Aims
Proton pump inhibitors (PPIs) are among the most widely used medications in the United States. Most PPI users have persistent hypergastrinaemia during treatment. However, gastric neuroendocrine ...tumours diagnosed in long‐term PPI users are rarely reported. Their clinicopathological features and prognosis are not characterised. It remains unclear whether or not they can be classified as Type III sporadic tumours.
Methods and results
We retrospectively characterised 66 gastric neuroendocrine tumours from patients without atrophic gastritis and gastrinoma from two tertiary care medical centres, including 38 tumours in patients who had used PPIs for at least 1 year and 28 tumours from patients without long‐term PPI use (control group, Type III tumours). Compared to controls, tumours from long‐term PPI users tended to be in the pT1–2 category (98% versus 79%, P = 0.09) and less often invaded the serosa (3% versus 18%, P = 0.08) or lymphovascular spaces (11% versus 32%, P = 0.06). Using Kaplan–Meier analysis, long‐term PPI users had significantly longer overall survival than controls (P = 0.035). While three control patients developed distant metastasis and seven died, long‐term PPI users were without distant metastasis (P = 0.06) or death (P = 0.002) during follow‐up. However, five long‐term PPI users developed additional gastric neuroendocrine tumour(s), while none of the controls did (P = 0.07).
Conclusions
Our results show that gastric neuroendocrine tumours of long‐term PPI users are probably less aggressive compared to Type III sporadic tumours and have an indolent disease course. Our findings support the classification of gastric neuroendocrine tumours in long‐term PPI users as a separate subtype.
There is limited data on the prevalence and mortality of venous thromboembolism (VTE) following oncologic surgery.
To evaluate the trends, factors, and mortality of VTE following major cancer ...surgery.
Patients undergoing colectomy, cystectomy, esophagectomy, gastrectomy, hysterectomy, lung resection, pancreatectomy, or prostatectomy were identified retrospectively using the Nationwide Inpatient Sample between January 1, 1999, and December 30, 2009, resulting in a weighted estimate of 2,508,916 patients.
Venous thromboembolism following major cancer surgery was assessed according to date, patient, and hospital characteristics. The determinants of in-hospital VTE were evaluated using logistic regression analysis.
Venous thromboembolism showed an estimated annual percentage increase of 4.0% (95% CI, 2.9% to 5.1%), which contrasts with a 2.4% (95% CI, -4.3% to -0.5%) annual decrease in mortality in VTE after major cancer surgery. In multivariate logistic regression analysis, older age (odds ratio OR, 1.03; P < .001), female sex (OR, 1.25; P < .001), black race (vs white; OR, 1.56; P < .001), Charlson comorbidity index score of 3 or more (OR, 1.85; P < .001), and Medicaid (vs private insurance; OR, 2.04; P < .001), Medicare (OR, 1.39; P < .001), and uninsured (OR, 1.49; P < .001) status were associated with an increased risk of VTE. Conversely, other (nonwhite and nonblack) race (OR, 0.75; P < .001) was associated with a lower risk of VTE. Among hospital characteristics, urban location (OR, 1.32; P < .001) and teaching status (OR, 1.08; P = .01) were associated with greater odds of VTE. Patients with vs without VTE experienced 5.3-fold greater odds of mortality.
During our study period, VTE events following major cancer surgery increased in frequency; however, associated VTE mortality decreased. Changing VTE detection guidelines and better management of this condition may explain our findings.
Extracellular vesicles and exomere nanoparticles are under intense investigation as sources of clinically relevant cargo. Here we report the discovery of a distinct extracellular nanoparticle, termed ...supermere. Supermeres are morphologically distinct from exomeres and display a markedly greater uptake in vivo compared with small extracellular vesicles and exomeres. The protein and RNA composition of supermeres differs from small extracellular vesicles and exomeres. Supermeres are highly enriched with cargo involved in multiple cancers (glycolytic enzymes, TGFBI, miR-1246, MET, GPC1 and AGO2), Alzheimer's disease (APP) and cardiovascular disease (ACE2, ACE and PCSK9). The majority of extracellular RNA is associated with supermeres rather than small extracellular vesicles and exomeres. Cancer-derived supermeres increase lactate secretion, transfer cetuximab resistance and decrease hepatic lipids and glycogen in vivo. This study identifies a distinct functional nanoparticle replete with potential circulating biomarkers and therapeutic targets for a host of human diseases.
Background
Numerous studies have recorded racial disparities in access to care for major cancers. We investigate contemporary national disparities in the quality of perioperative surgical oncological ...care using a nationally representative sample of American patients and hypothesize that disparities in the quality of surgical oncological care also exists.
Methods
A retrospective, serial, and cross-sectional analysis of a nationally representative cohort of 3,024,927 patients, undergoing major surgical oncological procedures (colectomy, cystectomy, esophagectomy, gastrectomy, hysterectomy, pneumonectomy, pancreatectomy, and prostatectomy), between 1999 and 2009.
Results
After controlling for multiple factors (including socioeconomic status), Black patients undergoing major surgical oncological procedures were more likely to experience postoperative complications (OR: 1.24;
p
< 0.001), in-hospital mortality (OR: 1.24;
p
< 0.001), homologous blood transfusions (OR: 1.52;
p
< 0.001), and prolonged hospital stay (OR: 1.53;
p
< 0.001). Specifically, Black patients have higher rates of vascular (OR: 1.24;
p
< 0.001), wound (OR: 1.10;
p
= 0.004), gastrointestinal (OR: 1.38;
p
< 0.001), and infectious complications (OR: 1.29;
p
< 0.001). Disparities in operative outcomes were particularly remarkable for Black patients undergoing colectomy, prostatectomy, and hysterectomy. Importantly, substantial attenuation of racial disparities was noted for radical cystectomy, lung resection, and pancreatectomy relative to earlier reports. Finally, Hispanic patients experienced no disparities relative to White patients in terms of in-hospital mortality or overall postoperative complications for any of the eight procedures studied.
Conclusions
Considerable racial disparities in operative outcomes exist in the United States for Black patients undergoing major surgical oncological procedures. These findings should direct future health policy efforts in the allocation of resources for the amelioration of persistent disparities in specific procedures.
The origin of serous endometrial intraepithelial carcinoma (SEIC) is debated, due to its premalignant and independently malignant nature. It often arises next to endometrial serous carcinoma (ESC), ...with a propensity for polypoid growth. We aimed to better characterize this discrepancy by analyzing the clinical, histologic, and immunohistochemical features of polypoid carcinoma associated with SEIC (P-SEIC), and compared them with usual endometrial serous carcinoma without SEIC (UESC). Consecutive patients with P-SEIC were recruited and compared with UESC controls from our institutional research center. Clinical, histologic, and immunohistochemical (IHC, ER, PR, P53, Napsin-A, WT1, P16) were analyzed. BRCA testing results and familial history were also extracted from clinical databases. Welch T test, Pearson χ, and Fisher exact test were performed in SPSS version 23. A total of 37 P-SEIC and 25 UESC were the basis of a case-control study. P-SEIC was associated with more bilateral ovarian involvement (P=0.026), yet showed lower rates of myometrial invasion (P=0.002). P-SEIC showed a statistically different IHC profile: p53+, p16+, ER+, PR+, and WT-1+, and high rates of Napsin-A, while UESC was p53+, p16+, WT-1-, Napsin-A-, with lower rates of ER and PR. We also identified 2 patients who received prophylactic salpingo-oophorectomy for BRCA mutations and who subsequently developed P-SEIC with its unique IHC pattern. Our results suggest different underlying expression profiles and possibly diverging molecular signatures between both P-SEIC and UESC. If confirmed in further molecular studies, it could lead to a distinct molecular subclass.
Hepatocyte Nuclear Factor 4-alpha (HNF4α) comprises a nuclear receptor superfamily of ligand-dependent transcription factors that yields twelve isoforms in humans, classified into promoters P1 or ...P2-associated groups with specific functions. Alterations in HNF4α isoforms have been associated with tumorigenesis. However, the distribution of its isoforms during progression from dysplasia to malignancy has not been studied, nor has it yet been studied in intraductal papillary mucinous neoplasms, where both malignant and pre-malignant forms are routinely clinically identified. We examined the expression patterns of pan-promoter, P1-specific, and P2-specific isoform groups in normal pancreatic components and IPMNs. Pan-promoter, P1 and P2 nuclear expression were weakly positive in normal pancreatic components. Nuclear expression for all isoform groups was increased in low-grade IPMN, high-grade IPMN, and well-differentiated invasive adenocarcinoma. Poorly differentiated invasive components in IPMNs showed loss of all forms of HNF4α. Pan-promoter, and P1-specific HNF4α expression showed shifts in subnuclear and sub-anatomical distribution in IPMN, whereas P2 expression was consistently nuclear. Tumor cells with high-grade dysplasia at the basal interface with the stroma showed reduced expression of P1, while P2 was equally expressed in both components. Additional functional studies are warranted to further explore the mechanisms underlying the spatial and differential distribution of HNF4α isoforms in IPMNs.
Aims
Gallbladders resected for non‐neoplastic diseases are systemically examined microscopically to rule out incidental dysplasia and carcinoma. The main aim of this study was to test whether a ...pre‐grossing algorithm can detect incidental gallbladder carcinoma. The secondary aim was to test whether the algorithm can detect high‐grade dysplasia.
Methods and results
A retrospective study of clinical, pathological and radiological findings in cholecystectomy recipients was performed on a test set to develop a classification and regression tree algorithm. Cholecystectomy cases were included; exclusion criteria were age <18 years, missing pathology reports, preoperative suspicion of neoplastic disease, and cholecystectomy for non‐gallbladder oncological disease. Five thousand nine hundred and eighty‐two cholecystectomies from 2006 to 2018 were included in the study, with 18 cases of incidental gallbladder carcinoma and 11 cases of high‐grade dysplasia. Three hundred and ninety controls were randomly selected for the testing set. Patient age, surgical approach, operation duration, dilatation of the biliary tract and gallbladder gross anomalies were statistically significant distinguishing factors in multivariate analysis (P < 0.00–0.026). Unsupervised testing with a conditional inference tree suggested that age, procedure type and operation duration can be used to identify incidental gallbladder carcinoma from controls, whereas high‐grade dysplasia also requires grossing parameters to identify half of the cases (5/11).
Conclusion
Readily available clinical parameters and postoperative data can be used to detect incidental gallbladder carcinoma. High‐grade dysplasia mostly requires grossing and microscopic examination.
Abstract Background The incidence of infected urolithiasis is unknown, and evidence describing the optimal management strategy for obstruction is equivocal. Objective To examine the trends of ...infected urolithiasis in the United States, the practice patterns of competing treatment modalities, and to compare adverse outcomes. Design, setting, and participants A weighted estimate of 396 385 adult patients hospitalized with infected urolithiasis was extracted from the Nationwide Inpatient Sample, 1999–2009. Outcome measurements and statistical analysis Time trend analysis examined the incidence of infected urolithiasis and associated sepsis, as well as rates of retrograde ureteral catheterization and percutaneous nephrostomy (PCN) for urgent/emergent decompression. Propensity-score matching compared the rates of adverse outcomes between approaches. Results and limitations Between 1999 and 2009, the incidence of infected urolithiasis in women increased from 15.5 (95% confidence interval CI, 15.3–15.6) to 27.6 (27.4–27.8)/100 000); men increased from 7.8 (7.7–7.9) to 12.1 (12.0–12.3)/100 000. Rates of associated sepsis increased from 6.9% to 8.5% ( p = 0.013), and severe sepsis increased from 1.7% to 3.2% ( p < 0.001); mortality rates remained stable at 0.25–0.20% ( p = 0.150). Among those undergoing immediate decompression, 113 459 (28.6%), PCN utilization decreased from 16.1% to 11.2% ( p = 0.001), with significant regional variability. In matched analysis, PCN showed higher rates of sepsis (odds ratio OR: 1.63; 95% CI, 1.52–1.74), severe sepsis (OR: 2.28; 95% CI, 2.06–2.52), prolonged length of stay (OR: 3.18; 95% CI, 3.01–3.34), elevated hospital charges (OR: 2.71; 95%CI, 2.57–2.85), and mortality (OR: 3.14; 95%CI, 13–4.63). However, observational data preclude the assessment of timing between outcome and intervention, and disease severity. Conclusions Between 1999 and 2009, women were twice as likely to have infected urolithiasis. Rates of associated sepsis and severe sepsis increased, but mortality rates remained stable. Analysis of competing treatment strategies for immediate decompression demonstrates decreasing utilization of PCN, which showed higher rates of adverse outcomes. These findings should be viewed as preliminary and hypothesis generating, demonstrating the pressing need for further study.
ABSTRACT Hepatocellular carcinoma (HCC) is a disease of high unmet medical need that has become a global health problem. The development of targeted therapies for HCC has been hindered by the ...incomplete understanding of HCC pathogenesis and the limited number of relevant preclinical animal models. We recently unveiled a previously uncharacterized YES kinase (encoded by YES1)-dependent oncogenic signaling pathway in HCC. To model this subset of HCC, we established a series of syngeneic cell lines from liver tumors of transgenic mice expressing activated human YES. The resulting cell lines (referred to as HepYF) were enriched for expression of stem cell and progenitor markers, proliferated rapidly, and were characterized by high SRC family kinase (SFK) activity and activated mitogenic signaling pathways. Transcriptomic analysis indicated that HepYF cells are representative of the most aggressive proliferation class G3 subgroup of HCC. HepYF cells formed rapidly growing metastatic tumors upon orthotopic implantation into syngeneic hosts. Treatment with sorafenib or the SFK inhibitor dasatinib markedly inhibited the growth of HepYF tumors. The new HepYF HCC cell lines provide relevant preclinical models to study the pathogenesis of HCC and test novel small-molecule inhibitor and immunotherapy approaches.
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