Meigs Syndrome and Elevated CA-125: Case Report and Literature Review of an Unusual Presentation Mimicking Ovarian Cancer.

Background and Objectives: Meigs syndrome is represented by a benign adnexal tumor, ascites, and hydrothorax. Even though the ovarian mass is often characterized by a fibroma-like origin, cancer antigen-125 (CA-125) serum levels could be elevated as in the development of ovarian cancer. Here, we present the case of a patient with Meigs syndrome and increased CA-125. Materials and Methods: We performed systematic research for articles including similar cases in PubMed, EMBASE, and Scopus in February 2023, adopting the string of idioms: "Meigs syndrome AND Cancer antigen 125", and following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results: Eligible records were 25. Hydrothorax was right-sided in 10 cases over 25; left-sided in two patients over 25. Concerning ascites, two patients showed more than 6 L of ascitic fluid, whereas three patients had 6 L or less. CA-125 elevation ranged from 149 IU/mL to 3803 IU/mL. Adnexal mass histotypes were: struma ovarii (12 cases), thecomas (two cases), fibrothecomas (five cases), fibromas (five cases), and one sclerosing stromal tumor (SST). Conclusions: In postmenopausal women with elevated CA-125 serum levels and an adnexal mass suspicious for malignancy at ultrasound (US), ascites and pleural effusion, surgery, and histopathological examination are necessary. MS is a diagnostic option, with an excellent prognosis after exeresis of the mass.

PD-L1 Overexpression in the Lungs of Subjects Who Died from COVID-19: Are We on the Way to Understanding the Immune System Exhaustion Induced by SARS-CoV-2?

Knowledge of the pathogenic mechanisms of severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2) is certainly a priority for the scientific community. Two main elements are involved in the biology of the most severe forms of coronavirus disease 2019 (COVID-19): the direct cytopathic effect of the virus against the host tissues, and a dysfunction of the immune system, characterized by the exhaustion of T lymphocytes. The exhaustion of T cells in COVID-19 is poorly understand, but some data could suggest a possible role of PD-1/PD-L1 axis. The aim of this study was to evaluate the possible role of PD-L1 expression in the pulmonary tissue in subjects affected by COVID-19. The presence of SARS-CoV-2 in the pulmonary tissue, and its exact location, was indagated by in situ hybridization; the expression of PD-L1 and CD8 in the same tissue was indagated by immunohistochemistry. Overall, PD-L1 resulted diffusely expressed in 70% of the cases, and an intense expression was observed in 43.5% of cases. Diffuse and intense presence of SARS-CoV-2 by in situ hybridization significantly correlated with an intense PD-L1 expression, and with expression of PD-L1 by pneumocytes. PD-L1 is overexpressed in the pulmonary tissue of subjects died from COVID-19, and mainly in subjects with a high viral load. These data suggest a possible role of PD-L1 in the immune system exhaustion at the basis of the severe forms of the disease.

ProEx C as Diagnostic Marker for Detection of Urothelial Carcinoma in Urinary Samples: A Review.

The gold standard for the detection of urothelial carcinoma is represented by urethro-cystoscopy and biopsy. Both procedures are invasive and expensive and therefore cytology is often used as first approach to investigate on a possible neoplasia, being a safe and cost-effective diagnostic modality of evaluation. Because cytology alone is not highly sensitive for detection of low grade urothelial carcinoma and recurrence of the disease, several adjunct markers and urine based tests for urothelial carcinoma have been developed, which can help in the final diagnosis. In particular, ProEx C is an immunohistochemical cocktail containing antibodies direct against topoisomerase IIα (TOP2A) and minichromosome maintenance 2 (MCM2) proteins. It proved to be a valid biomarker especially in detecting squamous intraepithelial lesions in cervical liquid-based samples and in discerning these lesions from their mimickers, as well as in ovarian, endometrial, vulvar, primary and metastatic melanomas, breast, pancreatic and renal cell carcinomas. This brief review covers the effective utility of ProEx C as adjunct tool in assessing the urothelial lesions in urine cytology, also providing prognostic and therapeutic information to help in clinical decisions.

Testicular and testicular adnexa tumors in the elderly.

Neoplasms in the testis and in the testicular adnexa of elderly patients are completely different from those observed in younger patients. Indeed, although conventional seminomas and nonseminomas are mainly observed in the age range of 20-45 years, spermatocytic seminoma, malignant Leydig tumors, and lymphomas in the testis and sarcomas in the paratesticular region are encountered in individuals older than 60 years of age. Here, we discuss the testis and paratesticular region neoplasm more commonly diagnosed in elderly men.

Aberrant expression of posterior HOX genes in well differentiated histotypes of thyroid cancers.

Molecular etiology of thyroid cancers has been widely studied, and several molecular alterations have been identified mainly associated with follicular and papillary histotypes. However, the molecular bases of the complex pathogenesis of thyroid carcinomas remain poorly understood. HOX genes regulate normal embryonic development, cell differentiation and other critical processes in eukaryotic cell life. Several studies have shown that HOX genes play a role in neoplastic transformation of several human tissues. In particular, the genes belonging to HOX paralogous group 13 seem to hold a relevant role in both tumor development and progression. We have identified a significant prognostic role of HOX D13 in pancreatic cancer and we have recently showed the strong and progressive over-expression of HOX C13 in melanoma metastases and deregulation of HOX B13 expression in bladder cancers. In this study we have investigated, by immunohistochemisty and quantitative Real Time PCR, the HOX paralogous group 13 genes/proteins expression in thyroid cancer evolution and progression, also evaluating its ability to discriminate between main histotypes. Our results showed an aberrant expression, both at gene and protein level, of all members belonging to paralogous group 13 (HOX A13, HOX B13, HOX C13 and HOX D13) in adenoma, papillary and follicular thyroid cancers samples. The data suggest a potential role of HOX paralogous group 13 genes in pathogenesis and differential diagnosis of thyroid cancers.

Critical Overview of Serous Endometrial Intraepithelial Cancer Treatment: Systematic Review of Adjuvant Options.

SEIC is a non-invasive lesion of the endometrial epithelium considered to be the precursor to uterine serous carcinoma (USC) and is just as aggressive as USC. Currently, there are no reliable data about the behavior and prognosis of SEIC; therefore, the therapeutic management approach is not clear. Method: A systematic search of the Pubmed, Scopus and Embase databases was conducted, following the recommendations in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results: Of the 296 studies that matched the search criteria, only 9 met the inclusion criteria, covering a total of 81 patients. The main disease-presenting pattern was AUB (abnormal uterine bleeding). In 31 cases, SEIC was associated with extrauterine disease. All patients underwent hysterectomy and salpingo-oophorectomy, while only 15 of the 81 patients received adjuvant treatments. In the patients receiving adjuvant therapy, the RR was 42.67%, the DFS was 35.71% and the OS was 57.13%. In patients subjected to follow-up alone, the RR was only 28.78%, the DFS was 59.1% and the OS was 66.6%. Conclusions: The presence of an extrauterine disease significantly worsens outcomes, regardless of adjuvant treatment. In cases of disease confined to the uterine mucosa alone, the prognosis is good and follow-up allows a good control of the disease; however, adjuvant therapy could further increase survival rates and reduce relapse rates.

Variable levels of spike and ORF1ab RNA in post-mortem lung samples of SARS-CoV-2-positive subjects: comparison between ISH and RT-PCR.

Post-mortem examination plays a pivotal role in understanding the pathobiology of the SARS-CoV-2; thus, the optimization of virus detection on the post-mortem formalin-fixed paraffin-embedded (FFPE) tissue is needed. Different techniques are available for the identification of the SARS-CoV-2, including reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), in situ hybridization (ISH), and electron microscopy. The main goal of this study is to compare ISH versus RT-PCR to detect SARS-CoV-2 on post-mortem lung samples of positive deceased subjects. A total of 27 samples were analyzed by RT-PCR targeting different viral RNA sequences of SARS-CoV-2, including envelope (E), nucleocapsid (N), spike (S), and open reading frame (ORF1ab) genes and ISH targeting S and Orf1ab. All 27 cases showed the N gene amplification, 22 out of 27 the E gene amplification, 26 out of 27 the S gene amplification, and only 6 the ORF1ab gene amplification. The S ISH was positive only in 12 out of 26 cases positive by RT-PCR. The S ISH positive cases with strong and diffuse staining showed a correlation with low values of the number of the amplification cycles by S RT-PCR suggesting that ISH is a sensitive assay mainly in cases carrying high levels of S RNA. In conclusion, our findings demonstrated that ISH assay has lower sensitivity to detect SARS-CoV-2 in FFPE compared to RT-PCR; however, it is able to localize the virus in the cellular context since it preserves the morphology.

Multiplex HPV RNA in situ hybridization/p16 immunohistochemistry: a novel approach to detect papillomavirus in HPV-related cancers. A novel multiplex ISH/IHC assay to detect HPV.

BACKGROUND: High-risk human papillomavirus (HR-HPV) is notoriously associated with tumor progression in a broad spectrum of malignancies. Detection of HR-HPV is clinically important in the management of HPV-related carcinomas, particularly in cervical cancer and oropharyngeal squamous cell carcinoma (OPSCC). Several methods for HPV detection are currently available including Polymerase chain reaction (PCR)-based techniques, DNA in situ hybridization (ISH), RNA ISH, and p16 immunohistochemistry (IHC). Currently, the guidelines for HPV detection in cervical carcinoma are available, while no clear consensus has not yet been reached on the gold standard for HPV testing in OPSCC. Multimodality testing could help to reliably identify patients with transcriptionally active high-risk HPV-positive. METHODS: We propose a multiplex approach carrying out HPV RNA ISH and p16 IHC on the same slide to detect simultaneously HPV E6/E7 transcripts and p16INK4a overexpression. We tested this assay in two different series one of the cervical cancers with p16-positive, as control, and the other of oropharyngeal squamous cell carcinomas with blind p16 status. RESULTS: The multiplex HPV RNA ISH /p16 IHC results in the series both of the cervical cancers and the oral-oropharyngeal cancers were fully concordant with the previous results achieved through the classic p16 IHC and HPV RNA scope carried out on two different slides. CONCLUSIONS: Our results suggesting several advantages of this technical approach, namely an easy interpretation fully in the light field, the feasibility in formalin-fixed paraffin-embedded tissue sections, complete automation and a potential wide spreadable for routine testing in several clinical laboratories.

A partial molar pregnancy associated with a fetus with intrauterine growth restriction delivered at 31 weeks: a case report.

INTRODUCTION: Molar pregnancies belong to a group of diseases classified as gestational trophoblastic diseases, which result from an altered fertilization. Partial molar pregnancy with a live fetus is a very rare condition, occurring in 0.005 to 0.01% of all pregnancies; it presents a challenging diagnosis, especially when clinical signs are almost completely absent. CASE PRESENTATION: Here we report a rare case of partial molar pregnancy in which a normal-appearing male fetus with diploid karyotype was delivered at 31 weeks gestation by a 37-year-old white woman. The pregnancy was characterized by an episode of threatened abortion in the first trimester and an ultrasonographic diagnosis of intrauterine growth restriction. Our patient did not report any suspicious symptoms for trophoblastic disease. Due to impaired umbilical artery velocimetry with an absence of the diastolic phase, she underwent an emergency caesarean section at 31 weeks and delivered an 880 g male baby. The male baby was normal without any complications at 3-month and 12-month follow-up and the mother had no evidence of recurrence after 3 and 12 months of follow-up. Pathological examination of the placenta showed changes of partial hydatidiform mole. CONCLUSION: Partial molar pregnancy with a live fetus is a very rare condition that presents a challenging diagnosis. Recognizing it is of primary importance for patient care and the placenta should always be investigated at birth, especially in a newborn with intrauterine growth restriction.

AXL Is a Novel Predictive Factor and Therapeutic Target for Radioactive Iodine Refractory Thyroid Cancer.

Papillary thyroid carcinomas (PTCs) have an excellent prognosis, but a fraction of them show aggressive behavior, becoming radioiodine (RAI)-resistant and/or metastatic. AXL (Anexelekto) is a tyrosine kinase receptor regulating viability, invasiveness and chemoresistance in various human cancers, including PTCs. Here, we analyze the role of AXL in PTC prognosis and as a marker of RAI refractoriness. Immunohistochemistry was used to assess AXL positivity in a cohort of human PTC samples. Normal and cancerous thyroid cell lines were used in vitro for signaling, survival and RAI uptake evaluations. 38.2% of human PTCs displayed high expression of AXL that positively correlated with RAI-refractoriness and disease persistence or recurrence, especially when combined with v-raf murine sarcoma viral oncogene homolog B(BRAF) V600E mutation. In human PTC samples, AXL expression correlated with V-akt murine thymoma viral oncogene homolog 1 (AKT1) and p65 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation levels. Consistently, AXL stimulation with its ligand growth arrest-specific gene 6 (GAS6) increased AKT1- and p65 NF-kB-phosphorylation and promoted survival of thyroid cancer cell lines in culture. Enforced expression or activation of AXL in normal rat thyroid cells significantly reduced the expression of the sodium/iodide symporter (NIS) and the radioiodine uptake. These data indicate that AXL expression levels could be used as predictor of RAI refractoriness and as a possible novel therapeutic target of RAI resistant PTCs.

A rare case of malignant solitary fibrous tumor in prostate with review of the literature.

BACKGROUND: Solitary fibrous tumor is an uncommon soft tissue neoplasm with intermediate biological behavior, which rarely metastasizes. Malignant solitary fibrous tumor, although not clearly defined, is rarely described in the prostate. The present case is characterized by some peculiarities if compared with previously reported cases of prostatic malignant solitary fibrous tumor. Firstly, it does not show a homogeneous morphology: part of the neoplasm (about 50%) showed the features of a conventional solitary fibrous tumor, while the remaining part showed the features of a malignant solitary fibrous tumor. In addition, the case is the first malignant solitary fibrous tumor reaching a huge diameter of 20 cm and replacing all prostatic parenchyma. Interestingly, normal prostatic parenchyma was observed on left-lobe trans-rectal needle-core biopsies, but was totally absent in surgical specimen. Since radical prostatectomy was carried out about 4 months after the biopsies, such discordant data may suggest exceedingly rapid growth of the neoplasm. CASE PRESENTATION: We report a case of a 62-year-old male, presented at medical observation for urinary retention, constipation and an enlarged prostate gland. A trans-rectal prostatic biopsy showed a low-grade spindle cell neoplasm. Histopathological examination of the prostatectomy specimen showed patternless architecture with hypocellular and hypercellular areas and hemangiopericytoma-like vessels. In some fields the neoplasm was characterized by a high mitotic index and evident cellular atypia. Immunohistochemically, neoplastic cells were positive for CD34, bcl2, CD99, STAT6 and partially for PgR. The neoplasm was diagnosed as a malignant solitary fibrous tumor. CONCLUSIONS: The differential diagnosis of spindle cells tumors arising in the prostrate is broad and includes lesions of epithelial and mesenchymal origin, primary prostatic lesions such as stromal tumors of uncertain malignant potential and stromal sarcoma, as well as anatomically ubiquitous soft tissue neoplasms. Solitary fibrous tumors should be considered in cases of prostatic tumors with a spindled morphology, but malignancy in such tumors is extremely rare in the prostate. A review of literature showed only four additional cases. Because of the unpredictable biological behavior and the possibility of recurrence, a long-term clinical and instrumental follow-up is recommended.

Aberrant Signaling through the HER2-ERK1/2 Pathway is Predictive of Reduced Disease-Free and Overall Survival in Early Stage Non-Small Cell Lung Cancer (NSCLC) Patients.

Background: Purpose of this study was to evaluate the contribution of the Extracellular-regulated protein kinase (ERK)-1/2 pathway to oncogenic signaling elicited by the tyrosine kinase receptor HER2 in Non-Small Cell Lung Cancer (NSCLC) and to assess the prognostic value of these oncoproteins in NSCLC patients. Methods: Immunohistochemistry was performed to determine expression and activation of HER2 and ERK1/2 (detected by phosphorylation of Y1248 and T202/Y204, respectively) using Tissue Micro Arrays (TMA) containing matched normal and neoplastic tissues from 132 NSCLC patients. Survival analysis was carried out using the Kaplan-Meier method. Univariate and multivariate analysis were used to evaluate the prognostic value of pERK1/2, pHER2 and a combination thereof with clinical-pathological parameters such as age, lymph node status (N), size (T), stage (TNM) and grade. Results: We found that HER2 was overexpressed in 33/120 (27%) and activated in 41/114 (36%) cases; ERK1/2 was activated in 44/102 (43%) cases. A direct association was found between pERK1/2 and pHER2 (23/41; p=0.038). In addition, patients positive for pERK1/2 and for both pHER2 and pERK1/2 showed significantly worse overall survival (OS) and disease-free survival (DFS) compared with negative patients. Univariate and multivariate analysis of patients' survival revealed that positivity for pHER2-pERK1/2 and for pERK1/2 alone were independent prognostic factors of poor survival in NSCLC patients. In particular, this association was significantly important for DFS in stage I+II patients. Conclusion: This study provides evidence that activated ERK1/2 and/or the combined activation of HER2 and ERK1/2 are good indicators of poor prognosis in NSCLC patients, not only in unselected patients but also in early stage disease.

Epithelial-mesenchymal transition in prostate cancer: an overview.

Prostate cancer is a main urological disease associated with significant morbidity and mortality. Radical prostatectomy and radiotherapy are potentially curative for localized prostate cancer, while androgen deprivation therapy is the initial systemic therapy for metastatic prostate disease. However, despite temporary response, most patients relapse and evolve into castration resistant cancer.Epithelial-mesenchymal transition (EMT) is a complex gradual process that occurs during embryonic development and/or tumor progression. During this process, cells lose their epithelial characteristics and acquire mesenchymal features. Increasing evidences indicate that EMT promotes prostate cancer metastatic progression and it is closely correlated with increased stemness and drug resistance.In this review, we discuss the main molecular events that directly or indirectly govern the EMT program in prostate cancer, in order to better define the role and the mechanisms underlying this process in prostate cancer progression and therapeutic resistance.

Micrornas in prostate cancer: an overview.

Prostate cancer is the second highest cause of cancer mortality after lung tumours. In USA it affects about 2.8 million men and the incidence increases with age in many countries. Therefore, early diagnosis is a very important step for patient clinical evaluation and for a selective and efficient therapy. The study of miRNAs' functions and molecular mechanisms has brought new knowledge in biological processes of cancer. In prostate cancer there is a deregulation of several miRNAs that may function as tumour suppressors or oncogenes. The aim of this review is to analyze the progress made to our understanding of the role of miRNA dysregulation in prostate cancer tumourigenesis.

PATZ1 expression correlates positively with BAX and negatively with BCL6 and survival in human diffuse large B cell lymphomas.

Non-Hodgkin lymphomas (NHLs) include a heterogeneous group of diseases, which differ in both cellular origin and clinical behavior. Among the aggressive malignancies of this group, the diffuse large B-cell lymphomas (DLBCLs) are the most frequently observed. They are themselves clinically and molecularly heterogeneous and have been further sub-divided in three sub-types according to different cell of origin, mechanisms of oncogenesis and clinical outcome. Among them, the germinal center B-cell-like (GCB) derives from the germinal center and expresses the BCL6 oncogene. We have previously shown that Patz1-knockout mice develop B-cell neoplasias, suggesting a tumor suppressor role for PATZ1 in human NHLs. Here, by immunohistochemical analysis of a tissue-microarray including 170 NHLs, we found that PATZ1 nuclear expression is down-regulated in follicular lymphomas and DLBCLs. Moreover, consistent with our previous results showing a PATZ1-dependent regulation of BCL6 and BAX transcription, we show that low PATZ1 nuclear expression significantly correlates with high BCL6 expression, mainly in DLBCLs, and with low BAX expression, also considering separately follicular lymphomas and DLBCLs. Finally, by analyzing overall and progression-free survival in DLBCL patients that underwent rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, low levels of PATZ1 were significantly associated to a worst outcome and demonstrated an independent prognostic factor in multivariate analysis, including known prognostic factors of DLBCL, IPI score and cell of origin (GCB/non-GCB). Therefore, we propose PATZ1 as a new prognostic marker of DLBCLs, which may act as a tumor suppressor by enhancing apoptosis through inhibiting and enhancing transcription of BCL6 and BAX, respectively.

Role of DNA repair machinery and p53 in the testicular germ cell cancer: a review.

Notwithstanding the peculiar sensitivity to cisplatin-based treatment, resulting in a very high percentage of cures even in advanced stages of the disease, still we do not know the biological mechanisms that make Testicular Germ Cell Tumor (TGCT) "unique" in the oncology scene. p53 and MDM2 seem to play a pivotal role, according to several in vitro observations, but no correlation has been found between their mutational or expression status in tissue samples and patients clinical outcome. Furthermore, other players seem to be on stage: DNA Damage Repair Machinery (DDR) , especially Homologous Recombination (HR) proteins, above all Ataxia Telangiectasia Mutated (ATM), cooperates with p53 in response to DNA damage, activating apoptotic cascade and contributing to cell "fate". Homologous Recombination deficiency has been assumed to be a Germ Cell Tumor characteristic underlying platinum-sensitivity, whereby Poly(ADP-ribose) polymerase (PARP), an enzyme involved in HR DNA repair, is an intriguing target: PARP inhibitors have already entered in clinical practice of other malignancies and trials are recruiting TGCT patients in order to validate their role in this disease. This paper aims to summarize evidence, trying to outline an overview of DDR implications not only in TGCT curability, but also in resistance to chemotherapy.

The stress hormone norepinephrine increases migration of prostate cancer cells in vitro and in vivo.

The metastatic process is the most serious cause of cancer death. Norepinephrine, secreted in chronic stress conditions, stimulates the motility of breast and colon cells through ß-adrenergic receptor. On these bases, we examined its possible role in metastasis formation and development in vitro and in vivo. Treatments with norepinephrine (ß2-adrenoreceptor agonist) in mice xenografted with human DU145 prostate cancer cells increased the metastatic potential of these cells. Specifically, we showed that treatment of mice with norepinephrine induced a significant increase of the migratory activity of cancer cells in a concentration-dependent manner and that this process was blocked by propanolol (ß-adrenergic antagonist). Mice treated with norepinephrine, displayed an increased number of metastatic foci of DU145 cells in inguinal lymph nodes and also showed an increased expression of MMP2 and MMP9 in tumor samples compared to controls. Moreover, we demonstrated that propanolol induced in norepinephrine treated DU145 cells a E-cadherin finger-like membrane protrusions driven by vimentin remodeling. Altogether these data suggest that ß2-AR plays an important role in prostate cancer metastasis formation and that the treatment with antagonist propanolol, could represents an interesting tool to control this process in cells overexpressing ß2AR.

Intratumor Heterogeneity of ALK-Rearrangements and Homogeneity of EGFR-Mutations in Mixed Lung Adenocarcinoma.

BACKGROUND: Non Small Cell Lung Cancer is a highly heterogeneous tumor. Histologic intratumor heterogeneity could be 'major', characterized by a single tumor showing two different histologic types, and 'minor', due to at least 2 different growth patterns in the same tumor. Therefore, a morphological heterogeneity could reflect an intratumor molecular heterogeneity. To date, few data are reported in literature about molecular features of the mixed adenocarcinoma. The aim of our study was to assess EGFR-mutations and ALK-rearrangements in different intratumor subtypes and/or growth patterns in a series of mixed adenocarcinomas and adenosquamous carcinomas. METHODS: 590 Non Small Cell Lung Carcinomas tumor samples were revised in order to select mixed adenocarcinomas with available tumor components. Finally, only 105 mixed adenocarcinomas and 17 adenosquamous carcinomas were included in the study for further analyses. Two TMAs were built selecting the different intratumor histotypes. ALK-rearrangements were detected through FISH and IHC, and EGFR-mutations were detected through IHC and confirmed by RT-PCR. RESULTS: 10/122 cases were ALK-rearranged and 7 from those 10 showing an intratumor heterogeneity of the rearrangements. 12/122 cases were EGFR-mutated, uniformly expressing the EGFR-mutated protein in all histologic components. CONCLUSION: Our data suggests that EGFR-mutations is generally homogeneously expressed. On the contrary, ALK-rearrangement showed an intratumor heterogeneity in both mixed adenocarcinomas and adenosquamous carcinomas. The intratumor heterogeneity of ALK-rearrangements could lead to a possible impact on the therapeutic responses and the disease outcomes.