Site Of Origin Research Articles

Association between GPC2 polymorphisms and neuroblastoma risk in Chinese children.

The cell surface glycoprotein glypican 2 (GPC2) has been shown to increase susceptibility to neuroblastoma, which is the most common malignancy in children. However, associations between single nucleotide polymorphism(s) of GPC2 and neuroblastoma risk remain unclarified. We conducted a case-control study to investigate two GPC2 polymorphisms (rs1918353 G>A and rs7799441 C>T) in 473 healthy controls and 402 pediatric patients with neuroblastoma. Single nucleotide polymorphism (SNP) genotyping was conducted on the samples by the TaqMan technique, and the data were subsequently analyzed by the t test, chi-squared test, and logistic regression model. In addition, we further performed stratification analysis by age, sex, tumor site of origin, or clinical stage to control confounding factors. According to the data of dominant models (GA/AA vs. GG: adjusted OR=0.99, 95% CI=0.76-1.29, p=0.943; CT/TT vs. CC: adjusted OR=0.91, 95% CI=0.70-1.19, p=0.498) or other comparisons, as well as the conjoint analysis (adjusted OR=1.22, 95% CI=0.93-1.59, p=0.152), we unfortunately proved that the analysis of single or multiple loci did not support any significant association of GPC2 polymorphisms with susceptibility to neuroblastoma. GPC2 polymorphisms (rs1918353 G>A and rs7799441 C>T) are unable to statistically affect neuroblastoma risk in Chinese children. Therefore, more samples, especially from patients of various ethnic backgrounds, are required to increase the sample size and verify the effect of GPC2 polymorphisms on neuroblastoma risk in the presence of ethnic factor.

Preventing Complications During Mapping and Ablation of Left Ventricular Summit Arrhythmias.

The left ventricular summit is a site of origin for idiopathic ventricular arrhythmias. With advancements in mapping and ablation techniques, sites previously considered inaccessible can now be approached. Anatomical knowledge of the 3-dimensional landmarks of this space is important, as critical structures reside within its boundaries and are potentially liable to collateral injury during ablation. This article reviews reported complications from ablation of ventricular arrhythmias arising from the left ventricular summit and its vicinity and discusses the pros and cons of different ablation technique and the role of an individualized anatomical approach to reduce procedural related complications and improve outcomes.

The challenging imaging and histopathologic features of diffusely infiltrating breast cancer

PurposeClinical, imaging and outcome observations indicate that diffusely infiltrating breast cancer, presenting as a large region of architectural distortion on the mammogram and conventionally termed classic infiltrating lobular carcinoma of diffuse type, represents a very unusual breast malignancy. This article aims to draw attention to the complex clinical, imaging, and large format thin and thick section histopathologic features of this malignancy, which challenges our current diagnostic and therapeutic management practices. MethodsProspectively collected data from the randomized controlled trial (1977–85) and from the subsequent, ongoing population-based mammography service screening (1985–2019) with more than four decades of follow up in Dalarna County, Sweden provided the database for investigating this breast cancer subtype. Large format thick (subgross) and thin section histopathologic images of breast cancers diagnosed as “diffusely infiltrating lobular carcinoma of the breast” were correlated with their mammographic tumour features (imaging biomarkers) and the long-term patient outcome. ResultsThis malignancy does not have a distinct tumour mass or focal skin retraction at clinical breast examination; instead, it causes an indistinct “thickening” and eventually shrinks the entire breast. A dominant feature is extensive architectural distortion on the mammograms caused by an excessive amount of cancer-associated connective tissue. Unlike other invasive breast malignancies, this subtype forms concave contours with the surrounding adipose connective tissue, a feature that makes it difficult to detect on mammograms. Women with this diffusely infiltrating breast malignancy have a 60% long-term survival. Its long-term patient outcome is surprisingly poor compared to that expected from its relatively favourable immunohistochemical biomarkers, including a low proliferation index and remains unaffected by adjuvant therapy. ConclusionsThe unusual clinical, histopathologic and imaging features of this diffusely infiltrating breast cancer subtype are consistent with a site of origin quite different from that of other breast cancers. Additionally, the immunohistochemical biomarkers are deceptive and unreliable because they indicate a cancer with favourable prognostic features predictive of a good long-term outcome. The low proliferation index is usually indicative of a breast cancer with a good prognosis, but in this subtype the prognosis is poor. If we are to improve the dismal outcome of this malignancy, it will be necessary to clarify its true site of origin, which will be a prerequisite for gaining a better understanding why current management efforts often fail and why the fatality rate is so unfortunately high. Breast radiologists should be watchful for the development of subtle signs of architectural distortion at mammography. Large format histopathologic technique enables adequate correlation of the imaging and histopathologic findings.

A rapid wide complex tachycardia

A rapid wide complex tachycardia

Surgical management of adult supraclavicular hemangioma: a case report

Introduction: Hemangioma is one of the most common vascular anomalies. It is classified into two types: superficial hemangioma, also known as capillary hemangioma, which appears as brilliant red macular masses, and deep hemangioma, which appears as a soft, non-fluctuating, poorly defined, and occasionally bosselated nodule. Surgical excision is recommended for cavernous-type tumors, which are less sure to regress. Despite its benign origin and behavior, it can develop in any body part. However, its size and origin site may vary and make surgical excision more challenging due to the importance of the structures surrounding the mass. Thus, this study aims to explain the surgical management of adult supraclavicular hemangioma. Case Description: We present a case of primary cavernous hemangioma in 36 years-old-woman with no history of health problems that extends to the supraclavicular area and was linked to essential structures. The surgical excision was performed through a double-incision technique to prevent iatrogenic damage to the system. Postoperative evaluations revealed no impairment of motoric and sensory hand functions, and the patient was discharged three days postoperatively. Histopathologic findings were consistent with the diagnosis of hemangioma. Conclusion: The supraclavicular approach in surgery is challenging due to its critical location and closeness to key neurovascular structures. To obtain the best surgical outcome, the essential operating concepts include thorough dissection and a modified method to limit the risk of functional status and mobility impairment.

Life-Threatening Hemorrhage from the Lingual Artery after a Genioplasty—Case Report and Review of Possible Complications Associated with Orthognathic Surgeries

Life-threatening hemorrhage after orthognathic surgery is rare. However, when it occurs, immediate diagnosis of the source of bleeding is imperative for successful management. The current report is the first to describe a rare life-threatening bleed from the left lingual artery following a genioplasty in a young healthy patient. Such occurrence also emphasizes the diverse anatomical course of the lingual artery and focuses on raising awareness about its numerous variations, sites of origin. Surgeons are often unaware of the anatomic variations of the lingual artery and its relation to the surrounding structures, which often lead to unexpected hemorrhages. Moreover, depending on severity, they can become challenging to manage and may lead to life-threatening complications. Taking into consideration the variations and the classification of the anatomical course of the lingual artery will improve surgical outcome, reduce morbidity, and lead to appropriate healing and recovery. This previously unpublished case regarding complications of lingual artery hemorrhage after genioplasty can bring awareness for future surgical considerations.

Enfortumab vedotin (EV) alone or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer (la/mUC): Subgroup analyses of confirmed objective response rate (cORR) from EV-103 cohort K.

499 Background: In EV-103 Cohort K (NCT03288545), EV and P in combination (EV+P) showed encouraging antitumor activity and a manageable safety profile when used as 1L therapy in patients (pts) w/ la/mUC who are ineligible for cisplatin, a population w/ high unmet need. Here we report results of an analysis of prespecified Cohort K subgroups known to be associated w/ poor outcomes. Methods: Pts who are cisplatin-ineligible w/ previously untreated la/mUC were randomized 1:1 to EV (1.25 mg/kg) as monotherapy on Days 1 and 8 or in combination w/ P (200 mg) on Day 1 of 3-week cycles. Primary endpoint is cORR per RECIST v1.1 by blinded independent central review w/ no formal statistical comparison between arms. Secondary endpoints included duration of response and safety (e.g. treatment-related adverse events, TRAEs). The cORR analysis was performed in prespecified subgroups including age, ECOG PS, liver metastasis, PD-L1 expression status, metastatic disease site at baseline, and primary disease site of origin. Results: 149 pts were treated: EV+P n=76; EV n=73; cORRs across key subgroups for both EV+P and EV monotherapy are shown in the table. For EV+P overall cohort, cORR (95%CI): 64.5% (52.7, 75.1); median DOR was not reached. cORRs were consistent across subgroups for EV+P including those w/ ECOG PS score of 1-2: 62.8% (46.7, 77.0) and presence of liver metastasis: 53.8% (25.1, 80.8). Among TRAEs of special interest in the EV+P arm, skin reactions occurred in n=51 (67.1%); peripheral neuropathy occurred in n=46 (60.5%). For EV+P, 68.4% of pts had TRAEs leading to interruption of either EV or P; 48.7% of pts had TRAEs leading to EV dose reduction. Median duration of EV+P treatment was 11 cycles. Conclusions: EV+P showed promising cORR in 1L cisplatin-ineligible pts w/ la/mUC; activity was consistently observed across a range of pre-specified subgroups including those with poor prognosis. EV+P TRAEs were manageable w/ close monitoring and appropriate dose modifications w/ a meaningful duration of treatment. EV+P has the potential to address high unmet needs in 1L la/mUC and MIBC and is being further evaluated in 3 Phase 3 trials (NCT04223856, NCT04700124, NCT03924895). Clinical trial information: NCT03288545 . [Table: see text]

Dissecting the molecular signatures underlying hybrid oncocytic tumors in Birt-Hogg-Dubé syndrome.

707 Background: Birt-Hogg-Dubé (BHD) syndrome is associated with an increased risk of renal tumors including the hybrid oncocytic tumors (HOT), renal oncocytoma (RO) and chromophobe renal cell carcinoma (CHRCC). HOT are known to exhibit morphological features overlapping between RO and CHRCC. The molecular underpinnings of HOT and the corresponding morphologic correlates remain poorly understood. Herein we aimed to understand the distinct molecular features underlying HOT and how the genomic phenotype differs from CHRCC. Methods: We performed next generation sequencing and single cell sequencing analysis to understand the clinico-pathologic aspects and tumor biology of HOT and CHRCC, including tumor development. This was followed by spatial transcriptome analysis of the distinct HOT tumor compartments, using nanoString GeoMX digital spatial profiler. The candidate biomarker expression was confirmed by immunohistochemistry (IHC) and RNA in situ hybridization (RNA-ISH), a unique gene expression visualization molecular technology. Results: We discovered unique gene expression signatures underlying the two distinct morphological patterns seen in HOT. FOXI1 and L1CAM show a striking mutually exclusive expression pattern in the two cellular populations seen within this tumor. The signature genes of RO like cells seen within HOT resembles the principal cells of the distal nephron seen in normal kidney; and the signature genes of the CHRCC like cells resembles the intercalated cells of the distal nephron. This suggests distal nephron as the cellular site of origin for HOT. We also nominated tumor specific biomarkers for HOT. Conclusions: We identified unique gene expression signatures which are definitional for HOT and nominated candidate diagnostic biomarkers to help distinguish HOT from other renal tumor subtypes with overlapping morphology. This finding would improve the diagnostic accuracy, assist familial genetic monitoring, and facilitate disease management.

Using Stable Isotopes to Determine Natal Origin and Feeding Habits of the Army Cutworm Moth, Euxoa auxiliaris (Lepidoptera: Noctuidae).

The army cutworm, Euxoa auxiliaris (Grote), is a migratory noctuid that is both an agricultural pest and an important late-season food source for grizzly bears, Ursus arctos horribilis (Linnaeus, Carnivora: Ursidae), within the Greater Yellowstone Ecosystem. Beyond the confirmation of the moths' seasonal, elevational migration in the mid-1900s, little else has been documented about their migratory patterns. To address this missing ecological component, we examined (1) migratory routes during their spring and fall migratory periods throughout their natal range, the Great Plains, and (2) natal origin at two of their summering ranges using stable hydrogen (δ2H) analyses of wings from samples collected within the areas of interest. Stable carbon (δ13C) and stable nitrogen (δ15N) analyses of wings were used to evaluate larval feeding habits of the migrants and agricultural intensity of natal origin sites, respectively. Results suggest that, rather than migrating exclusively east to west, army cutworm moths are also migrating north to south during their spring migration. Moths did not exhibit natal origin site fidelity when returning to the Great Plains. Migrants collected from the Absaroka Range had the highest probability of natal origin in Alberta, British Columbia, Saskatchewan, the most southern region of the Northwest Territories, and second highest probability of origin in Montana, Wyoming, and Idaho. Migrants collected in the Lewis Range had the highest probability of origin in the same provinces of Canada. Results suggest that migrants of the Absaroka Range fed exclusively on C3 plants as larvae and rarely fed in heavily fertilized agroecosystems.

A hybrid clinical and electrocardiographic score to predict the origin of outflow tract ventricular arrhythmias.

To predict the outflow tract ventricular arrhythmias (OTVA) site of origin (SOO) before the ablation procedure has important practical implications. The present study sought to prospectively evaluate the accuracy of a clinical and electrocardiographic hybrid algorithm (HA) for the prediction of OTVAs-SOO, and at the same time to develop and to prospectively validate a new score with improved discriminatory capacity. In this multicenter study, we prospectively enrolled consecutive patients referred for OTVA ablation (N = 202), and we divided them in a derivation sample and a validation cohort. Surface ECGs during OTVA were analyzed to compare previous published ECG-only criteria and to develop a new score. In the derivation sample (N = 105), the correct prediction rate of HA and ECG-only criteria ranged from 74 to 89%. R-wave amplitude in V3 was the best ECG parameter for discriminating LVOT origin in V3 precordial transition (V3PT) patients, and was incorporated to the novel weighted hybrid score (WHS). WHS correctly classified 99 (94.2%) patients, presenting 90% sensitivity and 96% specificity (AUC 0.97) in the entire population; WHS mantained a 87% sensitivity and 91% specificity (AUC 0.95) in patients with V3PT subgroup. The high discriminatory capacity was confirmed in the validation sample (N = 97): the WHS exhibited an AUC (0.93), and a WHS ≥ 2 allowed a correct prediction of LVOT origin in 87 (90.0%) cases, yielding a sensitivity of 87% and specificity of 90%; moreover, the V3PT subgroup showed an AUC of 0.92, and a punctuation ≥ 2 predicted an LVOT origin with a sensitivity of 94% and specificity of 78%. The novel hybrid score has proved to accurately anticipate the OTVA's origin, even in those with a V3 precordial transition. A Weighted hybrid score. B Typical examples of the use of the weighted hybrid score. C ROC analysis of WHS and previous ECG criteria for prediction of LVOT origin in the derivation cohort. D ROC analysis of WHS and previous ECG criteria for prediction of LVOT origin in the V3 precordial transition OTVA subgroup.

High-resolution structural-functional substrate-trigger characterization: Future roadmap for catheter ablation of ventricular tachycardia.

Patients with ventricular tachyarrhythmias (VT) are at high risk of sudden cardiac death. When appropriate, catheter ablation is modestly effective, with relatively high VT recurrence and complication rates. Personalized models that incorporate imaging and computational approaches have advanced VT management. However, 3D patient-specific functional electrical information is typically not considered. We hypothesize that incorporating non-invasive 3D electrical and structural characterization in a patient-specific model improves VT-substrate recognition and ablation targeting. In a 53-year-old male with ischemic cardiomyopathy and recurrent monomorphic VT, we built a structural-functional model based on high-resolution 3D late-gadolinium enhancement (LGE) cardiac magnetic resonance imaging (3D-LGE CMR), multi-detector computed tomography (CT), and electrocardiographic imaging (ECGI). Invasive data from high-density contact and pace mapping obtained during endocardial VT-substrate modification were also incorporated. The integrated 3D electro-anatomic model was analyzed off-line. Merging the invasive voltage maps and 3D-LGE CMR endocardial geometry led to a mean Euclidean node-to-node distance of 5 ± 2 mm. Inferolateral and apical areas of low bipolar voltage (<1.5 mV) were associated with high 3D-LGE CMR signal intensity (>0.4) and with higher transmurality of fibrosis. Areas of functional conduction delay or block (evoked delayed potentials, EDPs) were in close proximity to 3D-LGE CMR-derived heterogeneous tissue corridors. ECGI pinpointed the epicardial VT exit at ∼10 mm from the endocardial site of origin, both juxtaposed to the distal ends of two heterogeneous tissue corridors in the inferobasal left ventricle. Radiofrequency ablation at the entrances of these corridors, eliminating all EDPs, and at the VT site of origin rendered the patient non-inducible and arrhythmia-free until the present day (20 months follow-up). Off-line analysis in our model uncovered dynamic electrical instability of the LV inferolateral heterogeneous scar region which set the stage for an evolving VT circuit. We developed a personalized 3D model that integrates high-resolution structural and electrical information and allows the investigation of their dynamic interaction during arrhythmia formation. This model enhances our mechanistic understanding of scar-related VT and provides an advanced, non-invasive roadmap for catheter ablation.

Tumors of the Digestive System: Comprehensive Review of Ancillary Testing and Biomarkers in the Era of Precision Medicine

Immunotherapy has remained at the vanguard of promising cancer therapeutic regimens due to its exceptionally high specificity for tumor cells and potential for significantly improved treatment-associated quality of life compared to other therapeutic approaches such as surgery and chemoradiation. This is especially true in the digestive system, where high rates of mutation give rise to a host of targetable tumor-specific antigens. Many patients, however, do not exhibit measurable improvements under immunotherapy due to intrinsic or acquired resistance, making predictive biomarkers necessary to determine which patients will benefit from this line of treatment. Many of these biomarkers are assessed empirically by pathologists according to nuanced scoring criteria and algorithms. This review serves to inform clinicians and pathologists of extant and promising upcoming biomarkers predictive of immunotherapeutic efficacy among digestive system malignancies and the ancillary testing required for interpretation by pathologists according to tumor site of origin.

Diagnostic Accuracy of Cell Block and Immunohistochemistry in Effusion Cytology.

Introduction Although the cytology of effusion fluids is considered a routine laboratory test, it has recently emerged as an essential tool in determining the primary site of origin of carcinoma of unknown primary. The sensitivity for diagnosing malignancy has enhanced with the inclusion of cytospin, cell block (CB), and immunohistochemistry (IHC) to effusion fluid cytology due to the improvement in morphological preservation and good cellular yield. The purpose of this study was to assess the diagnostic yield, sensitivity, specificity, positive predictive value, and negative predictive value of IHC and CB in effusion cytology. Methodology An institution-based cross-sectional study was conducted over a period of six months on 150 cases of effusion fluids submitted for diagnostic purposes. After the preparation of cytospin, the residual amount of centrifuged deposit was mixed with CytoLyt solution, thrombin, and plasma, and CBs were prepared. IHC was applied to the CB. Calretinin was used for mesothelial cells, and BerEP4, TTF-1, ER, WT-1, and CD-X2 were used for the confirmation and origin of malignant cells. Results The mean age of the patients was 51.75 ± 16.63 years. The male-to-female ratio was 1:1.24. Out of 150 cases, 78 were pleural effusions, 68 were peritoneal effusions, and four were pericardial effusions. Out of 150 cases, based on cytological examination alone, 66 (44%) were classified as benign, 27 (18%) as malignant, and 57 (38%) were suspicious for malignancy. When cytology was combined with CB and IHC, the diagnostic yield was increased to benign 95 (63.33%), malignant 48 (32%), and suspicious for malignancy 7 (4.67%). The most common cause of malignant pleural effusion was breast carcinoma in females and lung carcinoma in males. The most common primary tumor in malignant peritoneal effusion was ovarian carcinoma in females and colonic adenocarcinoma in males. The sensitivity and specificity of combined cytology with cell block and IHC were 92.31% and 98.95%, respectively. This combination produced significantly better results (p-value = 0.001) for detecting malignancy and reduced suspicious cases from 38% to 4%. Conclusion CB, in combination with IHC, increases the diagnostic yield and aids in detecting malignancy at an unknown primary site in effusion fluids. Both of these techniques can thus enhance the sensitivity and specificity of the diagnosis of effusion cytology. Hence, CB and IHC have advanced utility over cytological smears in effusion fluid cytological diagnosis.

Incisional Release and Fat Grafting for the Surgical Management of Perioral Fibrosis in Scleroderma: A Technical Report and Institutional Review.

Scleroderma (systemic sclerosis [SSc]) is a rare autoimmune, connective tissue disorder. Perioral fibrosis is a local cutaneous complication, negatively impacting functional capabilities and aesthetic satisfaction. Fat grafting has been postulated to aid in the management of SSc fibrosis thanks to stem cell enrichment. This technique's success has been demonstrated using different graft origin sites and different injection targets. We aim to demonstrate our SSc patients' success using abdominal fat and perioral target. We queried our records for patients with preexisting SSc who underwent incisional release and fat grafting for perioral fibrosis from 2018 to 2021. For perioral release, a semisharp cannula was tunneled under the vermilion border into the vermilion and along the skin. For grafting, cannulas were used to infiltrate the fat with a retrograde filling technique in a radial-fanning manner. Their autoimmune diagnosis, anesthetic risk assessment, systemic disease complications, and degree of presenting symptoms were reviewed along with their postoperative outcomes. From 2018 to 2021, 16 patients diagnosed with SSc were treated with incisional release and fat grafting for the management of perioral fibrosis. Of the SSc patients, 8 presented with limited SSc, and 8 presented with diffuse SSc. The mean patient age was 54.31 years. All SSc patients presented with functional symptoms with the most common concern (n = 9) being "decreased mouth opening." Other common complaints were "difficulty eating" (n = 3) or "difficulty drinking" (n = 2). Some patients (n = 11) also presented with cosmetic concerns with "perioral rhytids" being the most common (n = 6). The mean number of systemic complications, at the time of presentation, was 3.06. The mean anesthetic risk assessment was 2.44. The average amount of fat grafted intraoperatively was 14.89 mL. Two patients with SSc required regrafting. For one patient, this was part of the original treatment plan and for the other due to fat resorption. Patients who followed up reported improved functionality and were pleased aesthetically. Patients with perioral fibrosis due to SSc can benefit from autologous fat grafting. Incisional release in combination with fat grafting can enhance procedure outcomes. This technique provides beneficial functional and aesthetic outcomes. Patients with both diffuse and limited disease are appropriate candidates for this procedure.

Initial negative concordance on unipolar and bipolar electrograms: a novel parameter for localizing the origin of premature ventricular contractions arising from pulmonary sinus cusps.

The features of the unipolar electrogram (UEGM) and bipolar electrogram (BEGM) have been utilized to identify the site of origin of idiopathic premature ventricular contractions (PVCs) arising from pulmonary sinus cusps (PSCs), but for these PVCs, whether a negative concordance in the initial waves of both EGMs recorded above pulmonary valves can be used as a parameter to localize the origin has not been previously studied. We aimed to assess whether an initial negative concordance (INC) between the UEGM and BEGM might determine the origin of PVCs mapped and ablated within PSCs. Data were collected from 22 patients undergoing successful radiofrequency catheter ablation for symptomatic idiopathic PVCs within PSCs. The morphological features of both the UEGM and the BEGM recorded at all ablation sites were analyzed. A total of 109 sites within PSCs were ablated in 22 patients with an age (mean ± SD) of 47.2 ± 17.2years. Ablation resulted in procedural success in all patients. The INC was observed at 18 of 22 (81.8%) successful ablation sites, contrasted with 3 of 87 (3.4%) unsuccessful sites (P < 0.001). The INC was consistent with the outcomes of conventional mapping parameters and proved to be an additional useful predictor of ablation success, with a sensitivity, specificity, positive predictive value and negative predictive value of 81.8%, 96.6%, 85.7% and 95.5%, respectively. An INC between the UEGM and the BEGM can predict the origin of PVCs arising from PSCs. An initial negative concordance between unipolar and bipolar electrograms indicates that the distal electrode of the ablation catheter is at the origin of premature ventricular contractions within pulmonary sinus cusps.

Trends in Gynecologic Carcinosarcoma Based on Analysis of the Surveillance Epidemiology End Result (SEER) Database.

Carcinosarcomas (malignant mixed Mullerian tumors) of a female genital organ are rare tumors associated with a poor survival. The purpose of this study was to identify site-specific differences in the incidence and prognosis in carcinosarcomas originating in the uterus, cervix, or ovary. The data of patients with gynecologic carcinosarcomas were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2016. The characteristics of gynecologic carcinosarcomas were compared using Pearson X2 and Fisher's exact tests. Kaplan-Meier models were used for cause-specific survival (CSS) analysis. The cohort included 7086 females, including 5731 cases of uterine carcinosarcoma, 161 cervical carcinosarcomas, and 1193 ovarian carcinosarcomas. The age-adjusted incidence rates of uterine, cervical, and ovarian carcinosarcoma were 3.9, 0.1, and 0.6 per 1,000,000, respectively. In the distribution of carcinosarcoma incidence by race, compared with the uterus or cervix, those originating from the ovary were unequally distributed in Caucasians (84.4% versus 69.6%, 67.7%; p < 0.001). The incidence of uterine carcinosarcoma steadily increased over time, from 2.2 in 2000 to 5.5 in 2016 (per 1,000,000), while cervical or ovarian carcinosarcoma showed no significant difference in incidence. The five-year CSS rates based on the site of origin (uterus, cervix, and ovary) were 39.9%, 33.1%, and 25.8%, respectively. The incidence rates of gynecologic carcinosarcoma, especially uterine carcinosarcoma, are gradually increasing. Although uterine carcinosarcoma is associated with a higher incidence than the others, it has a better prognosis compared with ovarian and cervical carcinosarcoma. The survival rates were worst in ovarian carcinosarcoma.

Characterizing bone metastases and skeletal-related events in patients with well-differentiated neuroendocrine neoplasms utilizing Ga68-DOTATE PET.

641 Background: Tumors of neuroendocrine origin are a rare, heterogenous group of neoplasms. Neuroendocrine neoplasms (NENs) are categorized by site of origin, differentiation status, and by grade (Ki-67 expression and/or mitotic rate), with prognostic variability accordingly. These tumors frequently metastasize to bone, with reported incidence between 6-12% by older SSTR imaging. Our study evaluates patients with well-differentiated tumors of neuroendocrine origin to determine the incidence of osseous metastases when evaluated with higher-sensitivity Ga68 DOTATATE PET scans. The study characterizes the clinical features. Methods: This study was performed at a single, 3-site, US tertiary-care institution. IRB approval was obtained. An automated data extraction tool was used to mine the electronic medical record by searching all positron emission tomography (PET) studies for keywords. Identified scans had to include a combination of the following keywords: “Dotatate” AND “met*” or “lesion” AND “bone” or “osse*” or “skel*”. The individual medical records from the generated report were reviewed to include only patients with 1) well-differentiated NETs of GI and pancreatic origin, lung carcinoid, paraganglioma/pheochromocytoma, or other/unknown primary site, and 2) patients with confirmed osseous metastatic disease. Patient data was entered into a database and evaluated in aggregate. Results: 1,948 PET scans of 1,473 patients were extracted from the EMR, from which 424 patients were identified for inclusion; scans were performed between 5/2018 and 5/2021. Calculated incidence of bone metastasis by Ga68 DOTATATE PET was 28.8%. Median age of included population was 61 years (range 14-92), 49.5% being male. Site of origin was 47.2% bowel NET, 18.9% pancreatic NET, 10.8% lung carcinoid, 10.6% paraganglioma/pheochromocytoma, 2.1% other site, and 10.4% unknown primary. Majority of patients were asymptomatic (64.0%), had sclerotic appearance (76.7%), Krenning 4 (71.4%), and &gt;3 sites (68.3%) of osseous disease. 94.6% of the population had disease of the axial skeleton; 65.6% appendicular. Only 57 patients (13.4%) with osseous disease suffered a fracture, despite metastases at high-risk sites. Fracture occurred at disproportionately low rates in NETs originating in bowel (22.8% of fractures), with proportionately higher rates among pancreatic NETS and paragangliomas/pheochromocytomas (31.6% and 22.8%, respectively). Fractures occurred at proportionately higher rates in higher-grade disease compared to low-grade. Conclusions: Osseous metastatic disease in well-differentiated NENs is evident at much higher rates when imaging with Ga68 DOTATATE PET compared with previously reported data. Nevertheless, fracture occurred at a low rate, suggesting that these patients are at a relatively low risk for skeletal-related events.

The Impact of DTYMK as a Prognostic Marker in Colorectal Cancer.

Overexpression of deoxythymidylate kinase (DTYMK) has been associated with more aggressiveness and pathological behaviors in hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC). However, the expression of DTYMK and its prognostic significance in colorectal cancer (CRC) patients are yet unknown. The goal of this study was to investigate the DTYMK immunohistochemistry reactivity in CRC tissues and to see how it correlated with various histological and clinical features as well as survival. Several bioinformatics databases and two tissue microarrays (TMAs) of 227 cases were used in this study. Immunohistochemistry assay was used to study the protein expression of DTYMK. Based on the GEPIA, UALCAN, and Oncomine databases, DTYMK expression has increased in tumor tissues at both RNA and protein levels in colorectal adenocarcinoma (COAD) compared to normal tissues. A high DTYMK H-score was found in 122/227 (53%) of the cases, whereas a low DTYMK H-score was found in 105/227. The age at diagnosis (P = 0.036), stage of the disease (P = 0.038), and site of origin (P = 0.032) were all linked to a high DTYMK H-score. Patients with high level of DTYMK had bad overall survival. Interestingly, high DTYMK protein level was associated with PSM2 (P = 0.002) and MSH2 (P = 0.003), but not with MLH2 or MSH6. This is the first study to cover the expression and prognostic significance of DTYMK in CRC. DTYMK was upregulated in CRC and could be considered as a prognostic biomarker.

Man with chest tightness and diaphoresis.

A 67-year-old male patient with chest tightness and diaphoresis presented to the emergency department 1 hour before admission. The patient had a myocardial infarction with stent implantation history for the left circumflex and right coronary arteries 1 month ago. On arrival, his blood pressure was 85/52 mmHg; pulse rate was 166 bpm, and temperature was 35.6°C. A 12-lead electrocardiogram (ECG) was performed immediately (Figure 1). The emergency physician also performed echocardiography (Figure 2) (Videos 1 and 2). Ventricular tachycardia secondary to a postinfarction left ventricular aneurysm. The patient underwent a 100J synchronized cardioversion and the electrocardiogram returned to sinus rhythm (Figure 3). Continuous intravenous amiodarone was administered. He was admitted to the intensive care unit (ICU), where a cardiologist performed successful radiofrequency catheter ablation. Coronary artery disease is the most common cause of left ventricular aneurysms. Echocardiography is the preferred diagnostic method for left ventricular aneurysms after cardiac events.1 The aneurysm's thin-walled dyskinetic or akinetic segments may be composed of dense scars with viable myocardium channels. It may be the site of origin for ventricular tachycardia.2 Antiarrhythmic drugs and radiofrequency catheter ablation are frequently used to reduce ventricular tachycardia frequency and shocks in patients with implantable cardioverter-defibrillators.3

Single-copy locus proteomics of early- and late-firing DNA replication origins identifies a role of Ask1/DASH complex in replication timing control.

The chromatin environment at origins of replication is thought to influence DNA replication initiation in eukaryotic genomes. However, it remains unclear how and which chromatin features control the firing of early-efficient (EE) or late-inefficient (LI) origins. Here, we use site-specific recombination and single-locus chromatin isolation to purify EE and LI replication origins in Saccharomyces cerevisiae. Using mass spectrometry, we define the protein composition of native chromatin regions surrounding the EE and LI replication start sites. In addition to known origin interactors, we find the microtubule-binding Ask1/DASH complex as an origin-regulating factor. Strikingly, tethering of Ask1 to individual origin sites advances replication timing (RT) of the targeted chromosomal domain. Targeted degradation of Ask1 globally changes RT of a subset of origins, which can be reproduced by inhibiting microtubule dynamics. Thus, our findings mechanistically connect RT and chromosomal organization via Ask1/DASH with the microtubule cytoskeleton.