The Day-To-Day Practice of MMR and MSI Assessment in Colorectal Adenocarcinoma: What We Know and What We Still Need to Explore.

BACKGROUND: The DNA mismatch repair (MMR) system is a highly preserved protein complex recognizing short insertions, short deletions, and single base mismatches during DNA replication and recombination. MMR protein status is identified using immunohistochemistry. Deficit in one or more MMR proteins, configuring deficient MMR status (dMMR), leads to frameshift mutations particularly clustered in microsatellite repeats. Thus, microsatellite instability (MSI) is the epiphenomenon of dMMR. In colorectal cancer (CRC), MMR/MSI status is a biomarker with prognostic and predictive value of resistance to 5-fluorouracil and response to immune checkpoint inhibitor therapy. SUMMARY: In this Review, we describe the challenges the practicing pathologist may face in relation to the assessment of MMR/MSI status and any open issues which still need to be addressed, focusing on pre-analytic issues, pitfalls in the interpretation, and technical aspects of the different assays. KEY MESSAGES: The current methods of detecting dMMR/MSI status have been optimized for CRCs, and whether these techniques can be applied to all tumor and specimen types is still not fully understood. Following the Food and Drug Administration (FDA), tissue/site agnostic drug approval of pembrolizumab for advanced/metastatic MSI tumors, MMR/MSI status in gastrointestinal tract is a common request from the oncologist. In this setting, several issues still need to be addressed, including criteria for sample adequacy.

Cap-assisted endoscopic mucosal resection as a salvage technique for challenging colorectal laterally spreading tumors.

BACKGROUND: Cap-assisted endoscopic mucosal resection (EMR-c) has emerged as a potential alternative to standard piecemeal wide-field EMR (WF-EMR) for the resection of laterally spreading tumors (LSTs). However, clear indications for this technique are still lacking. Our objective was to investigate the performance of salvage EMR-c after WF-EMR failure in the resection of large colorectal LSTs. METHODS: The data of consecutive patients undergoing WF-EMR for large colorectal LSTs (2015-2021) were analyzed in this single-center, retrospective, observational study. In the event of a WF-EMR failure, the procedure was switched to EMR-c in the same session. The efficacy of the two techniques was evaluated in terms of complete endoscopic resection, R0 resection, and recurrence rate. Safety was also assessed. RESULTS: Overall, the data from 81 WF-EMRs were collected. Eighteen cases of WF-EMR failure were switched to EMR-c in the same session and complete endoscopic resection was achieved in 17/18 patients (94.4%). No statistically significant difference was observed between WF-EMR and salvage EMR-c in terms of macroscopic radicality (P = 0.40) and R0 resection (P = 0.12). However, recurrence was more common with EMR-c (44.4% vs. 23.5%; P = 0.05), as were adverse events, particularly intraprocedural bleeding (27.8% vs. 7.9%; P = 0.04). CONCLUSION: EMR-c is an effective salvage technique for challenging colorectal LSTs following WF-EMR failure. Due to the elevated risk of adverse events associated with this procedure, careful patient selection, endoscopic expertise, and close follow-up are strongly recommended.

Neuroinflammatory Response to TNFα and IL1ß Cytokines Is Accompanied by an Increase in Glycolysis in Human Astrocytes In Vitro.

Astrogliosis has been abundantly studied in rodents but relatively poorly in human cells due to limited access to the brain. Astrocytes play important roles in cerebral energy metabolism, and are also key players in neuroinflammation. Astroglial metabolic and inflammatory changes as a function of age have been reported, leading to the hypothesis that mitochondrial metabolism and inflammatory responses are interconnected in supporting a functional switch of astrocytes from neurotrophic to neurotoxic. This study aimed to explore the metabolic changes occurring in astrocytes during their activation. Astrocytes were derived from human ReN cell neural progenitors and characterized. They were activated by exposure to tumor necrosis factor alpha (TNFα) or interleukin 1ß (IL1ß) for 24 h. Astrocyte reaction and associated energy metabolic changes were assessed by immunostaining, gene expression, proteomics, metabolomics and extracellular flux analyses. ReN-derived astrocytes reactivity was observed by the modifications of genes and proteins linked to inflammation (cytokines, nuclear factor-kappa B (NFκB), signal transducers and activators of transcription (STATs)) and immune pathways (major histocompatibility complex (MHC) class I). Increased NFκB1, NFκB2 and STAT1 expression, together with decreased STAT3 expression, suggest an activation towards the detrimental pathway. Strong modifications of astrocyte cytoskeleton were observed, including a glial fibrillary acidic protein (GFAP) decrease. Astrogliosis was accompanied by changes in energy metabolism characterized by increased glycolysis and lactate release. Increased glycolysis is reported for the first time during human astrocyte activation. Astrocyte activation is strongly tied to energy metabolism, and a possible association between NFκB signaling and/or MHC class I pathway and glycolysis is suggested.

HMGB1 is increased in adolescents with polycystic ovary syndrome (PCOS) and decreases after treatment with myo-inositol (MYO) in combination with alpha-lipoic acid (ALA).

PCOS treatment should be based on pathophysiology. High-mobility-group-box-1 (HMGB1) was shown to increase in PCOS patients as a consequence of reduced cystic-fibrosis-transmembrane-conductance-regulator (CFTR) expression in the ovary, and was associated with insulin resistance and inflammation, both features of PCOS. Inositols and ALA derivatives could have positive effects on insulin sensitivity, reduce androgens, and improve ovulation rhythm. The aim of this study was to verify changes in HMGB1, in metabolic and endocrine parameters in adolescents with PCOS compared with controls and after treatment with a combination of MYO + ALA. Twenty-three PCOS adolescents and 21 controls matched for age and BMI were enrolled. In all subjects, metabolic and hormonal parameters were assayed. Homeostatic index (HOMA-IR) and the triglyceride/HDL-cholesterol ratio were calculated. Ovarian volumes were evaluated. Patients were treated with MYO + ALA for 6 months. HMGB1 was measured using a specific ELISA assay. HMGB1 was increased in PCOS compared with controls (19.76 ± 5.99 versus 5.65 ± 1.88 ng/ml; p < .05) and normalized after treatment (2.27 ± 0.36 ng/ml, p < .05). Treatment significantly reduced insulin (24.0 ± 4.11 versus 12.13 ± 2.13 uU/ml), HOMA-IR (3.91 ± 0.41 versus 2.42 ± 0.45), and 17-hydroxyprogesterone (1.20 ± 0.15 versus 0.78 ± 0.11 ng/ml). Cholesterol, luteinizing hormone, 17-ß-estradiol, delta 4-androstenedione, and testosterone were unchanged. Circulating HMGB1 was increased in PCOS adolescents, and treatment was effective in normalizing HMGB1.

Current treatment for polycystic ovary syndrome: focus on adolescence.

Polycystic ovary syndrome (PCOS) is the most frequent endocrine disorder in women and it is associated with an increased rate of infertility. Its etiology remains largely unknown, although both genetic and environmental factors play a role. PCOS is characterized by insulin resistance, metabolic disorders and low-grade chronic inflammation. To date, the treatment of PCOS is mainly symptomatic and aimed at reducing clinical signs of hyperandrogenism (hirsutism and acne), at improving menstrual cyclicity and at favoring ovulation. Since PCOS pathophysiology is still largely unknown, the therapeutic interventions currently in place are rarely cause-specific. In such cases, the therapy is mainly directed at improving hormonal and metabolic dysregulations typical of this condition. Diet and exercise represent the main environmental factors influencing PCOS. Thus, therapeutic lifestyle changes represent the first line of intervention, which, in combination with oral contraceptives, represent the customary treatment. Insulin resistance is becoming an increasingly studied target for therapy, most evidence stemming from the time-honored metformin use. Relatively novel strategies also include the use of thiazolidinediones and GLP1-receptor agonists. In recent years, a nutraceutical approach has been added to the therapeutic toolkit targeting insulin resistance. Indeed, emerging data support inositol and alpha-lipoic acid as alternative compounds, alone or in combination with the aforementioned strategies, with favorable effects on ovulation, insulin resistance and inflammation. Nevertheless, additional studies are required in adolescents, in order to assess the effectiveness of diet supplements in preventing negative impacts of PCOS on fertility in adult age. This review focuses on the main therapeutic options for PCOS to date.

Acute Modifications of Left Ventricular Torsional Mechanics Induced by Cardiac Resynchronization Therapy Affect Short-Term Reverse Remodeling.

BACKGROUND: Left ventricular (LV) torsion is an important aspect of cardiac mechanics and is altered in heart failure patients. Cardiac resynchronization therapy (CRT) has a positive effect on LV function, but the exact mechanisms through which it works are not completely depicted. Our aim was to investigate (1) the acute CRT effect on LV torsional mechanics in heart failure patients using 3D speckle tracking echocardiography (3DSTE) and (2) its effect on short-term LV remodeling. Methods and Results: We considered 48 patients (age 72±11 years, 35 men) who received CRT. They underwent 3DSTE during CRT-on (biventricular stimulation) vs. CRT-off (intrinsic conduction/right atrial/ventricular stimulation alone), in a random fashion. Patients were classified as CRT responders based on LV systolic volume reduction ≥15% at 6 months (final population: 31 responders, 17 non-responders). Acute CRT positively affected responders in terms of LV torsion (from 0.32±0.06°/cm CRT-off to 0.41±0.06°/cm CRT-on), but adversely affected non-responders (from 0.54±0.08°/cm CRT-off to 0.28±0.08°/cm CRT-on, interaction P=0.02). A similar trend was confirmed for apical (interaction P<0.04), but not for basal torsion (interaction P=0.351). CONCLUSIONS: CRT has a positive role in acute recovery of LV torsion (particularly in its apical component) in responders, likely modulating the improvement in LV remodeling at early follow-up.

CFTR and FOXO1 gene expression are reduced and high mobility group box 1 (HMGB1) is increased in the ovaries and serum of women with polycystic ovarian syndrome.

We previously described increased HMGB1 and reduced FOXO1 dependent on CFTR loss of function in cystic fibrosis (CF) and we showed in vitro that HMGB1 was lowered by insulin. Reduced CFTR gene expression has been described in granulosa cells (GC) from PCOS-induced rats. We aimed at studying CFTR and FOXO1 gene expression in GC, HMGB1 concentrations in serum and follicular fluids (FF), and insulin and IL-6 in FF in PCOS women. Thirty PCOS and 36 non-PCOS women (CTRL) undergoing in vitro fertilization were enrolled. CFTR and FOXO1 gene expression were downregulated in PCOS (p ≤ .05). HMGB1 was higher in PCOS both in FF (p ≤ .05) and in serum (p < .005) whereas insulin was lower, and IL-6 was unchanged with respect to controls. 17-ß estradiol was higher in PCOS than in CTRL (p ≤ .005). HMGB1 correlated negatively with insulin in FF (p ≤ .005). The increase in HMGB1 both in FF and in serum, likely reflects both low grade inflammation and insulin sensitivity. IL-6 was unchanged possibly reflecting functions other than inflammation.

Obesity, Insulin Resistance, and Colorectal Cancer: Could miRNA Dysregulation Play A Role?

Obesity is associated with insulin resistance and low-grade inflammation. Insulin resistance is a risk factor for cancer. A recent chapter in epigenetics is represented by microRNAs (miRNAs), which post-transcriptionally regulate gene expression. Dysregulated miRNA profiles have been associated with diseases including obesity and cancer. Herein we report dysregulated miRNAs in obesity both in animal models and in humans, and we also document dysregulated miRNAs in colorectal cancer (CRC), as example of an obesity-related cancer. Some of the described miRNAs are found to be similarly dysregulated both in obesity, insulin resistance (IR), and CRC. Thus, we present miRNAs as a potential molecular link between obesity and CRC onset and development, giving a new perspective on the role of miRNAs in obesity-associated cancers.

Current Knowledge on Endocrine Disrupting Chemicals (EDCs) from Animal Biology to Humans, from Pregnancy to Adulthood: Highlights from a National Italian Meeting.

Wildlife has often presented and suggested the effects of endocrine disrupting chemicals (EDCs). Animal studies have given us an important opportunity to understand the mechanisms of action of many chemicals on the endocrine system and on neurodevelopment and behaviour, and to evaluate the effects of doses, time and duration of exposure. Although results are sometimes conflicting because of confounding factors, epidemiological studies in humans suggest effects of EDCs on prenatal growth, thyroid function, glucose metabolism and obesity, puberty, fertility, and on carcinogenesis mainly through epigenetic mechanisms. This manuscript reviews the reports of a multidisciplinary national meeting on this topic.

Inflammatory Diseases and Growth: Effects on the GH-IGF Axis and on Growth Plate.

This review briefly describes the most common chronic inflammatory diseases in childhood, such as cystic fibrosis (CF), inflammatory bowel diseases (IBDs), juvenile idiopathic arthritis (JIA), and intrauterine growth restriction (IUGR) that can be considered, as such, for the changes reported in the placenta and cord blood of these subjects. Changes in growth hormone (GH) secretion, GH resistance, and changes in the insulin-like growth factor (IGF) system are described mainly in relationship with the increase in nuclear factor-κB (NF-κB) and pro-inflammatory cytokines. Changes in the growth plate are also reported as well as a potential role for microRNAs (miRNAs) and thus epigenetic changes in chronic inflammation. Many mechanisms leading to growth failure are currently known; however, it is clear that further research in the field is still warranted.

Immature platelet fraction and high-on treatment platelet reactivity with ticagrelor in patients with acute coronary syndromes.

Residual high-on treatment platelet reactivity (HRPR) has been associated with a 2-9 fold increased risk of acute ischemic events in patients with acute coronary syndromes or coronary stenting. However, the mechanism of suboptimal platelet inhibition are still poorly understood. Aim of present study was to evaluate the role of the percentage of reticulated platelets on HRPR with ticagrelor. In patients treated with ASA (100-160 mg) and ticagrelor (90 mg twice a day) platelet reactivity and the reticulated platelets fraction (immature platelets fraction, IPF) were assessed at 30-90 days after acute coronary syndrome. Aggregation was assessed by multiple-electrode aggregometry. HRPR was defined as ADP test >417 AU*min. Our population is represented by 190 patients, divided according to tertiles values of IPF (<2.5; 2.5-3.99; ≥4 %). Higher IPF was associated to a larger platelet volume and lower platelets count (p < 0.001), and inversely related with a history of previous coronary revascularization (p = 0.03). Twenty-one out of 190 (11.0 %) patients displayed HRPR. No difference in the levels of circulating IPF was found in patients with or without HRPR (p = 0.25), with no correlation between the rate of reticulated platelets and platelet reactivity at ADP test (r = -0.084, p = 0.26). In fact no association was observed between high levels of IPF and the occurrence of HRPR (adjusted OR[95 % CI] = 0.69[0.34-1,37], p = 0.28), even after correction for baseline differences. In patients treated with ticagrelor, the levels of circulating reticulated platelets assessed at 30-90 days post-ACS are not associated with platelet reactivity or the occurrence of HRPR.

Vitamin D levels and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor.

BACKGROUND: Suboptimal platelet inhibition still represents an important challenge, especially for patients undergoing percutaneous coronary interventions (PCIs). However, very few are known so far on the predictors of high-residual platelet reactivity (HRPR) despite antiplatelet strategies. Increasing attention has been paid in the last years to the role of vitamin D in atherothrombosis. Therefore, the aim of our study was to evaluate the impact of vitamin D levels on platelet function in patients treated with dual antiplatelet therapy (DAPT). Patients treated with DAPT (ASA and clopidogrel or ticagrelor) after a recent acute coronary syndrome (ACS) or elective PCI were scheduled for platelet function assessment at 30-90 days post-discharge. Platelet function was assessed by whole blood impedance aggregometry (Multiplate®-Roche Diagnostics AG), HRPR was considered for ASPI test values > 862 AU*min (for ASA) and adenosine diphosphate (ADP) test values ≥417 AU*min (for ADP-antagonists). Fasting samples were obtained for main chemistry parameters and vitamin D level assessment. Our population is represented by 503 patients, who were divided according to vitamin D quartiles (≤9.1; 9.2-14.4; 14.5-21.7; >21.7 ng/ml). Lower vitamin D levels related with age (p = 0.04), diabetic status (p = 0.05), and previous coronary surgery (p = 0.007), therapy with beta-blockers and statins (p = 0.01 and p = 0.02). Vitamin D inversely related to the levels of total cholesterol (p = 0.01), triglycerides (p < 0.001), hemoglobin (p = 0.05), and HbA1c (p < 0.001). Significantly higher platelet reactivity was observed after platelet stimulation with ADP (p = 0.01), but not with other platelet activators. The prevalence of HRPR for ASA was low (1.2%) and not conditioned by Vitamin D levels (adjusted OR[95%CI] = 1.56[0.71-3.5], p = 0.27). HRPR with ADP-antagonists was observed in 26% of patients, and the rate increased with lower vitamin D quartiles (37.3% vs 22.2% vs 24.4% vs 20.2%, p = 0.005, adjusted OR[95%CI] = 1.23[1.02-1.49], p = 0.04). An absolute increase in HRPR with lower vitamin D levels was similarly observed among patients receiving ticagrelor (adjusted OR[95% CI] = 1.40[0.95-2.06], p = 0.08), and those on clopidogrel (adjusted OR[95%CI] = 1.31[0.99-1.75], p = 0.06). Thus, lower vitamin D levels are associated with higher platelet reactivity and impaired effectiveness of ADP-antagonists, while not influencing the effectiveness of ASA. Future studies will tell whether vitamin D supplementation can reduce platelet reactivity, overcoming the phenomenon of resistance to antiplatelet agents.

From Placenta to Polycystic Ovarian Syndrome: The Role of Adipokines.

Adipokines are cytokines produced mainly by adipose tissue, besides many other tissues such as placenta, ovaries, peripheral-blood mononuclear cells, liver, muscle, kidney, heart, and bone marrow. Adipokines play a significant role in the metabolic syndrome and in cardiovascular diseases, have implications in regulating insulin sensitivity and inflammation, and have significant effects on growth and reproductive function. The objective of this review was to analyze the functions known today of adiponectin, leptin, resistin, and visfatin from placenta throughout childhood and adolescence. It is well known now that their serum concentrations during pregnancy and lactation have long-term effects beyond the fetus and newborn. With regard to puberty, adipokines are involved in the regulation of the relationship between nutritional status and normal physiology or disorders of puberty and altered gonadal function, as, for example, premature pubarche and polycystic ovarian syndrome (PCOS). Cytokines are involved in the maturation of oocytes and in the regular progression of puberty and pregnancy.

Body Mass Index and Platelet Reactivity During Dual Antiplatelet Therapy With Clopidogrel or Ticagrelor.

INTRODUCTION: Dual antiplatelet therapy (DAPT) is considered essential in clinical management of patients undergoing percutaneous coronary revascularization or acute coronary syndromes. However, the optimal platelet inhibition is not always obtained, with high residual platelet reactivity (HRPR) increasing stent thrombosis and recurrent ischemic events. Aim of this study was to investigate the impact of body mass index (BMI) on platelet reactivity in patients on DAPT. METHODS: We included patients treated with acetylsalycilic acid (ASA) (100-160 mg) and clopidogrel (75 mg) or ticagrelor (90 mg twice a day) for acute coronary syndromes or drug-eluting stent implantation. Platelet reactivity was assessed at 30-90 days postdischarge by multiple-electrode aggregometry. HRPR for adenosine diphosphate (ADP) antagonists was defined as ADP test results >417 AU*min. HRPR for ASA was considered for ASPI test >862 AU*min. RESULTS: Our population is represented by 498 patients, 308 (61.8%) were treated with clopidogrel and 190 (38.2%) with ticagrelor. Overall, higher BMI was related with younger age (P = 0.003), higher prevalence of diabetes mellitus (P < 0.001), hypercholesterolemia (P = 0.017), hypertension (P < 0.001), chronic therapy with angiotensin-receptor blockers (P = 0.019), calcium channel blockers (P = 0.003). Higher values of BMI directly related with hemoglobin (P = 0.02), triglycerides (P < 0.001), glycemia (P = 0.035), HbA1c (P < 0.001), and inversely related with high-density lipoprotein cholesterol (P = 0.01). BMI did not influence the effectiveness of ASA, whereas it was associated to a nonsignificant trend for higher platelet reactivity (r = 0.08, P = 0.08) for ADP antagonists. In fact, 111 patients (22.3%) displayed HRPR at ADP test (>417 AU*min) with no statistically significant difference according to BMI {20.3% vs. 27.1% vs. 25.7%, P = 0.28; adjusted odds ratio [OR] [95% confidence interval (CI)] = 1.19 [0.86-1.64], P = 0.30}. However, results were different when considering separately patients receiving clopidogrel or ticagrelor. In the clopidogrel-treated subgroup, significantly higher ADP-mediated aggregation values were found in patients with higher BMI (r = 0.14, P = 0.023) that emerged as an independent predictor of HRPR with clopidogrel [OR (95% CI), 1.45 (1.01-2.12), P = 0.049]. On the contrary, no impact of BMI was observed in the ticagrelor-treated subgroup for platelet reactivity (r = -0.036, P = 0.62) or the prevalence of HRPR [adjusted OR (95% CI), 0.73 (0.39-1.36), P = 0.32]. CONCLUSIONS: This study shows that among patients treated with DAPT for coronary artery disease, higher BMI is related to increased platelet reactivity and a higher prevalence of HRPR in clopidogrel-treated patients while not significantly influencing the effectiveness of ticagrelor or ASA.

Vitamin D deficiency is independently associated with the extent of coronary artery disease.

BACKGROUND: Vitamin D (25-OH D3) deficiency represents a rising social and economic problem in Western countries. Vitamin D has been recently reported to modulate inflammatory processes, endothelium and smooth muscle cell proliferation and even platelet function, thus potentially modulating atherothrombosis. Great interest has been addressed on its impact on cardiovascular outcome, with contrasting results. The aim of current study was to evaluate the relationship between 25-OH D3 and the extent of coronary artery disease (CAD) in a consecutive cohort of patients undergoing coronary angiography. MATERIALS AND METHODS: Patients undergoing elective coronary angiography were included in a cross-sectional study. Fasting samples were collected for 25-OH D3 levels assessment. Significant CAD was defined as at least 1 vessel stenosis > 50%, while severe CAD as left main and/or trivessel disease, as evaluated by quantitative coronary angiography. RESULTS: Hypovitaminosis D was observed in 70·4% of 1484 patients. Patients were divided according to vitamin D tertiles (< 9·6; 9·6-18·4; ≥ 18·4). Lower vitamin D levels were associated with age, female gender (P < 0·001), renal failure (P = 0·05), active smoking (P = 0·001), acute coronary syndrome at presentation (P < 0·001), therapy with calcium antagonists (P = 0·02) and diuretics (P < 0·001), less beta-blockers (P = 0·02) and statins (P = 0·001) use. Vitamin D was directly related to haemoglobin (P < 0·001) and inversely with platelet count (P = 0·002), total and low-density-lipoprotein cholesterol (P = 0·002 and P < 0·001) and triglycerides (P = 0·01). Vitamin D did not influence angiographic features of coronary lesions, but was associated with higher prevalence of left main or right CAD (P = 0·03). Vitamin D deficiency was significantly associated with higher prevalence of CAD (adjusted OR [95%CI] = 1·32[1·1-1·6], P = 0·004) and severe CAD (adjusted OR [95%CI] = 1·18[1-1·39], P = 0·05). CONCLUSION: Hypovitaminosis D was observed in the vast majority of patients undergoing coronary angiography. Vitamin D deficiency is significantly associated with the prevalence and extent of CAD, especially for patients with values < 10 ng/mL. Therefore, future large studies are needed to evaluate whether vitamin D supplementation may prevent CAD and its progression.

Complete pathological response to pembrolizumab in pretreated pancreatic acinar cell carcinoma.

BACKGROUND: Therapeutic approach used for pancreatic ductal adenocarcinoma is usually translated also for the rarer acinar counterpart, which shows a different mutational landscape nevertheless. While dMMR/MSI-H status is rare in the ductal histotype, it appears to be more prevalent in pancreatic acinar cell carcinoma (PACC). CASE PRESENTATION: We report the case of a patient with locally advanced MSI-H PACC in whom the treatment with the anti-PD-1 pembrolizumab, administered as third line, made possible surgical resection, achieving even an exceptional pathological complete response. CONCLUSIONS: Treatment of PACC should be tailored based on the peculiar molecular features that distinguish PACC from ductal adenocarcinoma. Evaluation of potentially therapeutically targetable alterations should be mandatory in case of PACC diagnosis.

Increased genomic instability and reshaping of tissue microenvironment underlie oncogenic properties of Arid1a mutations.

Oncogenic mutations accumulating in many chromatin-associated proteins have been identified in different tumor types. With a mutation rate from 10 to 57%, ARID1A has been widely considered a tumor suppressor gene. However, whether this role is mainly due to its transcriptional-related activities or its ability to preserve genome integrity is still a matter of intense debate. Here, we show that ARID1A is largely dispensable for preserving enhancer-dependent transcriptional regulation, being ARID1B sufficient and required to compensate for ARID1A loss. We provide in vivo evidence that ARID1A is mainly required to preserve genomic integrity in adult tissues. ARID1A loss primarily results in DNA damage accumulation, interferon type I response activation, and chronic inflammation leading to tumor formation. Our data suggest that in healthy tissues, the increased genomic instability that follows ARID1A mutations and the selective pressure imposed by the microenvironment might result in the emergence of aggressive, possibly immune-resistant, tumors.

Recurrence rates after piecemeal endoscopic mucosal resection of large colorectal laterally spreading tumors.

Background: Piecemeal endoscopic mucosal resection (pEMR) is routinely employed for large laterally spreading tumors (LSTs). Recurrence rates following pEMR are still unclear, especially when cap-assisted EMR (EMR-c) is performed. We assessed the recurrence rates and recurrence risk factors post-pEMR for large colorectal LSTs, including both wide-field EMR (WF-EMR) and EMR-c. Methods: This was a single-center, retrospective study of consecutive patients who underwent pEMR for colorectal LSTs ≥20 mm at our institution between 2012 and 2020. Patients had a post-resection follow-up period of at least 3 months. A risk factor analysis was carried out using the Cox regression model. Results: The analysis included 155 pEMR: 51 WF-EMR and 104 EMR-c, with a median lesion size of 30 (range: 20-80) mm and a median endoscopic follow up of 15 (range: 3-76) months. Overall, disease recurrence occurred in 29.0% of cases; there was no significant difference in recurrence rates between WF-EMR and EMR-c. Recurrent lesions were safely managed by endoscopic removal, and at risk analysis lesion size was the only significant risk factor for recurrence (mm; hazard ratio 1.03, 95% confidence interval 1.00-1.06, P=0.02). Conclusions: Recurrence of large colorectal LSTs after pEMR occurs in 29% of cases. This rate is mainly dependent on lesion size, and the use of a cap during pEMR has no effect on recurrence. Prospective controlled trials are needed to validate these results.

Diagnosis and Management of Cardiovascular Risk in Patients with Polycythemia Vera.

Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by aberrant myeloid lineage hematopoiesis with excessive red blood cell and pro-inflammatory cytokine production. Patients with PV present with a range of thrombotic and hemorrhagic symptoms that affect quality of life and reduce overall survival expectancy. Thrombotic events, transformation into acute myeloid leukemia, and myelofibrosis are largely responsible for the observed mortality. Treatment of PV is thus primarily focused on symptom control and survival extension through the prevention of thrombosis and leukemic transformation. Patients with PV frequently experience thrombotic events and have elevated cardiovascular risk, including hypertension, dyslipidemias, obesity, and smoking, all of which negatively affect survival. To reduce the risk of thrombotic complications, PV therapy should aim to normalize hemoglobin, hematocrit, and leukocytosis and, in addition, identify and modify cardiovascular risk factors. Herein, we review what is currently known about the associated cardiovascular risk and propose strategies for diagnosing and managing patients with PV.