with isolated low-risk tubular adenomas (29/370, 7.8%; P = .024). The rate of advanced neoplasia upon surveillance in the LRA inclusive of SSP group (18.2%) was comparable with the rate observed in the index HRA without any SSP group (15.9%) (40/252, P = .709). CONCLUSIONS: The rate of advanced neoplasia upon surveillance in patients with initial low-risk SSPs is higher than in patients with initial isolated low-risk tubular adenomas and more similar to patients with initial high-risk tubular adenomas. These findings suggest that the rate of metachronous advanced neoplasia in patients with what are considered by USMSTF as "low-risk" SSPs is higher than in those without SSPs. Therefore, a surveillance interval that accounts for the presence of SSPs even in small lesions without cytologic dysplasia should be considered.

Four Synchronous Primary Malignancies of the Breast, Lung, Colon and Esophagus.

The literature contains few reports of patients with four more or more synchronous primary malignancies. We report the case of a 74-year-old woman who presented with synchronous primary malignant neoplasms of the breast (metaplastic carcinoma), lung (squamous cell carcinoma), esophagus (adenocarcinoma), and colon (adenocarcinoma). She was treated with multimodality therapy and demonstrated a favorable response at early follow-up. To our knowledge, this combination of synchronous primary malignancies has not been previously reported. The management of patients with multiple synchronous primary malignancies introduces a number of unique challenges which necessitate highly individualized treatment plans that may not strictly adhere to standard practices in the setting of a single malignancy.

Benign cystic mesothelioma associated with ipsilateral renal agenesis: a case report and review of literature.

Benign Cystic Mesothelioma (BCM) is an uncommon peritoneal lesion that usually occurs in reproductive age females with a history of abdominal surgery. Occasional expression of estrogen and progesterone receptor in these cells may explain female predilection. Reports of BCM in males are rare. We describe a case of BCM associated with ipsilateral renal agenesis in a young male without any surgical history. The cyst lining stained positive for cytokeratin, Wilms Tumor-1, epithelial membrane antigen, CD10, estrogen receptor, and progesterone receptor, and negative for PAX-8. Only three cases of BCM associated with congenital renal anomalies have been reported. To the best of our knowledge, this is the first case of BCM associated with ipsilateral renal agenesis in an adult male and the first male case of BCM displaying estrogen and progesterone receptor positivity. Such a case reveals the presence of congenital anomalies should be considered in patients with BCM.

Myocardial hydrophilic polymer emboli following cardiac catheterization: a case report and literature review.

BACKGROUND: Intravascular polymer emboli have been reported in the skin, lungs, and brain following vascular procedures utilizing hydrophilic polymer coated devices. The Cook arterial introducer sheath was the first of these devices to be introduced, after which case reports followed documenting sterile inflammation at the sheath access site, characterized histologically by perivascular granulomas containing hydrophilic polymer. More recently, hydrophilic polymer emboli have been reported in the vessels of the lungs and brain in association with ischemia and infarct following vascular procedures using polymer coated devices. METHODS: We report a case of intravascular myocardial emboli associated with acute myocardial infarction following cardiac catheterization. The patient was a 65-year-old man who received cardiac catheterization with placement of a bare metal stent following myocardial infarction. One month later, the patient presented with angina and died shortly after admission. RESULTS: Autopsy revealed hemopericardium with rupture of the left ventricle through an aneurismal defect within the area of prior infarction. Microscopically, an area of acute infarction was present within the aneurismal defect. Numerous small and medium-sized vessels within the left ventricle were occluded by basophilic amorphous granular material with an inflammatory giant cell response. CONCLUSION: The emboli were most frequent in the area of acute infarction, suggesting that the emboli may have resulted in ischemia leading to the patient's death. This is the third documented case of intramyocardial polymer emboli following cardiac catheterization and the first case to our knowledge to document an association between intravascular myocardial polymer emboli and acute myocardial infarction.

Development and validation of a plasma biomarker panel for discerning clinical significance of indeterminate pulmonary nodules.

INTRODUCTION: The recent findings of the National Lung Screening Trial showed 24.2% of individuals at high risk for lung cancer having one or more indeterminate nodules detected by low-dose computed tomography-based screening, 96.4% of which were eventually confirmed as false positives. These positive scans necessitate additional diagnostic procedures to establish a definitive diagnosis that adds cost and risk to the paradigm. A plasma test able to assign benign versus malignant pathology in high-risk patients would be an invaluable tool to complement low-dose computed tomography-based screening and promote its rapid implementation. METHODS: We evaluated 17 biomarkers, previously shown to have value in detecting lung cancer, against a discovery cohort, comprising benign (n = 67) cases and lung cancer (n = 69) cases. A Random Forest method based analysis was used to identify the optimal biomarker panel for assigning disease status, which was then validated against a cohort from the Mayo Clinic, comprising patients with benign (n = 61) or malignant (n = 20) indeterminate lung nodules. RESULTS: Our discovery efforts produced a seven-analyte plasma biomarker panel consisting of interleukin 6 (IL-6), IL-10, IL-1ra, sIL-2Rα, stromal cell-derived factor-1α+ß, tumor necrosis factor α, and macrophage inflammatory protein 1 α. The sensitivity and specificity of our panel in our validation cohort is 95.0% and 23.3%, respectively. The validated negative predictive value of our panel was 93.8%. CONCLUSION: We developed a seven-analyte plasma biomarker panel able to identify benign nodules, otherwise deemed indeterminate, with a high degree of accuracy. This panel may have clinical utility in risk-stratifying screen-detected lung nodules, decrease unnecessary follow-up imaging or invasive procedures, and potentially avoid unnecessary morbidity, mortality, and health care costs.