Category: 8. Health

Your mouth is a magician. Bite the inside of your cheek, and the wound may vanish without a trace in a couple of days. A preclinical study co-led by Cedars-Sinai, Stanford Medicine and the University of California, San Francisco (UCSF), has discovered one secret of this disappearing act. The findings, if confirmed in humans, could one day lead to treatments that enable rapid, scarless recovery from skin wounds on other parts of the body.

The study was published in the peer-reviewed journal Science Translational Medicine.

Our research began with two questions: Why does your mouth heal so much better than your skin? And if we figure that out, can we use that information therapeutically?”

Ophir Klein MD, PhD, executive vice dean of Children’s Health at Cedars-Sinai, executive director of Cedars-Sinai Guerin Children’s, the David and Meredith Kaplan Distinguished Chair in Children’s Health and co-corresponding author of the study

The need for therapies is clear. Wounds to the lining of the mouth typically disappear in one to three days. But skin wounds may take nearly three times as long to heal and can leave unsightly scars.

“Unfortunately, current treatments do not adequately resolve or prevent scarring because we do not fully understand the mechanism,” Klein said. “Our research helps fill in that knowledge gap.”

In the study, investigators analyzed tissue samples from the lining of the mouth, known as the oral mucosa, and the facial skin of laboratory mice. In the oral mucosa, they found a signaling pathway between cells, involving a protein called GAS6 and an enzyme called AXL, which blocks a different cellular pathway, known as FAK, that promotes scarring.

When the investigators inhibited the AXL enzyme in the laboratory mice, the oral mucosa wounds’ healing worsened, making them more like skin wounds. When AXL was stimulated in the skin wounds, they healed much like oral mucosa wounds, regenerating tissue more efficiently.

“This data shows that the GAS6-AXL pathway is potentially important for scarless healing in the mouth and that manipulating it may help reduce skin scars as well,” Klein said.

The next steps are to further determine how these preclinical findings apply to humans and to develop therapies to improve healing of skin wounds, according to Michael Longaker, MD, the Dean P. and Louise Mitchell Professor in the School of Medicine at Stanford University, and the study’s co-corresponding author.

“Further clinical studies should be performed to assess the nature of the relationship between AXL and scarring in humans,” Longaker said.

Microplastics are particles ranging from 1 micrometer to 5 millimeters in diameter, and nanoplastics, which are even smaller, are found in virtually every environment on Earth, from mountain peaks to ocean depths, and from the smallest animals in the food chain to human brain cells.

These particles can originate from the breakdown of larger plastic items or be intentionally manufactured for use in products, such as cosmetics, synthetic fabrics, and pharmaceuticals. Recent studies suggest that the human brain may contain up to a teaspoon of microplastics and nanoplastics, with the tiniest fragments primarily composed of polyethylene, the same material commonly used in plastic bags and food packaging.

These particles have been detected in areas such as the walls of blood vessels in the brain and within immune cells. However, it remains unclear whether microplastics contribute to the progression of neurological diseases or whether these conditions render the brain more susceptible to particle infiltration. In animal studies involving fish and rodents, prolonged exposure to nanoplastics has been linked to memory impairment, brain inflammation, and alterations in synaptic protein levels.

Beyond the brain, microplastics have been found in human feces, arterial plaques, and even the placenta. A study published in The New England Journal of Medicine linked the presence of microplastics in the arteries to a heightened risk for heart attack, stroke, and overall mortality.

Therapeutic Apheresis

According to a preliminary study published in Brain Medicine by researchers at Technische Universität Dresden in Dresden, Germany, therapeutic apheresis, a medical procedure that filters tiny particles from the blood, may help remove microplastics from the human body. The technique can capture particles as small as 200 nanometers, which is approximately 5000 times smaller than a millimeter.

In this study, the researchers evaluated the procedure in patients with myalgic encephalomyelitis, also known as chronic fatigue syndrome. They analyzed the waste fluid discarded during apheresis using a specialized infrared spectroscopy technique.

The analysis detected substances that matched the chemical signatures of polyamide and polyurethane, two common types of industrial plastics. This suggests that microplastics may have been successfully removed from the blood of patients during the procedure.

Notably, this study did not measure the total amount of microplastics removed or compare their levels in patients before and after apheresis. What has been demonstrated so far is the presence of microplastics in the waste material discarded by the device — an observation that suggests, but does not yet confirm, the effective removal of these substances from the human body.

Researchers have cautioned that the detected materials may reflect chemical structures common to proteins, meaning that further analysis is required to verify the exact nature of the removed particles. Nonetheless, the findings offer hope to researchers seeking to address the growing accumulation of microplastics in the human body.

The authors recommended conducting studies with larger groups and quantitative analyses comparing the levels of microplastics in the blood before and after the procedures. The authors concluded that “such analyses will help determine particle removal from blood and tissues and assess correlations with symptom improvement in conditions like myalgia encephalomyelitis/chronic fatigue syndrome.”

Alternative Approaches

Currently, evidence that microplastics are effectively removed from the human body after ingestion is limited.

A 2011 study examined bisphenol A (BPA) levels in blood, sweat, and urine samples from 20 individuals. In 16 cases, BPA appeared only in sweat, suggesting that induced perspiration may help eliminate certain compounds from the body. However, more studies are needed to assess its long-term safety and efficacy.

“That is why we focus on reducing exposure to microplastics in the first place,” said Nicholas Fabiano, MD, a psychiatry resident at the University of Ottawa, Ottawa, Ontario, Canada, and co-author of a related article in Brain Medicine.

The challenge of this research began with tracking the effects of microplastic particles. “From a clinical perspective, it is very difficult to establish a direct link between exposure to microplastics and adverse health outcomes,” said Fabiano.

To address this, he advocated the creation of new tools to measure dietary risks, such as a dietary microplastic index. “We propose the development of a Dietary Microplastic Index that could be integrated with existing dietary risk assessment tools to estimate microplastic exposure based on the types of food consumed,” he said.

This story was translated from Medscape’s Portuguese edition. 

As brain tumors grow, they must do one of two things: push against the brain or use finger-like extensions to invade and destroy surrounding tissue.

Previous research found tumors that push – or put mechanical force on the brain – cause more neurological dysfunction than tumors that destroy tissue. But what else can these different tactics of tumor growth tell us?

Now, the same team of researchers from the University of Notre Dame, Harvard Medical School/Massachusetts General Hospital, and Boston University has developed a technique for measuring a brain tumor’s mechanical force and a new model to estimate how much brain tissue a patient has lost. Published in Clinical Cancer Research, the study explains how these measurements may help inform patient care and be adopted into surgeons’ daily workflow.

During brain tumor removal surgery, neurosurgeons take a slice of the tumor, put it on a slide and send it to a pathologist in real-time to confirm what type of tumor it is. Tumors that originally arise in the brain, like glioblastoma, are prescribed different treatments than tumors that metastasize to the brain from other organs like lung or breast, so these differences inform post-surgical care. By adding a two-minute step to a surgeon’s procedure, we were able to distinguish between a glioblastoma tumor versus a metastatic tumor based on mechanical force alone.” 

Meenal Datta, assistant professor of aerospace and mechanical engineering at Notre Dame and co-lead author of the study

Datta and collaborators collected data from 30 patients’ preoperative MRIs and their craniotomies, which include exposing the brain and using Brainlab neuronavigation technology. This technology provides surgeons with real-time, 3D visualization during brain surgeries and is considered commonly available for neurological procedures. Neurosurgeons can use this technique to measure the bulge caused by brain swelling from the tumor’s mechanical forces before the tumor is resected.

Then this patient data was used to determine whether brain tissue was displaced by a tumor’s mechanical force or replaced by a tumor. The researchers found that when there is more mechanical force on the brain (displacement), the swelling will be more substantial. But when a tumor invades and destroys surrounding tissue (replacement), the swelling will be less significant.

The researchers created computational models based on a point system of measurements and biomechanical modeling that can be employed by doctors to measure a patient’s brain bulge, to determine the mechanical force that was being exerted by the tumor, and to determine the amount of brain tissue lost in each patient.

Funded by the National Institutes of Health, National Science Foundation and various cancer research foundations, this study is among the first to show how mechanics can distinguish between tumor types.

“Knowing the mechanical force of a tumor can be useful to a clinician because it could inform patient strategies to alleviate symptoms. Sometimes patients receive steroids to reduce brain swelling, or antipsychotic agents to counter neurological effects of tumors,” said Datta, an affiliate of Notre Dame’s Harper Cancer Research Institute. Datta recently showed that even affordable and widely used blood pressure medications can counter these effects. “We’re hoping this measurement becomes even more relevant and that it can help predict outcomes of chemotherapy and immunotherapy.”

To get a better idea of what else mechanical force could indicate, the research team used animal modeling of three different brain tumors: breast cancer metastasis to the brain, glioblastoma and childhood ependymoma.

In the breast cancer metastasis tumor, researchers used a form of chemotherapy that is known to work in reducing metastasis brain tumor size. While waiting for the tumor to respond to the chemotherapy, the team found that a reduction in mechanical force changed before the tumor size was shown to change in imaging.

“In this model, we showed that mechanical force is a more sensitive readout of chemotherapy response than tumor size,” Datta said. “Mechanics are sort of disease-agnostic in that they can matter regardless of what tumor you are looking at.”

Datta hopes that doctors employ the patient models from the study to continue to grow the field’s understanding of how mechanical force can improve patient care management.

In addition to Datta, co-lead authors include Hadi T. Nia at Boston University, Ashwin S. Kumar at Massachusetts General Hospital and Harvard Medical School, and Saeed Siri at Notre Dame. Other collaborators include Gino B. Ferraro, Sampurna Chatterjee, Jeffrey M. McHugh, Patrick R. Ng, Timothy R. West, Otto Rapalino, Bryan D. Choi, Brian V. Nahed, Lance L. Munn and Rakesh K. Jain, all at Massachusetts General Hospital and Harvard Medical School.

Datta is also affiliated with Notre Dame’s Eck Institute for Global Health, the Berthiaume Institute for Precision Health, NDnano, the Warren Center for Drug Discovery, the Lucy Family Institute for Data & Society and the Boler-Parseghian Center for Rare Diseases. She is also a concurrent faculty member in the Department of Chemical and Biomolecular Engineering and a faculty adviser for Notre Dame’s graduate programs in bioengineering and materials science and engineering.

CHENNAI: Dr. Danielle Beckman is a neuroscientist whose passion for studying the brain is helping to reveal how viral infections—like COVID-19—can affect brain health and possibly lead to long-term neurological conditions such as Alzheimer’s disease.

Originally from Rio de Janeiro, Brazil, Dr. Beckman dreamed of being a writer. But after taking a college physiology course, she became fascinated with the brain. Her interest turned personal when her grandmother developed dementia, pushing her to understand what happens inside the brain during these conditions. Working at UC Davis under expert guidance, Dr. Beckman and her team created new monkey models that mimic how viruses interact with the human brain.

A new study published in Genomic Press Brain Medicine reveals that these models have shown viruses like SARS-CoV-2 (the virus behind COVID-19) can reach brain cells quickly—within just seven days—and cause inflammation, a key contributor to memory problems and brain fog.

This is different from other viruses like HIV, which affect the brain more slowly.

Dr Beckman’s findings help explain why some people experience memory issues or “brain fog” after recovering from viral infections like COVID-19. Using advanced microscopy (a way to take detailed pictures of brain cells), Dr. Beckman has identified how viruses damage brain regions related to memory and thinking.

Long COVID

Dr. Beckman is also active in the Long COVID community, supporting people who are still sick months after infection. She hopes her work will lead to real treatments, especially since there are currently no approved therapies for Long COVID-related brain symptoms.

Alzheimer’s & Beyond

In addition to studying COVID-19, her team is working on better ways to study Alzheimer’s disease. They’ve created new monkey models that more closely reflect how the disease develops in humans—something rodents (like mice) can’t do as well. These models are helping scientists test new treatments more effectively.

While the ultimate goal of this research is to find ways to prevent or reduce brain damage caused by viruses—both in conditions like Long COVID and in more traditional neurodegenerative diseases like Alzheimer’s, it is also laying the foundation for future treatments that could help millions around the world.

Introduction

NME is a rare disorder associated with multiple diseases, including glucagonoma, chronic pancreatitis, nutritional deficiency, liver diseases, and inflammatory bowel disease. About 70% of cases of glucagonoma may present with NME, therefore NME is an important visual clue for the diagnosis, enabling timely intervention.

Glucagonoma is an unusual neuroendocrine tumor, derives from the pancreatic alpha cells with an estimated incidence of 1 in 20 million,¹ most commonly affecting people in their 50s.² The main manifestations are weight loss, NME, diabetes, diarrhea, anemia, and neuropsychiatric symptoms. NME is a crucial characteristic of glucagonoma. However, many primary dermatologists lack sufficient knowledge about the disorder, leading to potential misdiagnosis and missed diagnosis. Consequently, we report a case of typical NME combined with glucagonoma diagnosed in 2024 at Dermatology Hospital of Southern Medical University, designed to strengthen the diagnosis and differentiation ability of dermatologists.

Case Presentation

The patient was a 41-year-old male who presented with erythema with erosions on both lower limbs, accompanied by malnutrition and mild itching for the past three years. The patient was diagnosed with “eczema” in the local hospital. He had been treated with topical corticosteroids for years with improvement but frequently recurred. One month ago, the lesions gradually spread all over the body, with crusted papules and polycyclic plaques with a map-like margin mainly involving the face, groin, buttocks, and extremities. And his tongue appeared beefy red and fissuring (Figure 1). No nail abnormality was found.

Figure 1 Clinical appearance. (a) Scattered erythematous seborrheic plaques on the face. (b) Bright red, swollen tongue; multiple fissures; beefy tongue appearance. (c) Well-defined erythema with raised borders and yellow crusting on both inguinal areas and scrotum. (d and e) Multiple erythema and erosion on the buttocks and knees. (f) Well-defined erythema with raised borders and yellow crusting on both ankles.

Laboratory analysis found a serum glucagon level of more than 128 pmol/L (normal range, 2 to 18 pmol/L). Anti-bp180 and anti-bp230, cortisol levels were negative. A skin biopsy was performed and showed parakeratosis, inflammatory crust, spongiosis, localized necrosis in the upper epidermis, lymphocytes infiltrating peri-follicular and peri-vascular areas, and eosinophilic infiltration (Figure 2). A contrast-enhanced abdominal computed tomographic scan revealed an enhancing pancreatic body tail mass and liver metastases (Figure 3).

Figure 2 Histological findings of plaque on the left thigh. Parakeratosis, spongiosis, localized necrosis in the upper epidermis. (HE, x 400).

Figure 3 Enhanced abnormal computed tomography scan. Showing a pancreatic body tail mass (right arrow) and intrahepatic mass (left arrow), confirming glucagonoma.

Diagnostic Evaluation

The clinical presentation was characteristic of NME, confirmed by histopathological examination of skin biopsy. In accordance with the known correlation between NME and glucagonoma, serum glucagon levels were found to be significantly elevated. Subsequent abdominal CT demonstrated a pancreatic neuroendocrine tumor, establishing the definitive diagnosis of glucagonoma. Therefore, the diagnosis of NME combined with glucagonoma was made.

Treatment with microelements such as zinc, Vitamin B, folic acid, antihistamines, and topical corticosteroids. The rash reduced slightly. However, the patient refused surgical treatment for financial reasons.

Discussion

Glucagonoma is a neuroendocrine tumor characterized by excessive proliferation of α-cells in the pancreas, with a higher prevalence in women than men. The tumor typically grows slowly and can metastasize. Due to the excessive secretion, glucagonoma syndrome occurs, which may present with NME, weight loss, diabetes, diarrhea, anemia, and neuropsychiatric symptoms.³ NME manifests as scaly, erosive, ring-shaped erythema with the formation of pustules and large blisters. Other manifestations may include nail dystrophy, cheilitis, and stomatitis.

Given the rarity of NME, reports on the condition are few both nationally and internationally, and a standardized diagnostic criterion has not yet been made. In 2018, Xuechen Cao and Yan Lu reviewed and summarized previous cases and proposed diagnostic criteria for glucagonoma.⁴ The primary diagnostic criteria(Table-1) include (1) Imaging revealing a pancreatic mass, (2) Elevated plasma glucagon levels (>1000 ng/L), (3) Typical NME manifestations, (4) A history of multiple endocrine neoplasia. Secondary criteria include (1) New-onset diabetes (fasting plasma glucose, oral glucose tolerance test), (2) low serum zinc levels and hypoaminoacidemia, (3) Unexplained weight loss and diarrhea, (4) Cheilitis or glossitis. In this case, the patient met the primary criteria of (1), (2), and (3), as well as the secondary criterion of (4), confirming the diagnosis of NME associated with glucagonoma.

Table 1 the Diagnostic Criteria and Differential Diagnosis

Given its rarity and prolonged clinical course, NME is frequently misdiagnosed as eczema. In such cases, dermatologists should maintain a high clinical suspicion for associated systemic diseases. Several conditions can present with NME-like skin rashes, including Acrodermatitis Enteropathica (AE), pemphigus erythematosus(PE), drug eruption, essential fatty acid deficiency, vitamin deficiency-related dermatitis, and pseudoglucagonoma syndrome.

AE: it is a rare, recessively inherited disorder associated with zinc metabolism abnormalities, typically presenting in infancy with symptoms such as eczema-like dermatitis, crusting, bullae, and pustules, commonly affecting the extremities and perioral areas.⁵ Additional symptoms include hair loss, diarrhea, stomatitis, photophobia, nail dystrophy, abnormal hair texture, growth retardation, and emotional disorders. Especially common in artificially fed infants, with few in adulthood.⁶ The serum zinc level is always low.⁷

PE: the lesions appear as erythematous patches, often found on the face, neck, chest, and other areas, and may have an irregular shape with unclear borders. It may also present in a linear or ring-shaped pattern, with associated vesicles and bullae. Mucosal involvement, such as oral ulcers, throat pain, and ocular inflammation, may also occur. The disease progresses rapidly, with vesicles easily rupturing to form ulcers, and lesions may spread to adjacent skin, occasionally accompanied by secondary infections. Hematoxylin-eosin stain (HE) typically shows superficial epidermal acantholysis, usually located in the granular layer or upper epidermis. Spongiosis and dermal eosinophilic infiltration can be observed, and DIF typically reveals antibodies between epidermal keratinocytes as well as scattered granular deposits of antibodies along the basement membrane zone (BMZ).⁸

Drug Eruption: it manifests in various clinical forms, with severe reactions presenting as generalized erythema, vesicles, and erosion. Drug eruption usually has a clear history of drug exposure before the onset of the rash, typically resulting from a non-anticipated inflammatory response affecting the skin and/or mucous membranes as a result of drugs entering the body through oral ingestion, inhalation, injection, suppositories, or topical absorption.² It often shows a clear response to corticosteroid therapy.

The pathogenesis of NME remains unclear. Hyperglucagonemia is believed to play a significant role, because excessive glucagon secretion induces amino acid metabolic dysregulation, culminating in hypoaminoacidemia and consequent impairment of epidermal protein synthesis. And surgical removal of glucagonomas or somatostatin analogs can control the skin rash.^6,9 Additionally, hypoaminoacidemia, micronutrient depletion, and deficiencies in essential fatty acids and zinc should also be considered, as nutritional support and topical zinc therapy have been used to improve symptoms.¹⁰ Surgical resection is considered the only curative treatment.¹¹ If left untreated, glucagonomas may metastasize to distant organs such as the liver and lungs, leading to progressive clinical deterioration and ultimately life-threatening complications. Surgical options include simple excision (for tumors <2 cm) with regional lymphadenectomy, pancreaticoduodenectomy with regional lymphadenectomy, distal pancreatectomy, and splenectomy. However, over half of glucagonomas are metastatic at diagnosis, with liver metastasis being the most common.¹² Liver transplantation is considered a potential treatment for patients with liver metastasis. Transarterial chemoembolization (TACE), radiofrequency ablation, and surgery combined may offer advantages in resecting isolated metastatic tumors. Pharmacological treatments for glucagonoma include chemotherapy, somatostatin analogs, and targeted molecular therapies.¹³ Molecular targeted therapy: Agents such as sunitinib and everolimus inhibit specific molecular aberrations within tumors, thereby significantly prolonging progression-free survival (PFS).¹⁴

Conclusion

NME mainly presents a chronic course, but the recurrent rash seriously affects the patient’s quality of life. The lesions in our case are characterized by generalized erythema with erosions, which are easily misdiagnosed as pemphigus, eczema, and drug eruption, highlighting the importance of precise imaging to exclude pancreatic tumors, when facing similar conditions. Since NME might be the only clue for the early detection of this tumor, it is very important to correctly diagnose. This requires collaborative efforts from dermatologists, endocrinologists, gastroenterologists, and oncologists. This interdisciplinary approach is essential for the timely diagnosis and management of this rare condition. All in all, this case underscores the importance of recognizing NME as a dermatologic marker for systemic malignancies, necessitating collaborative care for timely diagnosis and treatment.

Ethics Statement

The publications of images were included with the patient’s consent.

Consent Statement

The patient had given written informed consent for the publication of his clinical details. Institutional approval is not required for this case study.

Acknowledgments

The authors would like to thank the patient for participation in this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This work was supported by The “Set Sail” Program for Young PhD Researchers in Basic and Applied Medical Research (SL2023A04J02432).

Disclosure

The authors report no conflicts of interest in this work.

References

1. He S, Zeng W, Geng S, Jia J. Glucagonoma syndrome with atypical necrolytic migratory erythema. Indian J Dermatol Venereol Leprol. 2021;87(1):49–53. doi:10.4103/ijdvl.IJDVL_588_18

2. Yang WJ, Hu HH, Guo H, Li JH. Generalized migratory erythema in an elderly woman Necrolytic migratory erythema. J Dtsch Dermatol Ges. 2022;20(2):231–234. doi:10.1111/ddg.14664

3. Liu JW, Qian YT, Ma DL. Necrolytic migratory erythema. JAMA Dermatol. 2019;155(10):1180. doi:10.1001/jamadermatol.2019.1658

4. Cao X, Yan L. 坏死松解性游走性红斑临床研究进展. 中华医学杂志. 2018;98(33):2694–2696. doi:10.3760/cma.j.issn.0376-2491.2018.33.019

5. Maverakis E, Fung MA, Lynch PJ, et al. Acrodermatitis enteropathica and an overview of zinc metabolism. J Am Acad Dermatol. 2007;56(1):116–124. doi:10.1016/j.jaad.2006.08.015

6. van Beek AP, de Haas ER, van Vloten WA, Lips CJ, Roijers JF, Canninga-van Dijk MR. The glucagonoma syndrome and necrolytic migratory erythema: a clinical review. Eur J Endocrinol. 2004;151(5):531–537. doi:10.1530/eje.0.1510531

7. Zou P, Du Y, Yang C, Cao Y. Trace element zinc and skin disorders. Front Med Lausanne. 2022;9:1093868. doi:10.3389/fmed.2022.1093868

8. Hobbs LK, Noland MB, Raghavan SS, Gru AA. Pemphigus erythematosus: a case series from a tertiary academic center and literature review. J Cutan Pathol. 2021;48(8):1038–1050. doi:10.1111/cup.13992

9. Zhang M, Wang S. 胰体尾切除术成功治愈坏死松解性游走性红斑1例. 中国皮肤性病学杂志. 1–5. doi:10.13735/j.cjdv.1001-7089.202402049

10. Chen L, Guo X, Huihui W, Sun W, Ding H. 营养缺乏所致坏死松解性游走性红斑样皮损. 临床皮肤科杂志. 2022;51(05):282–285. doi:10.16761/j.cnki.1000-4963.2022.05.008

11. John AM, Schwartz RA. Glucagonoma syndrome: a review and update on treatment. J Eur Acad Dermatol Venereol. 2016;30(12):2016–2022. doi:10.1111/jdv.13752

12. Adams DR, Miller JJ, Seraphin KE. Glucagonoma syndrome. J Am Acad Dermatol. 2005;53(4):690–691. doi:10.1016/j.jaad.2005.04.071

13. Remes-Troche JM, García-de-acevedo B, Zuñiga-Varga J, Avila-Funes A, Orozco-Topete R. Necrolytic migratory erythema: a cutaneous clue to glucagonoma syndrome. J Eur Acad Dermatol Venereol. 2004;18(5):591–595. doi:10.1111/j.1468-3083.2004.00981.x

14. Öberg K. Management of functional neuroendocrine tumors of the pancreas. Gland Surg. 2018;7(1):20–27. doi:10.21037/gs.2017.10.08

Cystectomy is a major surgery that requires the removal of the bladder and the creation of a urinary diversion. It’s a component of treatment for many patients with bladder cancer and may be an option for patients with other conditions, like neurogenic bladder and fistula repair. Now, surgeons at Cleveland Clinic are increasingly using nerve-sparing techniques for cystectomy that preserve sexual function and quality of life without compromising cancer treatment.

“There’s been a shift in the urologic cancer community in terms of prioritizing quality-of-life outcomes without compromising cancer treatment,” says Nima Almassi, MD. “Historically, cystectomy has been performed with a wide resection to maximize oncologic treatment and avoid positive margins and cancer recurrence.”

Prospective studies have shown that patients generally report positive quality-of-life outcomes across most domains following cystectomy, with a few exceptions. Body image, especially for patients who need a stoma, urinary function, and sexual function tend to be areas where patients report a decreased quality of life. For men undergoing cystectomy, a wide (non-nerve sparing) resection will cause severe erectile dysfunction. Nerve-sparing cystectomy represents one method of potentially improving quality of life outcomes for men undergoing surgery.

Postoperative sexual outcomes in men and women

Urologic oncologists like Dr. Almassi say that many patients don’t need to sacrifice their sexual function because of treatment. For male patients undergoing cystectomy, erectile dysfunction (ED) is a very common side effect, but nerve-sparing cystectomy can help temper it.

The Cleveland Clinic team has also been focused on improving the bladder cancer experience in women, which includes evaluating similar nerve-sparing and organ-sparing techniques to preserve reproductive anatomy and obviate surgical menopause and sexual dysfunction. Prospective studies ongoing at Cleveland Clinic have shown that women who undergo vaginal-sparing cystectomy appear to have less prolapse than women, but the data are still early when it comes to sexual function.

Patient selection is key

Patients eligible for this type of surgery have a good baseline ED and are motivated to preserve it. Additionally, they must be free of specific disease characteristics that could complicate oncologic control, such as cancer abutting or involving the neurovascular bundle. Preoperative MRI imaging can guide patient selection.

Similarly, aggressive subtypes of bladder cancer with high risk of being locally advanced may not be suitable for a nerve-sparing surgical approach. “In this case, we would not recommend nerve-sparing out of concern it could compromise cancer control,” says Dr. Almassi.

A positive institutional experience

Nerve-sparing cystectomy requires the surgeon to dissect the neurovascular bundles off the bladder and prostate. “We have found that this has yielded much better erectile function in patients after surgery without compromising oncologic outcomes. For all patients who we’ve deemed eligible for this, we have not had positive surgical margins,” notes Dr. Almassi.

Using validated questionnaires, patients report their erectile function about every three months for a year. The team is finding that around six months postoperatively, most patients experience only mild ED, and that remains consistent. Even three months following the surgery, he says, patients typically are recovering well but are often not yet sexually active at this time.

“Most patients’ erectile function ends up returning to within three points on a 25-point scale from their preoperative baseline, suggesting erectile function can recover to similar levels to what it was before surgery.”

Part of the center’s protocol is starting patients on tadalafil, and they may still be using it when function is assessed postoperatively, Dr. Almassi remarks.

The Cleveland Clinic team opts for a robotic approach, owing to better visualization and access to the neurovascular bundle. However, performing this technique with open surgery is also achievable in experienced hands. “The way the field has transitioned, fewer surgeons in high volume centers perform open cystectomy,” he explains.

A call for screening candidates

“Optimizing quality of life for our patients is a major focus for our group. Studies show that sexual function declines after cystectomy. We have an opportunity to safely personalize a surgical technique in select patients to help preserve functional outcomes,” says Dr. Almassi. “We certainly encourage our colleagues to consider screening patients who may be good candidates.”

Due to time constraints and surging patient volumes, elderly emergency department patients are not routinely screened for delirium. A Cleveland Clinic geriatrician is making a case for why that should change, however, showing that even a 60-second test can accurately detect confused patients who may otherwise slip through the cracks.

Although delirium screenings are routine for older patients being admitted to the hospital or ICU, they are not yet commonplace in emergency departments, explains Saket Saxena, MD, Codirector of the geriatric emergency department at Cleveland Clinic. “Unfortunately, elderly patients who present with acute conditions often wait hours or days to be fully screened for delirium,” he says, “However, we know that recognizing the disorder early can significantly improve patient care.”

Dr. Saxena is the principal author of a recent study that evaluated 4AT, a bedside screening tool for delirium in emergency department patients. The study found that 4AT, which takes around one minute to complete, can detect delirium with a positivity rate of 14%, a number that is consistent with the general population. Interestingly, about 7% of those determined to have delirium did not initially present with a complaint of altered mental status.

Combatting diagnostic challenges

When people imagine delirium, he notes, they often think of patients who are agitated or even aggressive – getting out of bed, struggling or pulling out their lines. However, a significant number of these patients have hypoactive delirium, a condition that prompts a quiet, docile demeanor. Although these patients may not appear obviously confused, they will sleep a lot, eat little and decline to actively participate in conversations or therapies.

“That is the type of delirium that often gets missed when patients are transitioned from emergency to inpatient care,” explains Dr. Saxena.

Although hypoactive delirium can be particularly difficult to identify because it can easily be explained away by simple fatigue or “not being hungry,” the disorder can have a significant impact on patient outcomes.

“Nutritional status cannot be maintained if the patient isn’t eating,” explains Dr. Saxena. “And if the patient isn’t getting out of bed, the chances of debilitation rise; muscular strength is lost, and the risk of blood clots in the legs increases. All of these factors play a role in how these patients perform during hospitalization and beyond.” In fact, studies have found that patients with delirium have a length of stay that’s twice as long as those without, he notes.

Historically, Cleveland Clinic has used the Confusion Assessment Method to screen patients for delirium in the hospital or ICU; however, no method has been used to formally assess delirium in the emergency department. In preparation for the study, Dr. Saxena worked with triage nurses to identify the delirium screening tool they were most comfortable using in an emergency setting. The 4AT method, which was deemed easy to learn and administer, was chosen as the preferred rapid delirium test. Patients were flagged for screening if they were over 65 years old and medically complex, and all patients over age 80 were screened.

Clinical implications

The rapid test begins by asking the person accompanying the patient if they are concerned about or have noticed any changes in the patient’s mental status. If the caregiver answers yes, the assessment is completed by asking the patient “orientation” questions that evaluate their ability to understand today’s date, where they are, and their date of birth and age. Their attention span is measured by asking the patient to name the months of the year backwards.

Any patient who receives a score of four or more is flagged for delirium.

Dr. Saxena said the study demonstrates that while detecting delirium in the acute setting is challenging, it can be done quickly and accurately using a rapid test like the 4AT method. Among Dr. Saxena’s future goals are improving interdepartmental communication about high-risk geriatric patients. “This approach helps ensure continuity of care throughout the hospital stay by making subsequent caregivers aware of any diagnoses – including delirium – that were made in the emergency department.

Despite the rising incidence of rheumatoid arthritis (RA), extra-articular manifestations have become rare in the era of modern treat-to-target therapy. However, they still present clinical challenges — particularly in the case of rheumatoid nodules. In addition to the need to rule out serious differential diagnoses and address potential complications, especially those involving the lungs, these recurrent inflammatory granulomas can affect daily life not only cosmetically but also functionally.

Christopher Edwards, MD, professor of rheumatology at University Hospital Southampton in Southampton, England, discussed the clinical relevance and management of rheumatoid nodules during the 2025 Annual Meeting of the European Alliance of Associations for Rheumatology.

When Edwards began his career in rheumatology, the presence of rheumatoid nodules was considered a key diagnostic criterion for RA. If not found on the hands, clinicians often examined the elbows and Achilles tendons, which are also common sites. Histologically, rheumatoid nodules are granulomatous inflammatory lesions that evolve through multiple stages. While often subcutaneous, they can also be found on the sclera, larynx, heart valves, and — most significantly — in the lungs.

Biopsy When Malignancy Is Suspected

Pulmonary nodules can present diagnostic difficulties. “I’ve seen patients who were initially told they had lung metastases,” Edwards recalled. Waiting for further imaging and biopsy can be highly distressing for patients. Granulomatosis with polyangiitis can also resemble rheumatoid nodules, further complicating the diagnosis.

It is especially important to distinguish these nodules from infections such as tuberculosis. Patients with RA are at increased risk for infection due to both the underlying disease and immunosuppressive treatment. Like tuberculomas, pulmonary rheumatoid nodules can undergo central necrosis when exposed to tumor necrosis factor-alpha inhibitors, leading to cavitation or even pneumothorax. “Any cavity in the lung can become infected,” Edwards cautioned.

Diagnosing Peripheral Nodules

Diagnosing peripheral rheumatoid nodules is usually straightforward. These nodules typically feel rubbery on palpation and are movable relative to the underlying tissue. Important differential diagnoses include gouty tophi, lipomas, epidermoid cysts, infectious granulomas, sarcoidosis, and neoplastic lesions.

Imaging tools such as ultrasound or fine-needle aspiration can help clarify the diagnosis, particularly when gout is suspected. “Biopsy is rarely required — only if there’s concern about a neoplastic or malignant process,” Edwards explained.

Better Disease Control, Fewer Nodules

“In my practice, I see very few nodules these days,” said Edwards. Epidemiological data support this trend: The 10-year cumulative incidence of subcutaneous nodules in RA patients decreased from 30.9% between 1985 and 1999 to 15.8% between 2000 and 2014.

Multiple factors likely contributed to this decline, including the earlier initiation of more effective therapies and a reduction in smoking rates. Smoking remains a major risk factor for nodule development, along with long-standing, severe RA, male sex, and seropositivity for rheumatoid factor or anti-cyclic citrullinated peptide antibodies. “Patients with nodules are almost always seropositive,” Edwards noted.

These findings suggest that maintaining tight control of disease activity is more critical for preventing nodules than concerns about drug-induced nodulosis.

Little Reason to Discontinue Methotrexate

“There was a time when we worried that methotrexate might be causing nodules,” Edwards said, referring to anecdotal reports of increased nodulosis after initiating methotrexate (MTX). “But now we’re using more MTX and seeing fewer nodules.”

He emphasized that the presence of nodules alone should not prompt discontinuation of MTX. “It wasn’t a reason to stop methotrexate back then, and it’s not a reason now — though in some cases, it may justify a more aggressive treatment approach.”

Other medications — particularly tumor necrosis factor inhibitors like etanercept — have also been linked to nodule development, though Edwards suggested this may reflect reporting bias. “It might not be causal,” he said.

Often, treatment isn’t necessary. “Sometimes it’s just a matter of observation,” Edwards noted. Painful or functionally limiting nodules may be managed with local glucocorticoid injections to reduce discomfort and soften the nodules. However, he admitted he had never personally injected a rheumatoid nodule.

He also cautioned against injections over the elbow. “There’s something about the skin and the olecranon bursa that makes infections more likely in that area. I saw one patient who needed plastic surgery after an infection left a significant wound.”

Rheumatoid nodules also have a tendency to recur.

When to Consider Surgery

“Surgery can benefit some patients,” Edwards said. Surgical removal may be warranted for nodules that ulcerate, become infected, or impair function — such as large nodules on the thumb or fingertip that interfere with gripping. “Patients are usually happy to regain function, even if the nodule comes back a couple of years later.” Nodules that are consistently irritated by shoes or clothing straps may also merit removal.

Pulmonary rheumatoid nodules — unlike subcutaneous ones — often contain B cells and typically respond well to rituximab or abatacept. “These lung nodules tend to shrink or stabilize with rituximab, and certainly, no new ones seem to develop,” Edwards noted. Case reports and small series have also documented improvement with Janus kinase inhibitors.

This story was translated from Medscape’s German edition.

Challenges in space exploration are driving new approaches to delivering eye care in the most inaccessible environments, according to Steven Laurie, PhD, senior scientist and technical lead with the Cardiovascular and Vision Laboratory at NASA’s Johnson Space Center in Houston, Texas.

His talk at the Heidelberg 2025 International SPECTRALIS Symposium – And Beyond (ISS) spotlighted how technologies originally designed for spaceflight, like the Heidelberg Spectralis OCT2 and portable Mini OCT, are setting the stage for autonomous medical diagnostics in deep space—and potentially in the most remote regions here on Earth.

Sheryl Stevenson, executive editor with the Eye Care Network, caught up with Laurie to learn how spaceflight is driving innovations in extreme telemedicine—on orbit and beyond.

Sheryl Stevenson: What are the key takeaways from your presentation?

Steven Laurie, PhD: Astronauts onboard the International Space Station (ISS) use the Heidelberg Spectralis OCT2 to image their eyes, and these images have revealed structural changes in the retina and optic nerve head. I will discuss the unique approach NASA has developed to support these data collection activities, including use of remote guidance from Earth. I will end by sharing our experience with a new device Heidelberg Engineering is developing, the Mini OCT, that is smaller in mass and volume than the Spectralis, and that will not require the remote guidance from Earth.

SS: What are the unique ophthalmic challenges that astronauts face during extended space missions, and how is telemedicine being adapted to address them?

SL: In 2011, the first reports were published documenting the development of optic disc edema and choroidal folds in astronauts flying ~6 month missions to the ISS. Soon after, NASA began using the Spectralis OCT2 to track the development of these findings throughout the mission, and this requires real-time video and communication support from experts on the ground to guide crewmembers in the collection of the OCT images. Over the last 10+ years NASA has used telemedicine to support astronauts in collecting OCT images throughout their spaceflight missions, revealing ophthalmic changes in 60% to 70% of crewmembers.

SS: Can you describe the technologies or protocols that enable effective diagnosis and intervention when specialists are millions of miles away?

SL: The ISS orbits ~250 miles above the surface of the Earth, allowing for only ~1-2 second communication delays between experts in mission control, and crewmembers onboard the ISS. We utilize a video feed from within the ISS cabin, 2-way audio, and screen-sharing of the Heidelberg software to collect the OCT images. Images are downlinked and can be reviewed by experts within hours of data collection. Crewmembers receive two 1-hour long training classes on how to use the hardware before their mission. This training utilizes very specific wording and directions to guide crew through acquisition of OCT images.

SS: How might innovations developed for spaceflight telemedicine translate to patient care in remote or underserved areas here on Earth?

SL: The experience that NASA has developed in using remote guidance to collect OCT images on the ISS highlights that remote telemedicine for collecting OCT images is possible and can be utilized to generate high-quality data. While this represents a great opportunity for remote or underserved populations, it still requires the hardware to be in the remote location, and for real-time audio, video, and screen-sharing communication with experts at a different location. The advancements with the new Mini OCT device represents the next frontier for patients to access medical devices in remote locations without requiring the communication pathways or additional technicians to support data collection. This expands the opportunity from telemedicine supported in real-time by clinicians, to autonomous data collection that only requires transmission of the final images to clinicians.

SS: Anything else to add that you feel would be helpful for our audience to know?

SL: As NASA looks toward sending astronauts back to the Moon and on to Mars, the distance from Earth will limit the real-time communication that we enjoy when crew members are on the ISS. Thus, our ability to utilize remote guidance and real-time communication with experts on the ground will no longer be possible. Technology such as the Mini OCT represents one possible solution to this problem, where astronauts can autonomously collect OCT images on themselves, and then have those images sent back to Earth for assessments by clinical experts. We are excited to see the progression of this technology that may benefit astronauts, as well as patients on Earth.

Alexander T. Reddy, MD

Assistant Professor of Medicine
Division of Gastroenterology
Duke University School of Medicine
Durham, North Carolina

Amit Patel, MD, AGAF, FACG

Professor of Medicine
Division of Gastroenterology
Duke University School of Medicine & Durham Veterans Affairs Medical Center
Durham, North Carolina

---

Dysphagia, the sensation of difficulty swallowing, may be experienced by up to 1 in 6 adults in the United States, according to population-based survey data,^1,2 and is frequently encountered in gastroenterology clinical practice. Esophageal dysphagia may stem from various disease states, so discerning among potential etiologies is critical to facilitate effective, patient-tailored management. The initial evaluation of dysphagia should include a careful clinical history and physical exam, followed by consideration of diagnostic investigations, as appropriate.

Clinicians typically should pursue upper endoscopy with consideration of esophageal biopsies as a first step for esophageal-phase dysphagia.³ Additional physiologic testing such as high-resolution esophageal manometry (HRM) with provocative maneuvers,^4,5 functional lumen imaging probe (FLIP) panometry,^6,7 and/or a barium esophagram (typically as a timed upright barium esophagram)⁸ may be used for further assessment based on the clinical context and endoscopic findings. Here, we present 3 hypothetical cases that illustrate practical approaches to clinical presentations of esophageal dysphagia, highlighting the use of modern diagnostic and therapeutic options.

Case 1

A 30-year-old man with a history of asthma was referred for 2 years of intermittent dysphagia to solids. His symptoms occurred several times weekly, particularly with meats, and were localized retrosternally. He had not used any pharmacotherapy to manage his symptoms. His physical exam was unremarkable, and upper endoscopy revealed esophageal edema (decreased vascularity), mild rings, exudates, and longitudinal furrows (Figure 1A; Eosinophilic Esophagitis [EoE] Endoscopic Reference Score [EREFS] of E1R1Ex1F2S0 [edema = 1, rings = 1, exudates = 1, furrows = 2, and strictures = 0]).^9,10 Biopsies from the upper and lower esophagus revealed peak eosinophil counts of 50 and 40 eosinophils per high-power field, respectively.

Diagnosis: EoE

EoE is a chronic allergen-induced, immune- mediated disease of the esophagus resulting in symptoms of esophageal dysfunction, particularly dysphagia in adults.¹¹ The clinicopathologic diagnosis requires compatible esophageal symptoms along with an eosinophil-predominant infiltrate on histologic assessment of endoscopic biopsies, with peak eosinophil counts of at least 15 eosinophils per high-power field.¹¹ Clinicians should exclude alternate etiologies for esophageal eosinophilia (eg, gastroesophageal reflux disease [GERD], medication adverse effects, infection, achalasia, and hypereosinophilic syndrome) before making a diagnosis of EoE.

Scoring tools such as the EREFS at endoscopic evaluation, as above,^9,10 and the Index of Severity for EoE¹² facilitate the standardization and systematic reporting of disease severity. Although the recognition and diagnosis of EoE have increased rapidly in recent decades,¹³ endoscopic findings of EoE may be subtle and/or overlooked, potentially contributing to diagnostic delay.¹⁴ Therefore, at least 2 to 4 esophageal biopsies from at least 2 levels of the esophagus should be pursued in all patents with symptoms suspicious for EoE, including at the time of food impaction.^10,11,15

Management

After a discussion of potential dietary and pharmacologic management options for EoE, the patient opted for 40 mg of omeprazole twice daily. Repeat endoscopy 2 months later demonstrated no improvement either endoscopically (based on EREFS) or histologically (based on peak eosinophil counts on esophageal biopsies).

The patient then opted to switch to swallowed fluticasone (220 mcg at 4 puffs twice daily; total daily dose, 1,760 mcg). Evaluation after 2 months of adherence with fluticasone again demonstrated no significant improvement in his symptoms, EREFS, or peak eosinophil counts on esophageal biopsies. Based on his lack of response with proton pump inhibitor (PPI) and topical corticosteroid therapy, along with shared decision-making regarding his strong preference to avoid dietary elimination approaches, the patient started 300 mg of dupilumab (Dupixent, Regeneron/Sanofi) weekly. When evaluated 3 months after starting dupilumab, the patient reported resolution of dysphagia. His previous endoscopic findings of EoE had normalized, and no eosinophils were present on upper and lower esophageal biopsies (Figure 1B). Given dupilumab’s effectiveness, the patient opted to continue on it as maintenance therapy.

For the management of EoE, clinicians should focus on both inflammatory and potential fibrostenotic aspects to improve patient symptoms and minimize complications such as food impaction, stricture formation, and esophageal perforation.¹¹ Anti-inflammatory treatment options include strategic dietary elimination,¹⁶ PPIs, topical steroids (ie, budesonide or fluticasone formulations), and dupilumab.¹⁷

Dupilumab, approved for EoE by the FDA in May 2022, is a monoclonal antibody that blocks the effects of interleukin (IL)-4 and IL-13 involved in the type 2 inflammatory cascade.¹¹ Given limited head-to-head clinical trial data among the anti-inflammatory options, individual disease characteristics and patient preferences via shared decision-making should guide treatment selection.¹⁸

Strategies for optimizing management include counseling on the risks and benefits of treatment options, consultation with gastroenterology-trained nutritionists when pursuing food elimination diets, and structured, timely assessment of response after initiating therapy. A willingness to pursue alternative therapies if indicated, as demonstrated in this case, is crucial. Beyond its use in patients with EoE who are nonresponsive to or intolerant of other therapies, dupilumab can be considered earlier in the management algorithm when a patient has concomitant atopic conditions that also could be treated with dupilumab.¹⁹ Endoscopic dilation as an adjunct to anti-inflammatory approaches can be safely used to treat fibrostenotic features of EoE, including strictures and luminal narrowing. Finally, maintaining effective dietary or pharmacologic therapy can help prevent histologic inflammation and symptom recurrence.¹¹

Case 2

A 55-year-old woman with a history of hypertension was referred for 2 years of progressively worsening dysphagia to solids and liquids, with regurgitation, which now is happening on a daily basis. One year prior, she was evaluated by an outside provider with an unrevealing upper endoscopy and esophageal biopsies. The patient had been taking omeprazole for several months without symptom benefit. Esophageal HRM was discussed and pursued, which revealed 100% failed peristalsis with panesophageal pressurization on single wet swallows and an elevated median integrated relaxation pressure (IRP) of 30 mm Hg in the primary supine position (Figure 2A).

Diagnosis: Type II Achalasia

Achalasia is an esophageal motility disorder characterized by abnormal esophageal peristalsis and incomplete relaxation of the lower esophageal sphincter, classically defined by an abnormally elevated median IRP on esophageal HRM.^4,20 Thresholds for abnormal IRP vary based on patient position and HRM equipment manufacturer. Threshold values are 15 mm Hg in the supine position and 12 mm Hg in the upright position for Medtronic HRM systems, and 22 mm Hg in the supine position and 15 mm Hg in the upright position for the Diversatek and Laborie HRM systems.^4,21

Achalasia is classified into 3 types based on peristaltic patterns at HRM, which can help guide prognosis and therapeutic interventions: Type I achalasia consists of 100% failed peristalsis without evidence of panesophageal pressurization, type II achalasia demonstrates 100% failed peristalsis with panesophageal pressurization in 20% or more of swallows, and type III achalasia is characterized by premature contraction in 20% or more of swallows without evidence of peristalsis.^4,20 Patients who are initially suspected of having GERD but who do not respond to acid-suppressive therapy should be evaluated for achalasia.^20,22

Management

Due to worsening symptoms, the patient underwent upper endoscopy with FLIP, which revealed an American Foregut Society hiatus grade 1 with no mechanical obstruction. FLIP assessment revealed an esophagogastric junction-distensibility index (EGJ-DI) of 0.6 mm²/mm Hg at a 60-mL fill volume and a maximum EGJ diameter of 8 mm at a 70-mL fill volume, consistent with a reduced EGJ opening (REO), and no esophageal body contractile response (Figure 2B).

After discussion of treatment options based on her symptoms and diagnostic findings, the patient opted for per-oral endoscopic myotomy (POEM). At follow-up, she reported resolution of dysphagia and regurgitation symptoms off omeprazole. Surveillance endoscopy with FLIP and wireless pH monitoring 6 months after POEM revealed no reflux esophagitis, an EGJ-DI of 3 mm²/mm Hg with an EGJ diameter of 18 mm, and physiologic esophageal acid exposure times (AETs) less than 4% on all 4 days of the pH study.

In a workup of suspected achalasia, a high-quality endoscopic exam should exclude the presence of pseudoachalasia or other causes of mechanical obstruction. Particularly in the setting of diagnostic uncertainty (eg, manometric EGJ outflow obstruction, borderline IRP, abnormal provocative maneuvers at HRM), evaluation with FLIP and/or a timed upright barium esophagram can be helpful in evaluation, as well as to increase confidence in an actionable diagnosis.^8,20

FLIP is increasingly recognized as a useful tool for esophageal motility evaluation and should be considered if alternate investigations for dysphagia are inconclusive; it may even be considered as part of index endoscopy when the procedure and expertise are readily available.^7,23 As per new consensus and American Gastroenterological Association Clinical Practice Update guidance, an EGJ-DI less than 2.0 mm²/mm Hg and maximum EGJ diameter less than 12 mm on FLIP are classified as REO (as in this case), while a normal EGJ opening (EGJ-DI =2.0 mm²/mm Hg and maximum EGJ diameter =16 mm) has a high negative predictive value for achalasia spectrum disorders on HRM.^6,7

For the management of achalasia, definitive therapies with well-established clinical benefit include pneumatic dilation, surgical laparoscopic Heller myotomy (LHM) accompanied by partial fundoplication to help prevent GERD, and POEM. All 3 approaches are comparable and may be considered reasonable options for types I and II achalasia, with selection guided by individual patient characteristics, local expertise, discussions of potential risks and outcomes (eg, POEM may be associated with GERD), and shared decision-making.^20,24 POEM is the preferred treatment for type III achalasia, given the potential to tailor the myotomy to the spastic segment of the esophageal body.^20,25,26 A botulinum toxin injection typically should be reserved for patients who are not candidates for the more definitive therapies described above.²⁰ When available, intra-procedural FLIP during myotomy, whether POEM or LHM, may be helpful in tailoring or guiding the adequacy of disruption to the lower esophageal sphincter.²⁶ Finally, patients who undergo POEM should be monitored for GERD, with treatment offered as appropriate.²⁶

Case 3

A 50-year-old man with a history of obesity and diabetes mellitus was referred for endoscopy after experiencing 3 months of dysphagia to solids. He reported long-standing heartburn and regurgitation, for which he took over-the-counter antacids on an as-needed basis. Upper endoscopy revealed Los Angeles Grade D esophagitis with luminal narrowing at the EGJ (Figure 3A). He was started on 40 mg of omeprazole twice daily with plans for repeat upper endoscopy.

Diagnosis: Erosive Esophagitis (EE) And Peptic Stenosis

GERD is a common condition in which refluxate of acidic contents from the stomach into the esophagus results in bothersome symptoms (commonly heartburn, regurgitation, and noncardiac chest pain). While these typical symptoms in the absence of alarm symptoms can prompt a 4- to 8-week trial of PPI therapy with assessment of response,²⁷ GERD can lead to the formation of peptic strictures, mechanical narrowing that can cause dysphagia. Per the updated Lyon Consensus, the presence of LA Grades B/C/D EE, peptic stricture, and/or biopsy-proven Barrett’s esophagus represent conclusive evidence for a diagnosis of GERD (as in this case).²⁸

If these findings are not present on endoscopy, a diagnosis of GERD may be established with ambulatory reflux monitoring, with distal esophageal AETs more than 6% indicating the presence of pathologic GERD.^27,28 If ambulatory reflux monitoring is inconclusive based on AET, then adjunctive evidence such as numbers of reflux episodes, reflux symptom association, and mean nocturnal baseline impedance may support a diagnosis of GERD.^29-31 A personalized approach to management is warranted, with further evaluation and/or escalation of anti-reflux therapy, including invasive anti-reflux interventions, pursued thoughtfully with shared decision-making.^27,32,33

Management

The patient returned for follow-up endoscopy 2 months later on 40 mg of omeprazole twice daily. Although he reported partial improvement in his dysphagia, upper endoscopy demonstrated LA Grade C esophagitis and ongoing luminal narrowing at the EGJ. Given persistent and severe EE and stricture despite adherence with a high dose of omeprazole, the patient was switched to 20 mg of vonoprazan (Voquezna, Phathom) daily. After 1 month of vonoprazan therapy, upper endoscopy revealed resolution of his reflux esophagitis (Figure 3B).

Across 2 endoscopies, the patient’s peptic stricture was successfully dilated to a diameter of 18 mm using through-the-scope balloon dilators (Figure 3C). He reported resolution of his dysphagia and reflux symptoms at follow-up.

In the setting of EE, optimized antisecretory therapy facilitates healing and can be followed by repeat upper endoscopy to document healing and exclude the presence of Barrett’s esophagus.³⁴ High-dose PPIs are most commonly used as first-line therapy for the healing of EE given their effectiveness, accessibility, safety profile, and cost.²⁷ However, potassium-competitive acid blockers (P-CABs) such as vonoprazan, which received FDA approval for EE in November 2023, are a newer class of antisecretory medications that can provide more potent acid inhibition than PPI formulations, with faster onset of action and longer duration of effect and without premeal dosing requirements.^35,36

Although P-CABs currently are less accessible and more costly than PPIs in the United States, they may be superior to PPIs for the healing and maintenance of healing of more severe (LA Grades C/D) EE and may be associated with more rapid healing.^36,37 Beyond representing an effective therapeutic option for patients with more severe EE and those with documented reflux who fail twice-daily PPI therapy (as in this case), the rapid onset of acid inhibition of P-CABs raises their potential utility as on-demand therapy for reflux-related symptoms.^36,38

For peptic strictures, endoscopic dilation, whether employing balloon or bougie techniques, is safe and effective.^39,40

Conclusion

Through these representative hypothetical cases, we have outlined practical approaches to the evaluation of esophageal dysphagia and the basic management of EoE, achalasia, and reflux esophagitis with peptic stenosis, incorporating clinical pearls and more recent esophageal diagnostic and therapeutic advances, such as dupilumab, FLIP, POEM, and vonoprazan. As demonstrated through these cases, we are fortunate as gastroenterology providers to be able to thoughtfully evaluate our patients with dysphagia with the assistance of insightful diagnostic modalities and also, when indicated, treat our patients with a growing arsenal of effective, patient-tailored management options.

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