Frequency and Nature of Genomic Alterations in ERBB2-Altered Urothelial Bladder Cancer.

BACKGROUND: Human epidermal growth factor-2 (HER2) overexpression is an oncogenic driver in many solid tumors, including urothelial bladder cancer (UBC). In addition, activating mutations in the ERBB2 gene have been shown to play an oncogenic role similar to ERBB2 amplification. OBJECTIVE: To describe and compare the frequency and nature of genomic alterations (GA) of ERBB2-altered (mutations, amplification) and ERBB2 wild-type UBC. PATIENTS AND METHODS: Using a hybrid capture-based comprehensive profiling assay, 9518 UBC cases were grouped by ERBB2 alteration and evaluated for all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genome-wide loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was measured by immunohistochemistry (Dako 22C3). Categorical statistical comparisons were performed using Fisher's exact tests. RESULTS: A total of 602 (6.3%) UBC cases featured ERBB2 extracellular domain short variant (SV) GA (ECDmut+), 253 (2.7%) cases featured ERBB2 kinase domain SV GA (KDmut+), 866 (9.1%) cases had ERBB2 amplification (amp+), and 7797 (81.9%) cases were ERBB2 wild-type (wt). European genetic ancestry of ECDmut+ was higher than ERBB2wt. Numerous significant associations were observed when comparing GA by group. Notably among these, CDKN2A/MTAP loss were more frequent in ERBB2wt versus ECDmut+ and amp+. ERBB3 GA were more frequent in ECDmut+ and KDmut+ than ERBB2wt. TERT GA were more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. TOP2A amplification was significantly more common in ECDmut+ and amp+ versus ERBB2wt, and TP53 SV GA were significantly higher in ERBB2 amp+ versus ERBB2wt. Mean TMB levels were significantly higher in ECDmut+, KDmut+, and amp+ than in ERBB2wt. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBEC) signature was more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. No significant differences were observed in PD-L1 status between groups, while gLOH-high status was more common in amp+ versus ERBB2wt. MSI-high status was more frequent in KDmut+ versus ERBB2wt, and in ERBB2wt than in amp+. CONCLUSIONS: We noted important differences in co-occurring GA in ERBB2-altered (ECDmut+, KDmut+, amp+) versus ERBB2wt UBC, as well as higher mean TMB and higher APOBEC mutational signature in the ERBB2-altered groups. Our results can help refine future clinical trial designs and elucidate possible response and resistance mechanisms for ERBB2-altered UBC.

Association of the Streptococcus bovis/Streptococcus equinus Complex With Colorectal Neoplasia: A Systematic Review and Meta-analysis.

Background: Invasive infection with Streptococcus bovis/Streptococcus equinus complex (SBSEC) bacteria is associated with underlying colorectal neoplasia. However, the link between intestinal or fecal colonization with SBSEC isolates or antibody responses to SBSEC members and colorectal cancer is not thoroughly investigated in the literature. Methods: We searched the PubMed, EMBASE, and Web of Science databases for case-control studies as well as retrospective or prospective cohort studies reporting an association between SBSEC bacteria and colorectal neoplasia. Results: We identified 22 studies (15 case-control and 7 cohort) that met our inclusion criteria. Among the cohort studies, patients with SBSEC bacteremia were 3.73 times more likely to have underlying colorectal cancer compared with individuals with no bacteremia (relative risk [RR], 3.73; 95% CI, 2.79-5.01), whereas the risk of underlying colorectal adenoma in patients with SBSEC bacteremia was not significantly increased (RR, 5.00; 95% CI, 0.83-30.03). In case-control studies, patients with colorectal cancer were 2.27 times more likely to have evidence of intestinal or fecal colonization with SBSEC isolates (odds ratio [OR], 2.27; 95% CI, 1.11-4.62) and immunoglobulin G (IgG) antibody responses to SBSEC antigens (OR, 2.27; 95% CI, 1.06-4.86) compared with controls. Patients with colorectal adenoma were not more likely to be colonized with SBSEC isolates compared with controls (OR, 1.12; 95% CI, 0.55-2.25). Conclusions: Apart from the well-established association of SBSEC bacteremia and underlying colorectal cancer, intestinal or fecal colonization with SBSEC isolates and IgG antibody responses to SBSEC antigens were higher in patients with colorectal cancer compared with controls. Neither bacteremia from SBSEC isolates nor colonization with SBSEC bacteria was associated with underlying colorectal adenoma.

Response and Outcomes of Maintenance Avelumab After Platinum-Based Chemotherapy (PBC) in Patients With Advanced Urothelial Carcinoma (aUC): "Real World" Experience.

BACKGROUND: Platinum-based chemotherapy (PBC) followed by avelumab switch maintenance in nonprogressors is standard first line (1L) treatment for advanced urothelial carcinoma (aUC). We describe clinical features and outcomes in a "real-world' cohort treated with avelumab maintenance for aUC. MATERIALS AND METHODS: This was a retrospective cohort study of patients (pts) who received 1L switch maintenance avelumab after no progression on PBC for aUC. We calculated progression-free survival (PFS) and overall survival (OS) from initiation of maintenance avelumab. We also described OS and PFS for specific subsets using Cox regression and observed response rate (ORR). RESULTS: A total of 108 pts with aUC from 14 sites treated with maintenance avelumab were included. There was a median of 6 weeks1-30 from end of PBC to avelumab initiation; median follow-up time from avelumab initiation was 8.8 months (1-42.7). Median [m]PFS was 9.6 months (95%CI 7.5-12.1) and estimated 1-year OS was 72.5%. CR/PR (vs. SD) to 1L PBC (HR = 0.33, 95% CI 0.13-0.87) and ECOG PS 0 (vs. ≥1), (HR = 0.15, 95% CI 0.05-0.47) were associated with longer OS. The presence of liver metastases was associated with shorter PFS (HR = 2.32, 95% CI 1.17-4.59). ORR with avelumab maintenance was 28.7% (complete response 17.6%, partial response 11.1%), 29.6% stable disease, 26.9% progressive disease as best response (14.8% best response unknown). CONCLUSIONS: Results seem relatively consistent with findings from JAVELIN Bladder100 trial and recent "real world" studies. Prior response to platinum-based chemotherapy, ECOG PS 0, and absence of liver metastases were favorable prognostic factors. Limitations include the retrospective design, lack of randomization and central scan review, and possible selection/confounding biases.

Impact of COVID-19 lockdown on smoking and vaping: systematic review and meta-analysis.

OBJECTIVES: COVID-19 and the implementation of lockdowns have impacted daily lives worldwide. This systematic review and meta-analysis aimed to investigate the impact of lockdowns on the smoking and vaping behaviours of adults during the pandemic. STUDY DESIGN: This was a systematic review and meta-analysis. METHODS: A systematic literature search was conducted up to 28 April 2022 in the following databases: PubMed, Embase and Web of Science. RESULTS: In total, 77 studies met the inclusion criteria for this review. In 34 studies, an increase in smoking behaviour was reported for the majority of participants; however, in 21 and 18 studies, 'no change' and 'decrease' in smoking were the predominant responses, respectively. The results from the meta-analysis, which examined the change in the number of cigarettes smoked per day, showed no difference between the pre- and post-lockdown periods: 0.81 weighted mean difference (95% confidence interval, -0.59 to 2.21). Regarding vaping, three of seven studies reported an increase in smoking for the majority of participants, whereas 'no change' and 'decrease' were the predominant answers in the other four studies. CONCLUSIONS: The results show that lockdowns led most participants to increase smoking/vaping, whereas a decrease or cessation of smoking/vaping was only reported in the minority of participants. Attention should be given to the non-communicable diseases that could arise as a result of the increase in smoking/vaping during lockdowns, and further research in this area is needed.

Critical evaluation and comparison of nutritional clinical practice guidelines for cancer patients.

BACKGROUND: The growing incidence of cancer globally, and the importance of nutrition support for these patients, emphasize the need for the development of nutritional clinical practice guidelines and consensus papers (CPGs) in the field. Numerous relevant CPGs have been published by several organizations worldwide. The aim of this systematic review was to compare the content of the existing CPGs and evaluate the quality of their development using the AGREE-II tool. METHODS: A systematic literature search in PubMed, Embase and Web of Science databases was conducted for the identification of relevant CPGs and consensus papers. Eligible CPGs was blindly evaluated by four appraisers according to the Appraisal of Guidelines for Research and Evaluation ΙΙ (AGREE-II) tool. RESULTS: In total 15 CPGs were identified and were evaluated. All but one set of CPGs underlined the importance of nutritional screening and assessment, whereas recommendations on nutritional interventions, supplements, management of complications and nutritional follow-up were also reported by several organizations. AGREE-II results showed that two CPGs were characterized as high, eight as moderate and five as low regarding their quality of development. CONCLUSIONS: Variety on recommendations could be observed between CPGs that should be considered when applied into clinical practice. Limitations of the existing CPGs could be the fact that they are non-specific and only a minority of them are focused to specific cancer types. Frequent updates for CPGs and inclusion of more nutritional topics should be considered for some CPGs. Improvement of the quality of the CPGs development should also be pursued in future.

Treatment Rechallenge With Immune Checkpoint Inhibitors in Advanced Urothelial Carcinoma.

OBJECTIVES: To examine patient and disease characteristics, toxicity, and clinical outcomes for patients with advanced urothelial carcinoma (aUC) who are rechallenged with immune checkpoint inhibitor (ICI)-based therapy. PATIENTS AND METHODS: In this retrospective cohort, we included patients treated with ICI for aUC after having prior ICI treatment. Endpoints included the evaluation of radiographic response and disease control rates with first and second ICI courses, outcomes based on whether there was a change in ICI class (anti-PD-1 vs. anti-PD-L1), and assessment of the reasons for ICI discontinuation. RESULTS: We identified 25 patients with aUC from 9 institutions who received 2 separate ICI courses. ORR with first ICI and second ICI were 39% and 13%, respectively. Most patients discontinued first ICI due to progression (n = 19) or treatment-related toxicity (n = 4). Thirteen patients received non-ICI treatment between the first and second ICI, and 12 patients changed ICI class (anti-PD-1 vs. anti-PD-L1) at rechallenge. Among 10 patients who changed ICI class, 8 (80%) had progressive disease as best response with second ICI, while among 12 patients re-treated with the same ICI class, only 3 (25%) had progressive disease as best response at the time of rechallenge. With second ICI, most patients discontinued treatment due to progression (n = 18) or patient preference (n = 2). CONCLUSIONS: A proportion of patients with aUC rechallenged with ICI-based regimens may achieve disease control, supporting clinical trials in that setting, especially with ICI-based combinations. Future studies are needed to validate our results and should also focus on identifying biomarkers predictive of benefit with ICI rechallenge.

Vitamin D as a chemopreventive agent in colorectal neoplasms. A systematic review and meta-analysis of randomized controlled trials.

Colorectal cancer (CRC) is the third most common cancer in both sexes and the second in terms of mortality. Apart from genetic predisposition, dietary and lifestyle factors have been implicated in the development of CRC. Several studies suggested that vitamin D (VitD) might be a promising strategy in CRC prevention, while other studies did not confirm this finding. The aim of our study was to examine the role of Vit-D supplementation in the prevention of colorectal neoplasms (CRC and polyps). We conducted a systematic search in Pubmed, Embase and Web of Science databases for Randomized Controlled Trials (RCTs) examining the incidence of colorectal neoplasms in patients taking Vit-D supplementation compared to placebo. We synthetized results using Risk Ratio along with 95% Confidence Intervals (CIs). Nine RCTs (N = 71,386) were included. Non-significant correlations were observed between Vit-D supplementation and CRC incidence (RR:1.06, p = 0.52). Similarly, non-significant associations were observed between the use of Vit-D supplements and colorectal adenoma incidence (RR:1.00, p = 0.91). Advanced adenomas (OR:1.05, p = 0.63) and serrated polyps (RR:1.03, p = 0.63) were also not significantly inversely associated with Vit-D supplementation. Our study shows that Vit-D does not seem to have a role in the chemoprevention of colorectal neoplasms. However, additional well-designed studies are needed in order to draw safe conclusions. A potentially beneficial role of Vit-D supplementation in CRC primary prevention in individuals with severe vitamin D deficiency as well in the primary prevention of early-onset CRC, requires further investigation.

Effects of different exercise programs on the cardiorespiratory reserve in HFpEF patients: a systematic review and meta-analysis.

HFpEF represents a heterogeneous syndrome with complex pathophysiological substrates and multiple clinical manifestations. Recently, much attention has been focused on cardiac rehabilitation programs for HFpEF patients, and several studies have examined the effects of exercise training on this specific population. This systematic review and meta-analysis included studies on adult patients with HFpEF and evaluated the impact of exercise on the cardiorespiratory fitness variables measured during CPET. The primary outcome was the difference in the change in the peak oxygen uptake (Δpeak VO2) between the groups. Literature search involved PubMed/MEDLINE, Cochrane/CENTRAL and Scopus databases. From an initial 5,143 literature records, we identified 18 studies fulfilling the inclusion criteria; 11 studies with 515 patients were finally included in the primary outcome analysis. Δpeak VO2 between baseline and study end was significantly higher in the groups of exercise training versus control (WMD 2.25 ml/kg/min, 95% CI 1.81-2.70). Exercise training resulted in greater change in the 6-minute walking test (6MWT) distance (WMD 2.25 m, 95% CI 1.81-2.70). Health-related quality of life (HRQoL) (WMD: -3.36, 95% CI -9.42 to 2.70, I2 = 14%, p = 0.33) and echocardiographic indices of diastolic function showed no differences between exercise and control groups at study end. In the subgroup analysis, no difference between resistance versus aerobic exercise was noted in Δpeak VO2, but high-intensity interval training showed a greater increase in peak VO2 versus aerobic exercise (WMD 1.62 ml/kg/min, 95% CI 0.96-2.29, I2 = 0%, p = 0.82). Exercise training in HFpEF results in significant improvements in peak VO2 and 6MWT distance as compared to those for controls. High-intensity interval training may offer greater enhancement of the exercise capacity of these patients than standard aerobic exercise.

Substance Use During Pregnancy: A Comparative Review of Major Guidelines.

IMPORTANCE: Substance use during pregnancy is a major health issue for both the mother and the fetus, but it also represents an important public health concern. OBJECTIVE: The aim of this review was to summarize and compare recommendations from recently published guidelines on substance use during pregnancy and especially regarding alcohol, smoking, and drug use. EVIDENCE ACQUISITION: A descriptive review of guidelines from the Royal Australian and New Zealand College of Obstetricians and Gynaecologists, the World Health Organization (WHO), the Society of Obstetricians and Gynaecologists of Canada, and the American College of Obstetricians and Gynecologists on substance use was conducted. Regarding the term "substance use," the most recently published Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition substances were used. RESULTS: All the reviewed guidelines recommend appropriate counseling and screening women regarding alcohol, smoking, and drug use during the antenatal period, while the management options vary. More specifically, the prompt management of alcohol dependence is emphasized by all the guidelines except from the Royal Australian and New Zealand College of Obstetricians and Gynaecologists, which makes no recommendation upon. The use of alcohol during breastfeeding should be avoided. Regarding smoking cessation, all guidelines recommend the use of certain psychosocial, behavioral interventions, and pharmacotherapy. All the guidelines, except the one from the WHO, suggest screening drug users for coexistent sexually transmitted infections. Brief interventions are considered beneficial, while a gradual decrease in benzodiazepines is suggested, as well as the discontinuation of marijuana and methamphetamine use. However, there is controversy regarding breastfeeding in those women as the WHO recommends in favor, whereas the Society of Obstetricians and Gynaecologists of Canada and the American College of Obstetricians and Gynecologists recommend against this practice. Finally, all the guidelines state that, following delivery, close monitoring of the neonate is needed. CONCLUSIONS: The diversity of guidelines' recommendations concerning substance use reflects the different ways of the management of pregnant women during routine antenatal care due to absence of strong evidence. More research in the areas of dispute may allow the adoption of an international consensus, in order to early detect and appropriately manage pregnant women with harmful addictions.

Vascular endothelial damage in COPD: current functional assessment methods and future perspectives.

Introduction: Cardiovascular disease is a major cause of death in chronic obstructive pulmonary disease (COPD), but the relationship between these two entities is not fully understood; smoking, inflammation, arterial stiffness and endothelial dysfunction are significant determinants. Endothelial dysfunction is not only associated with cardiovascular disease, but also with COPD severity.Areas covered: Several functional methods have been developed to evaluate endothelial function in healthy and diseased individuals; from the invasive angiography of epicardial coronary arteries and Venous-Occlusion-Plethysmography, to more modern, noninvasive approaches such as Flow-Mediated-Dilatation, Peripheral-Arterial-Tonometry and Near-Infrared-Spectroscopy, all these methods have boosted clinical research in this field. In this context, this narrative review, which included articles published in PubMed and Scopus up to 25-November-2020, summarizes available functional methods for endothelial damage assessment in COPD and discusses existing evidence on their associations with comorbidities and outcomes in this population.Expert opinion: Accumulated evidence suggests that endothelial dysfunction occurs in early stages of CΟPD and worsens with pulmonary obstruction severity and during acute exacerbations. Novel methods evaluating endothelial function offer a detailed, real-time assessment of different parameters related to vascular function and should be increasingly used to shed more light on the role of endothelial damage on cardiovascular and COPD progression.

Correction to: Giant nonfunctioning adrenal tumors: two case reports and review of the literature.

In the publication of this article [1], there is an error in the Family Name and Given Name of the authors since these were interchanged.

Giant nonfunctioning adrenal tumors: two case reports and review of the literature.

BACKGROUND: There are an estimated 1-2 cases per million per year of adrenocortical carcinoma in the USA. It represents a rare and aggressive malignancy; it is the second most aggressive endocrine malignant disease after anaplastic thyroid carcinoma. Non-secretory adrenal masses are diagnosed late due to a mass effect or metastatic disease or found incidentally (adrenal incidentalomas). CASE PRESENTATION: The first case report describes a 39-year-old Greek woman who presented to our department with complaints of repeated symptoms of flatulence and epigastric discomfort over a few months. The second case report is about a 67-year-old Greek woman who presented to our department after being evaluated for fatigue, mass effect, and epigastric discomfort. Both of them were diagnosed as having a nonfunctioning adrenocortical carcinoma and underwent open adrenalectomy. CONCLUSIONS: Approximately 60% of patients with adrenocortical carcinoma present with symptoms and signs of hormonal secretion. Our cases' adrenocortical carcinomas were not functional. Hormone secretion is not a discriminating feature between benign and malignant adrenocortical masses. The silent clinical nature of nonfunctioning adrenocortical carcinoma results in late diagnosis, while the majority of patients present with locally advanced and/or metastatic disease. Adrenocortical carcinoma is a rare endocrine tumor with a poor prognosis that can be diagnostically challenging and demands high clinical suspicion. The work-up for adrenal masses must include determination of whether the mass is functioning or nonfunctioning and whether it is benign or malignant.

Genetic Aspects of Keratoconus: A Literature Review Exploring Potential Genetic Contributions and Possible Genetic Relationships with Comorbidities.

INTRODUCTION: Keratoconus (KC) is a complex, genetically heterogeneous, multifactorial degenerative disorder that is accompanied by corneal ectasia which usually progresses asymmetrically. With an incidence of approximately 1 per 2000 and 2 cases per 100,000 population presenting annually, KC follows an autosomal recessive or dominant pattern of inheritance and is, apparently, associated with genes that interact with environmental, genetic, and/or other factors. This is an important consideration in refractive surgery in the case of familial KC, given the association of KC with other genetic disorders and the imbalance between dizygotic twins. The present review attempts to identify the genetic loci contributing to the different KC clinical presentations and relate them to the common genetically determined comorbidities associated with KC. METHODS: The PubMed, MEDLINE, Google Scholar, and GeneCards databases were screened for KC-related articles published in English between January 2006 and November 2017. Keyword combinations of "keratoconus," "risk factor(s)," "genetics," "genes," "genetic association(s)," and "cornea" were used. In total, 217 articles were retrieved and analyzed, with greater weight placed on the more recent literature. Further bibliographic research based on the 217 articles revealed another 124 relevant articles that were included in this review. Using the reviewed literature, an attempt was made to correlate genes and genetic risk factors with KC characteristics and genetically related comorbidities associated with KC based on genome-wide association studies, family-based linkage analysis, and candidate-gene approaches. RESULTS: An association matrix between known KC-related genes and KC symptoms and/or clinical signs together with an association matrix between identified KC genes and genetically related KC comorbidities/syndromes were constructed. CONCLUSION: Twenty-four genes were identified as potential contributors to KC and 49 KC-related comorbidities/syndromes were found. More than 85% of the known KC-related genes are involved in glaucoma, Down syndrome, connective tissue disorders, endothelial dystrophy, posterior polymorphous corneal dystrophy, and cataract.