TROPION-Breast01: Datopotamab deruxtecan vs chemotherapy in pre-treated inoperable or metastatic HR+/HER2- breast cancer.

Improving the prognosis for patients with metastatic HR+/HER2- breast cancer remains an unmet need. Patients with tumors that have progressed on endocrine therapy and/or are not eligible for endocrine therapy had limited treatment options beyond chemotherapy. Antibody-drug conjugates are a novel and promising treatment class in this setting. Datopotamab deruxtecan (Dato-DXd) consists of a TROP2-directed humanized IgG1 monoclonal antibody attached via a serum-stable cleavable linker to a topoisomerase I inhibitor payload. TROPION-Breast01 is an ongoing phase III study that is evaluating the efficacy and safety of Dato-DXd compared with investigator's choice of standard-of-care chemotherapy in patients with inoperable or metastatic HR+/HER2- breast cancer who have received one or two prior lines of systemic chemotherapy in the inoperable or metastatic setting. Clinical Trial Registration: NCT05104866 (ClinicalTrials.gov).

Antibody-drug conjugates are a type of drug with two parts: an antibody that directs the drug to the cancer cells and a cancer-cell killing toxic payload. By binding to cancer cells before releasing the payload, treatment is directed to the site of action so there are fewer side effects in the rest of the body. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugates made up of datopotamab (antibody) and DXd (payload) which are joined together via a stable linker. Datopotamab binds to a protein found on cancer cells called TROP2; it then goes inside and releases the DXd payload to kill the tumor cells. DXd may leak out to surrounding cancer cells and kill those as well. The TROPION-Breast01 study is comparing Dato-DXd with standard-of-care chemotherapy. Around 700 patients will take part, who have: Tumors that cannot be surgically removed. Tumors that are hormone receptor-positive and do not have HER2 overexpression. Had one or two lines of previous chemotherapy (after the tumor could not be surgically removed, or had spread). Had tumor growth despite hormonal therapy or are ineligible for hormonal therapy. Patients who meet the entry criteria will be randomly assigned to a treatment group in equal numbers to either Dato-DXd or an appropriate chemotherapy, out of four options chosen by the treating doctor. At the end of the study, researchers will look at whether the patients who receive Dato-DXd live longer without their breast cancer getting worse, compared with patients who receive chemotherapy. This study is also looking at how the treatment affects patients' quality of life.

Tips, Trends, and Truths: A Study of Psoriasis Treatment Content on TikTok.

INTRODUCTION: With more than two billion downloads since its launch, TikTok is the fastest-growing video-sharing platform in the world. Many people turn to TikTok for dermatologic medical information. However, there is limited data about psoriasis and psoriasis treatment content on this social media platform. OBJECTIVE: To compare the viewer engagement, content quality, and viewer experience of psoriasis treatment TikTok videos between physicians and non-physicians. METHODS: We searched the terms "psoriasis" and "psoriasis treatment" on TikTok. Video characteristics were collected. Content quality was evaluated using DISCERN. Viewer experience was assessed using the AVA. RESULTS: Viewer engagement did not significantly differ between physicians and non-physician content creators (0.033 plus/minus 0.005 vs 0.047 plus/minus 0.001, P=0.066). Compared to non-physicians, physicians created videos of higher quality (DISCERN: 1.76 plus/minus 0.058 vs 1.44 plus/minus 0.032, P<0.001) and of greater viewer experience (AVA: 2.55 plus/minus 0.183 vs 1.96 plus/minus 0.081, P=0.001). However, there is room for improvement in terms of creating videos of higher quality by both physicians and non-physicians. CONCLUSION: TikTok can be a powerful tool to promote health literacy and dispel misinformation. Dermatologists may consider focusing their efforts on creating comprehensive educational content and incorporating trending features to reach a wider audience. J Drugs Dermatol. 2024;23(2): doi:10.36849/JDD.7050e.

Cutaneous leiomyosarcoma: a retrospective review of 45 cases.

Primary cutaneous leiomyosarcoma (LMS) is a rare soft tissue tumour type with two subtypes, dermal and subcutaneous. As deeper tumours confer a worse prognosis, they require a more aggressive approach. Conversely, a more conservative surgical approach for dermal LMS has been suggested. Few studies have comprehensively reported both clinical surgical and histological excision margins. Therefore, we sought to provide margin recommendations based on our experience and review of the existing literature. We undertook a retrospective case-note review (1998-2019) of cutaneous LMS management to establish histological/surgical margins using pathology/electronic patient records. The diagnosis was made and classified by an experienced dermatopathologist according to the World Health Organization classification. In the dermal LMS cohort (n = 35), mean peripheral and deep histological margins were 5.4 mm (range 0.5-20) and 5.6 mm (range 0.1-14.5), respectively. The incomplete excision rate was 31% (11 of 35). There were no recurrences. In the subcutaneous LMS cohort (n = 10), mean peripheral and deep histological margins were 5.7 mm (range 0.2-14) and 1.1 mm (range 0.2-1.7), respectively. The incomplete excision rate was 40% (4 of 10). The recurrence rate was 20% (2 of 10) despite achieving histological clearance after 1 year. One lung metastasis occurred 1 year following an adequately excised primary scalp LMS. Thus, for dermal LMS we propose a clinical margin of 5-10 mm (depending on lesion size) at the initial excision or at scar re-excision following involved/close histological peripheral and/or deep margins (i.e. < 1 mm). For subcutaneous LMS, we suggest a clinical margin of 15-20 mm (depending on lesion size) to achieve a peripheral histological clearance of 10 mm and negative deep margin (i.e. > 1 mm), down to the periosteum/fascia/muscle according to anatomical site. If this is not achieved, a re-excision would be recommended. However, prospective studies are needed for optimal guidance.

Evaluating Sentiment, Engagement, and Perception of Biologics Among Patients with Psoriasis and Psoriatic Arthritis on Reddit.

BACKGROUND: Limited analyses of social media content among psoriasis (PsO) and psoriatic arthritis (PsA) patients exist. These patients may turn to social media to gain insight into treatments such as biologics. OBJECTIVES: This study aims to analyze the content, sentiment, and engagement of social media posts regarding biologics for PsO and PsA. METHODS: Posts and comments discussing biologics were extracted from publicly accessible PsO and PsA Reddit groups. Posts were assigned higher (HOT) and lower order (LOT) themes, sentiments, and engagement scores. RESULTS: Of 1141 posts extracted, 705 posts were classified under the HOT general/efficacy. Twelve lower order themes (LOTs) were identified: general advice/experience (10.2%), symptoms improved (36.6%), switching biologics (10.5%), and time to results (13.4%). 61.3% of content was of positive sentiment, 24.0% was neutral, and 14.7% was of negative sentiment. The mean sentiment score, defined as the average of all posts' sentiment scores (where negative=-1, neutral=0, and positive=1), was overall positive at 0.47, 95% CI [.41-.52]. Mean sentiment scores between LOTs were significantly different (P<0.001). Information regarding biologics on Reddit is mostly positive; however, there remains a significant number of users expressing dissatisfaction with their efficacy or with biologics in general. Many users sought anecdotal advice. CONCLUSION: These findings can help guide educational efforts to anticipate concerns and appease hesitancy regarding biologics and their efficacy. J Drugs Dermatol. 2023;22(3):306-309. doi:10.36849/JDD.7124.

No Racial Differences Found in Access to Biologics: A Population-Based Study of Psoriasis Patients in the United States.

BACKGROUND: Conflicting evidence exists regarding the role of race in access to biologics for patients with psoriasis. OBJECTIVE: To compare biologic use among adult and pediatric United States psoriasis patients of different racial backgrounds. METHODS: Population-based study of US psoriasis patients using the 2003 to 2018 Medical Expenditure Panel Survey (MEPS). RESULTS: Among 31,525,500 adults and children with psoriasis (weighted), 3,026,578 (9.6%) were on biologics. Among psoriasis patients, 27,464,864 (87.1%) self-identified as white, 2,033,802 (6.5%) self-identified as Black, 1,173,435 (3.7%) self-identified as Asian or Pacific Islander, and 853,399 (2.7%) self-identified as other races. Among those on biologics, 2,778,239 (91.8%) self-identified as white, 84,971 (2.8%) identified as Black, 89,452 (3.0%) self-identified as Asian or Pacific Islander, and 73,917 (2.4%) self-identified as other races. Multivariate logistic regression revealed no significant differences in biologic access between whites and non-whites after adjusting for sociodemographic factors including insurance status (OR for Blacks: 0.347 [0.118, 1.021], P=0.055; OR for Asians: 0.616 [0.240, 1.579], P=0.311; OR for other races: 0.850 [0.216, 3.336], P=0.814. CONCLUSION: The results of this study suggest that race alone is not independently associated with access to biologics among adult US psoriasis patients. Additional studies are necessary to evaluate factors independently associated with biologics access among adults and children with psoriasis in the US. J Drugs Dermatol. 2023;22(8):835-837. doi:10.36849/JDD.7134 Reddy R, Khan S, Yee D, et al. No racial differences found in access to biologics: a population-based study of psoriasis patients in the United States. .

Differences in accessing dermatology offices, primary care offices, and emergency departments between Hispanics and Non-Hispanic White Patients.

How Hispanic patients access dermatologic care for skin diseases is unknown. This study aims to determine if differences exist in accessing the emergency department (ED), primary care, and outpatient dermatologic offices for skin diseases between Hispanic and non-Hispanic White patients. This cross-sectional study used nationally representative data from the Medical Panel Expenditure Survey (MEPS) from 2016-2019. A total of 109,337,668 (weighted) patients with any skin disease diagnosed at an ED, primary care, or dermatology visit were identified. Hispanics comprised 13.0% and non-Hispanic Whites comprised 68.8% of this subpopulation. Overall, 94.1% of Hispanic patients attended a primary care visit for their skin complaint, 5.8% saw a dermatologist, and 0.1% attended an ED visit. Compared to non-Hispanic Whites, Hispanics were more likely to attend a primary care visit (aOR 1.865; 95%CI, 1.640-2.122) and less likely to attend an outpatient dermatology visit (aOR 0.536; 95%CI, 0.471-0.610), after adjusting for insurance status, education, income, sex, age, and comorbidities. Our study suggests that, compared to non-Hispanic Whites, Hispanic patients access primary care more frequently and outpatient dermatologic offices less frequently for their skin conditions. Language barriers, less familiarity with the healthcare system, and lack of adequate health insurance may play roles in this observation.

"I'm Off My Meds": Public Perception of Interactions Between SARS-CoV-2 Vaccines and Anti-Psoriatic Treatments Online.

IMPORTANCE: Psoriasis patients may seek information about the SARS-CoV-2 vaccine and their diagnosis from social media platforms. Analyses of social media interactions may help guide dermatologists’ educational efforts during this pandemic. OBJECTIVES: This study analyzed the content and sentiment of online social media posts about the medication interaction between SARS-CoV-2 vaccines and anti-psoriatic therapies among psoriasis patients. DESIGN: Publicly accessible Facebook and Reddit groups regarding psoriasis and psoriatic arthritis were identified. Posts uploaded between March 1, 2021, and July 31, 2021, with information about the SARS-CoV-2 vaccine and psoriasis and psoriatic arthritis, were extracted. Themes, sentiment scores, and engagement scores were assigned to each post. RESULTS: 477 posts contained content pertaining to the vaccine and psoriatic medications. 19 (4%) of the posts contain negative sentiment, 232 (48.6%) contain neutral sentiment, and 226 (47.4%) contain positive sentiment. Several themes emerged from this study. A majority of posts (32.5%) contained concerns about holding or stopping medications prior to obtaining the vaccine. Other common concerns included fear of negative reaction (21.8%) and uncertainty about the ability to generate an efficient immune response to the vaccine while on anti-psoriatic medications (19.9%). CONCLUSIONS AND RELEVANCE: Concerns identified by our content analysis should be incorporated into education efforts to address the reasons for vaccine hesitancy among patients with psoriatic diseases. These patient concerns can also help guide our strategy for implementing evidence-based recommendations on COVID-19 vaccination. J Drugs Dermatol. 2022;21(8):901-905. doi:10.36849/JDD.6853.

Biologics to breast milk: A cross-sectional study of popular eczema treatment content on TikTok.

We conducted a cross-sectional study to compare viewer engagement, content quality and viewer experience of eczema related medical content on TikTok between health care professionals and non-health care professionals. Compared to non-health care professionals, health care professionals created videos of higher quality and superior viewing experience. Viewer engagement did not differ significantly between videos made by health care professionals and non-health care professionals. Overall, content creators should focus on producing comprehensive, evidence-based videos.

Meningeal contribution to migraine pain: a magnetic resonance angiography study.

The origin of migraine pain is unknown but possibly implicates the dura mater, which is pain sensitive in proximity to the meningeal arteries. Therefore, subtle changes in vessel calibre on the head pain side could reflect activation of dural perivascular nociceptors that leads to migraine headache. To test this hypothesis, we measured circumference changes of cranial arteries in patients with cilostazol-induced unilateral migraine without aura using 3 T high resolution magnetic resonance angiography. The middle meningeal artery was of key interest, as it is the main supply of the dura mater. We also measured the superficial temporal and external carotid arteries as additional extracranial segments, and the middle cerebral, the cerebral and cavernous parts of the internal carotid (ICAcerebral and ICAcavernous), and the basilar arteries as intracranial arterial segments. Magnetic resonance angiography scans were performed at baseline, migraine onset, after sumatriptan, and ≥27 h after migraine onset. Thirty patients underwent magnetic resonance angiography scans, of which 26 patients developed unilateral attacks of migraine without aura and were included in the final analysis. Eleven patients treated their migraine with sumatriptan while the remaining 15 patients did not treat their attacks with analgesics or triptans. At migraine onset, only the middle meningeal artery exhibited greater circumference increase on the pain side (0.24 ± 0.37 mm) compared to the non-pain side (0.06 ± 0.38 mm) (P = 0.002). None of the remaining arteries revealed any pain-side specific changes in circumference (P > 0.05), but exhibited bilateral dilation. Sumatriptan constricted all extracerebral arteries (P < 0.05). In the late phase of migraine, we found sustained bilateral dilation of the middle meningeal artery. In conclusion, onset of migraine is associated with increase in middle meningeal artery circumference specific to the head pain side. Our findings suggest that vasodilation of the middle meningeal artery may be a surrogate marker for activation of dural perivascular nociceptors, indicating a meningeal site of migraine headache.10.1093/brain/awy300_video1awy300media15983750185001.

Escherichia coli Harboring mcr-1 in a Cluster of Liver Transplant Recipients: Detection through Active Surveillance and Whole-Genome Sequencing.

mcr-1, a plasmid-associated gene for colistin resistance, was first described in China in 2015, but its spread in the United States is unknown. We report detection of mcr-1-carrying Escherichia coli ST117 in a cluster of three liver transplant recipients.

CGRP, a target for preventive therapy in migraine and cluster headache: Systematic review of clinical data.

INTRODUCTION: Migraine and cluster headache are challenging to manage, with no tailored preventive medications available. Targeting the calcitonin gene-related peptide (CGRP) pathway to treat these headaches may be the first focused therapeutic option to date, with the potential for promising efficacy. METHODS: We systematically searched PubMed and clinicaltrials.gov for randomized controlled trials investigating the preventive potential of monoclonal antibodies against the CGRP pathway in the treatment of migraine and cluster headache. RESULTS: The literature search returned a total of 136 records, of which 32 were eligible for review. DISCUSSION: Clinical data from phase II and III trials of the four monoclonal antibodies targeting the CGRP pathway: Eptinezumab, erenumab, fremanezumab, and galcanezumab, collectively show a positive effect in the preventive treatment of episodic and chronic migraine. Multiple phase II and III trials are under way to further determine the efficacy and safety of this new drug class. It may be particularly important to assess the cardiovascular effects of long-term CGRP blockade. Phase III trials are also currently in progress for the preventive treatment of cluster headache. CONCLUSION: Efficacy of anti-CGRP monoclonal antibodies spells a promising future for the many patients suffering from migraine, and possibly also for the smaller but severely-affected population with cluster headache.

Investigating macrophage-mediated inflammation in migraine using ultrasmall superparamagnetic iron oxide-enhanced 3T magnetic resonance imaging.

BACKGROUND: Initiating mechanisms of migraine headache remain poorly understood and a biomarker of migraine does not exist. Inflammation pertaining to the wall of cerebral arteries and brain parenchyma has been suggested to play a role in migraine pathophysiology. OBJECTIVE: We conducted the first experimental human study to investigate macrophage-mediated inflammation as a possible biomarker of migraine. METHODS: Using ultrasmall superparamagnetic iron oxide (USPIO)-enhanced 3T magnetic resonance imaging (MRI), we investigated the presence of macrophages in cerebral artery walls and in brain parenchyma of patients with migraine without aura. We used the phosphodiesterase-3-inhibitor cilostazol as an experimental migraine trigger, and investigated both patients who received sumatriptan treatment, and patients who did not. To validate our use of USPIO-enhanced MRI, we included a preclinical mouse model with subcutaneous capsaicin injection in the trigeminal V1 area. The study is registered at ClinicalTrials.gov with the identifier NCT02549898. RESULTS: A total of 28 female patients with migraine without aura underwent a baseline MRI scan, ingested cilostazol, developed a migraine-like attack, and underwent an USPIO-enhanced MRI scan > 24 hours after intravenous administration of USPIO. Twelve patients treated their attack with 6 mg s.c. sumatriptan, while the remaining 16 patients received no migraine-specific rescue medication. The preclinical model confirmed that USPIO-enhanced MRI detects macrophage-mediated inflammation. In patients, however, migraine attacks were not associated with increased USPIO signal on the pain side of the head compared to the non-pain side. CONCLUSION: Our findings suggest that migraine without aura is not associated with macrophage-mediated inflammation specific to the head pain side.

Successive Emergence of Ceftazidime-Avibactam Resistance through Distinct Genomic Adaptations in blaKPC-2-Harboring Klebsiella pneumoniae Sequence Type 307 Isolates.

Ceftazidime-avibactam (CAZ-AVI) is a promising novel treatment for infections caused by carbapenem-resistant Enterobacteriaceae (CRE). Despite improved treatment outcomes compared to those achieved with aminoglycoside- and colistin-based regimens, the rapid evolution of CAZ-AVI resistance during treatment has previously been reported in Klebsiella pneumoniae sequence type 258 (ST258) blaKPC-3-harboring isolates. Here, we report the stepwise evolution and isolation of two phenotypically distinct CAZ-AVI-resistant Klebsiella pneumoniae isolates from a patient with pancreatitis. All susceptible (n = 3) and resistant (n = 5) isolates were of the ST307 clonal background, a rapidly emerging clone. Taking advantage of short-read Illumina and long-read Oxford Nanopore sequencing and full-length assembly of the core chromosome and plasmids, we demonstrate that CAZ-AVI resistance first occurred through a 532G → T blaKPC-2 point mutation in blaKPC-2 (D179Y protein substitution) following only 12 days of CAZ-AVI exposure. While subsequent isolates exhibited substantially decreased meropenem (MEM) MICs (≤2 µg/ml), later cultures demonstrated a second CAZ-AVI resistance phenotype with a lower CAZ-AVI MIC (12 µg/ml) but also MEM resistance (MIC > 128 µg/ml). These CAZ-AVI- and MEM-resistant isolates showed evidence of multiple genomic adaptations, mainly through insertions and deletions. This included amplification and transposition of wild-type blaKPC-2 into a novel plasmid, an IS1 insertion upstream of ompK36, and disruption of the rfb gene locus in these isolates. Our findings illustrate the potential of CAZ-AVI resistance to emerge in non-K. pneumoniae ST258 clonal backgrounds and alternative blaKPC variants. These results raise concerns about the strong selective pressures incurred by novel carbapenemase inhibitors, such as avibactam, on isolates previously considered invulnerable to CAZ-AVI resistance. There is an urgent need to further characterize non-KPC-mediated modes of carbapenem resistance and the intrinsic bacterial factors that facilitate the rapid emergence of resistance during treatment.

Reproducibility of migraine-like attacks induced by phosphodiesterase-3-inhibitor cilostazol.

Introduction The phosphodiesterase-3-inhibitor cilostazol induces migraine-like attacks in patients with migraine without aura, and may be used as a pharmacological trigger in human experimental models of migraine. However, the reproducibility of cilostazol-induced migraine-like attacks has never been investigated. Methods We performed a post-hoc analysis of clinical data from two brain-imaging studies including subjects who had received cilostazol 200 mg orally. Only subjects who developed migraine-like attacks on study day 1 were included on study day 2. After cilostazol ingestion, subjects and the investigator recorded headache intensity and characteristics once every hour on a purpose-developed questionnaire. Primary end-points included incidence and time to onset of migraine-like attacks between two separate study days. Results Thirty-four subjects completed both experimental days and were included in this study. Thirty-four out of 34 subjects (100%) developed migraine-like attacks after cilostazol ingestion on both study days 1 and 2. Time to onset of migraine was five hours (range 1-8 hours) on study day 1 and four hours (range 1-8 hours) on study day 2, p = 0.16. We found no difference in median peak headache score, median time to peak headache score, or median time to intake of rescue medication between study days 1 and 2. Conclusion A second-time administration of cilostazol reproduces migraine-like attacks in all subjects who report an attack after their first cilostazol induction. There was no difference in time to migraine onset between separate inductions. Experimental migraine provocation using cilostazol is a highly efficient and useful approach for studying the ictal phase of migraine without aura.

Pharmacotherapy for Perinatal Depression.

Perinatal depression is associated with serious risks for the mother, baby, and family. When considering treating perinatal depression with a drug indicated for the treatment of depression, the major concerns are whether the drug increases the risks of teratogenicity, pregnancy complications, poor neonatal adaptation, or neurodevelopmental disorders. Although different studies have produced different results, the majority have not shown increases in risk for selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, or the noradrenergic/dopaminergic drug bupropion. In this review we will discuss the reproductive safety data for these medications as well as monoamine oxidase inhibitors and benzodiazepines.

Migraine induction with calcitonin gene-related peptide in patients from erenumab trials.

BACKGROUND: Migraine prevention with erenumab and migraine induction by calcitonin gene-related peptide (CGRP) both carry notable individual variance. We wanted to explore a possible association between individual efficacy of anti-CGRP treatment and susceptibility to migraine induction by CGRP. METHODS: Thirteen migraine patients, previously enrolled in erenumab anti-CGRP receptor monoclonal antibody trials, received CGRP in a double-blind, placebo-controlled, randomized cross-over design to investigate their susceptibility to migraine induction. A standardized questionnaire was used to assess the efficacy of previous antibody treatment. The patients were stratified into groups of high responders and poor responders. Primary outcomes were incidence of migraine-like attacks and area under the curve of headache intensity after infusion of CGRP and placebo. All interviews and experiments were performed in laboratories at the Danish Headache Center, Copenhagen, Denmark. RESULTS: Ten high responders and three poor responders were included. CGRP induced migraine-like attacks in ten (77%) patients, whereof two were poor responders, compared to none after placebo (p = 0.002). The area under the curve for headache intensity was greater after CGRP, compared to placebo, at 0-90 min (p = 0.009), and 2-12 h (p = 0.014). The median peak headache intensity score was 5 (5-9) after CGRP, compared to 2 (0-4) after placebo (p = 0.004). CONCLUSIONS: Patients with an excellent effect of erenumab are highly susceptible to CGRP provocation. If an association is evident, CGRP provocation could prove a biomarker for predicting antibody treatment efficacy. TRIAL REGISTRATION: Retrospectively registered at clinicaltrials.gov with identifier: NCT03481400 .

Male and female sex hormones in primary headaches.

BACKGROUND: The three primary headaches, tension-type headache, migraine and cluster headache, occur in both genders, but all seem to have a sex-specific prevalence. These gender differences suggest that both male and female sex hormones could have an influence on the course of primary headaches. This review aims to summarise the most relevant and recent literature on this topic. METHODS: Two independent reviewers searched PUBMED in a systematic manner. Search strings were composed using the terms LH, FSH, progesteron*, estrogen*, DHEA*, prolactin, testosterone, androgen*, headach*, migrain*, "tension type" or cluster. A timeframe was set limiting the search to articles published in the last 20 years, after January 1st 1997. RESULTS: Migraine tends to follow a classic temporal pattern throughout a woman's life corresponding to the fluctuation of estrogen in the different reproductive stages. The estrogen withdrawal hypothesis forms the basis for most of the assumptions made on this behalf. The role of other hormones as well as the importance of sex hormones in other primary headaches is far less studied. CONCLUSION: The available literature mainly covers the role of sex hormones in migraine in women. Detailed studies especially in the elderly of both sexes and in cluster headache and tension-type headache are warranted to fully elucidate the role of these hormones in all primary headaches.