Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer-related mortality worldwide. Despite therapeutic advancements over recent decades, the prognosis for patients with metastatic CRC (mCRC) remains poor. Approximately 2%-4% of mCRC cases exhibit human epidermal growth factor receptor 2 (HER2) amplification or overexpression, defining a distinct molecular subtype. This HER2-positive status is strongly associated with primary resistance to anti-epidermal growth factor receptor (EGFR) therapies, which are the standard of care for patients with RAS wild-type tumors. Beyond its well-established role in breast and gastric cancers, HER2 has emerged as a pivotal biomarker and actionable therapeutic target in mCRC. However, selecting appropriate treatment strategies remains challenging due to patient heterogeneity and diverse molecular subtypes. This review systematically summarizes the molecular biology, diagnostic strategies, and advances in targeted therapies for HER2-positive mCRC. On the diagnostic front, we discuss the applications of immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and circulating tumor DNA (ctDNA) detection technologies. We highlight discrepancies in diagnostic criteria across key clinical trials—such as HERACLES, DESTINY, and MOUNTAINEER—underscoring the urgent need for standardized, CRC-specific definitions to ensure consistent patient selection and comparability of efficacy data across studies. Although NGS enables comprehensive genomic profiling, its cost-effectiveness relative to traditional methods must be carefully considered. Therapeutically, we summarize clinical trial data for HER2-directed agents, including tyrosine kinase inhibitors (TKIs) such as tucatinib and lapatinib, monoclonal antibodies like trastuzumab, bispecific antibodies, and antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan. We review dual-targeting strategies and note recent FDA approvals that represent significant milestones in second-line treatment. Additionally, we explore the potential of combining immune checkpoint inhibitors with HER2-targeted therapies to enhance antitumor immunity through mechanisms including antibody-dependent cellular cytotoxicity (ADCC) and modulation of the tumor microenvironment. ADCs enable precise delivery of cytotoxic payloads, reducing off-target toxicity while effectively inhibiting oncogenic pathways. A substantial portion of this review is dedicated to dissecting the molecular mechanisms underlying primary and acquired resistance to HER2-targeted therapies—persistent challenges that limit clinical benefit. These mechanisms include reactivation of downstream signaling pathways such as PI3K/AKT/mTOR and MAPK, concurrent mutations in genes like KRAS or BRAF, and alterations in HER2 expression that compromise treatment efficacy. For instance, specific HER2 mutations (e.g., L755S) can reduce drug binding affinity, while ctDNA monitoring facilitates early detection of emerging resistance clones during disease progression, thereby enabling timely therapeutic adjustments. Tumor heterogeneity and dynamic interactions with the microenvironment further complicate resistance patterns observed in clinical practice. HER2-targeted therapy represents a new frontier in precision oncology for mCRC, offering renewed hope for improving patient outcomes. Realizing this potential will require continued optimization of diagnostic algorithms and treatment workflows. Future efforts must focus on overcoming resistance, validating liquid biopsy approaches for dynamic monitoring, and establishing unified clinical guidelines. HER2 has become an essential biomarker for stratifying mCRC patients beyond traditional RAS and BRAF status, underscoring the shift from empiric treatment to biomarker-driven precision medicine. International, multidisciplinary collaboration will be critical to validate emerging biomarkers and refine treatment algorithms globally.

Objective: To understand the current status and associated factors of sleep problems among preschool children in Hainan Province, so as to provide scientific evidence for improving sleep health in this population. Methods: From January 2021 to June 2022, a total of 4 105 preschool children aged 3-6 years from 62 kindergartens in Hainan Province were selected using stratified cluster random sampling method. Demographic information and lifestyle habits were collected through the Hainan Province Child Growth and Development Survey Questionnaire. The Children s Sleep Habits Questionnaire (CSHQ) was employed to assess sleep status. Unconditional binary Logistic regression model was applied to investigate the associated factors of sleep problems among preschool children. Results: The overall CSHQ score for children was 58.03±18.84, with 80.95% of preschool children exhibiting sleep related issues. The top three most prevalent sleep problem domains were bedtime resistance (72.42%), sleep anxiety ( 54.88 %), and parasomnias (38.86%). Logistic regression analysis revealed that higher family annual income ( OR=0.60, 95%CI = 0.45-0.79), higher maternal education level ( OR=0.53, 95%CI =0.32-0.89), regular or daily vitamin D supplementation ( OR=0.77, 95%CI =0.60-0.99), and fully self initiated eating behavior ( OR=0.71, 95%CI =0.59-0.85) were negatively related with children s sleep problems; in addition, screen exposure ( OR=1.27, 95%CI =1.06-1.51) and picky eating ( OR= 1.47 , 95%CI =1.21-1.78) were positively related to children s sleep problems (all P <0.05). Conclusion The high detection rate of sleep problems among preschool children in Hainan Province is multifactorially associated with family environment, dietary habits, and lifestyle behaviors.

ObjectiveChronic atrophic gastritis (CAG) is usually diagnosed by gastroscopy and histopathological biopsy. These procedures remain the reference standard, but their invasive nature and resource requirements may limit their use in large-scale population screening and repeated follow-up. A convenient and reproducible method for noninvasive auxiliary screening may help identify individuals who require further endoscopic assessment. Fingertip photoplethysmography (PPG) provides a noninvasive recording of peripheral pulse waves and allows harmonic features to be extracted from the signal. In this study, the so-called meridian-related variables were defined as PPG-derived harmonic parameters labelled according to meridian nomenclature, rather than as direct measurements of meridian physiology. This study aimed to compare these harmonic parameters between patients with CAG and non-CAG controls, identify parameters that remained different after age adjustment, and develop a multivariable model for noninvasive auxiliary screening and pre-endoscopic risk stratification of CAG. MethodsA total of 343 participants were included, comprising 171 patients with CAG and 172 non-CAG controls. CAG diagnosis was established using gastroscopy and histopathology as the reference standard. Fingertip PPG signals were collected using a PPG-based pulse acquisition device. Eight PPG-derived harmonic parameters labelled according to meridian nomenclature were extracted for analysis. Between-group differences were first assessed using nonparametric tests. Age-adjusted analyses were then performed to reduce potential confounding by age. The false discovery rate (FDR) method was applied for multiple-comparison correction. A multivariable logistic regression model integrating age and multiple harmonic parameters was constructed. Model performance was evaluated using receiver operating characteristic (ROC) analysis and the area under the curve (AUC). Internal validation performance was assessed using stratified five-fold cross-validation and bootstrap optimism correction. Threshold performance was examined using both a high-specificity strategy and a Youden index-based cutoff. Decision curve analysis was used to evaluate the model’s net clinical benefit across a range of threshold probabilities. ResultsAll eight harmonic parameters were non-normally distributed. In the univariate analysis, the stomach-labelled harmonic parameter (ST), bladder-labelled harmonic parameter (BL), and liver-labelled harmonic parameter (LR) differed between the CAG and non-CAG groups. After age adjustment and FDR correction, only ST and BL remained statistically significant. Compared with non-CAG controls, patients with CAG showed higher ST values and lower BL values. This finding indicates an associated differential harmonic pattern that was not fully explained by age distribution. However, the discriminative ability of a single harmonic parameter was limited. The best-performing single indicator was ST, with an AUC of 0.652 (95% CI: 0.595-0.707). The multivariable model integrating age and multiple harmonic parameters achieved an AUC of 0.791 (95% CI: 0.743-0.835), representing an improvement of 0.139 over ST alone. In internal validation, stratified five-fold cross-validation yielded a mean AUC of 0.753 (95% CI: 0.715-0.781), and the bootstrap optimism-corrected AUC was 0.748. These results suggest that the model retained moderate discriminative performance after internal validation.At a specificity of at least 95%, the model achieved a sensitivity of only 40.4% (95% CI: 25.7%-49.7%). This high-specificity cutoff may be suboptimal as the preferred threshold for an initial screening setting because of the potential risk of missed CAG cases. The Youden index-based optimal cutoff was 0.419, corresponding to a sensitivity of 80.7% and a specificity of 62.8%. This threshold may better match the practical aim of noninvasive auxiliary screening, where sensitivity is usually prioritized to reduce missed cases. Decision curve analysis showed that, within a threshold probability range of 10%-55%, the model provided higher net clinical benefit than the reference strategies of recommending gastroscopy for all participants or for none. ConclusionPatients with CAG showed associated harmonic differences in fingertip PPG-derived features, mainly characterized by higher ST and lower BL values after age adjustment and FDR correction. Compared with a single harmonic parameter, the multivariable model showed better overall discrimination and retained moderate internal validation performance. These findings suggest that PPG-derived harmonic parameters labelled according to meridian nomenclature may provide auxiliary information for noninvasive auxiliary screening and front-line triage before gastroscopic confirmation in CAG. The present results support further validation rather than immediate clinical implementation. External validation in independent, multicenter, and preferably prospective screening cohorts is needed to assess the model’s generalizability, screening performance, and potential clinical utility.

ObjectiveChronic atrophic gastritis (CAG) is usually diagnosed by gastroscopy and histopathological biopsy. These procedures remain the reference standard, but their invasive nature and resource requirements may limit their use in large-scale population screening and repeated follow-up. A convenient and reproducible method for noninvasive auxiliary screening may help identify individuals who require further endoscopic assessment. Fingertip photoplethysmography (PPG) provides a noninvasive recording of peripheral pulse waves and allows harmonic features to be extracted from the signal. In this study, the so-called meridian-related variables were defined as PPG-derived harmonic parameters labelled according to meridian nomenclature, rather than as direct measurements of meridian physiology. This study aimed to compare these harmonic parameters between patients with CAG and non-CAG controls, identify parameters that remained different after age adjustment, and develop a multivariable model for noninvasive auxiliary screening and pre-endoscopic risk stratification of CAG. MethodsA total of 343 participants were included, comprising 171 patients with CAG and 172 non-CAG controls. CAG diagnosis was established using gastroscopy and histopathology as the reference standard. Fingertip PPG signals were collected using a PPG-based pulse acquisition device. Eight PPG-derived harmonic parameters labelled according to meridian nomenclature were extracted for analysis. Between-group differences were first assessed using nonparametric tests. Age-adjusted analyses were then performed to reduce potential confounding by age. The false discovery rate (FDR) method was applied for multiple-comparison correction. A multivariable logistic regression model integrating age and multiple harmonic parameters was constructed. Model performance was evaluated using receiver operating characteristic (ROC) analysis and the area under the curve (AUC). Internal validation performance was assessed using stratified five-fold cross-validation and bootstrap optimism correction. Threshold performance was examined using both a high-specificity strategy and a Youden index-based cutoff. Decision curve analysis was used to evaluate the model’s net clinical benefit across a range of threshold probabilities. ResultsAll eight harmonic parameters were non-normally distributed. In the univariate analysis, the stomach-labelled harmonic parameter (ST), bladder-labelled harmonic parameter (BL), and liver-labelled harmonic parameter (LR) differed between the CAG and non-CAG groups. After age adjustment and FDR correction, only ST and BL remained statistically significant. Compared with non-CAG controls, patients with CAG showed higher ST values and lower BL values. This finding indicates an associated differential harmonic pattern that was not fully explained by age distribution. However, the discriminative ability of a single harmonic parameter was limited. The best-performing single indicator was ST, with an AUC of 0.652 (95% CI: 0.595-0.707). The multivariable model integrating age and multiple harmonic parameters achieved an AUC of 0.791 (95% CI: 0.743-0.835), representing an improvement of 0.139 over ST alone. In internal validation, stratified five-fold cross-validation yielded a mean AUC of 0.753 (95% CI: 0.715-0.781), and the bootstrap optimism-corrected AUC was 0.748. These results suggest that the model retained moderate discriminative performance after internal validation.At a specificity of at least 95%, the model achieved a sensitivity of only 40.4% (95% CI: 25.7%-49.7%). This high-specificity cutoff may be suboptimal as the preferred threshold for an initial screening setting because of the potential risk of missed CAG cases. The Youden index-based optimal cutoff was 0.419, corresponding to a sensitivity of 80.7% and a specificity of 62.8%. This threshold may better match the practical aim of noninvasive auxiliary screening, where sensitivity is usually prioritized to reduce missed cases. Decision curve analysis showed that, within a threshold probability range of 10%-55%, the model provided higher net clinical benefit than the reference strategies of recommending gastroscopy for all participants or for none. ConclusionPatients with CAG showed associated harmonic differences in fingertip PPG-derived features, mainly characterized by higher ST and lower BL values after age adjustment and FDR correction. Compared with a single harmonic parameter, the multivariable model showed better overall discrimination and retained moderate internal validation performance. These findings suggest that PPG-derived harmonic parameters labelled according to meridian nomenclature may provide auxiliary information for noninvasive auxiliary screening and front-line triage before gastroscopic confirmation in CAG. The present results support further validation rather than immediate clinical implementation. External validation in independent, multicenter, and preferably prospective screening cohorts is needed to assess the model’s generalizability, screening performance, and potential clinical utility.

Objective To analyze the epidemiological characteristics of poisonous mushroom-related foodborne disease incidents in Chongqing from 2010 to 2024, and to provide a scientific basis for effective prevention and control of mushroom-related foodborne diseases. Methods Data of poisonous mushroom related foodborne disease incidents reported by the CDCs of 39 districts and counties in Chongqing from 2010 to 2024 were collected, and their epidemic characteristics were analyzed. Results A total of 264 poisonous mushroom poisoning outbreaks were reported in Chongqing from 2010 to 2024, resulting in 1 046 cases of illness, 543 hospitalizations, and 15 deaths, with a mortality rate of 1.43%. The peak of poisoning incidents was from June to October, accounting for 89.02% of the total number of incidents. The top three high-incidence areas were Pengshui Miao Tujia Autonomous County, Dianjiang County, and Nanchuan District. Poisonous mushroom poisoning incidents occurring in household settings, accidental picking and ingestion, and cases involving unidentified mushroom species accounted for 89.02%, 83.33%, and 90.15% of all foodborne disease outbreak incidents, respectively. Conclusion Foodborne disease incidents related to poisonous mushrooms in Chongqing City show an upward trend, and the effectiveness of prevention and control needs to be improved. Based on their seasonal, regional and household clustering characteristics, efforts should be made before the peak season of mushroom poisoning in high-risk areas, targeting key populations with health education, monitoring and early warning, food safety supervision, and medical treatment.

Introduction: Steroid cell tumors are rare sex cord-stromal tumors, accounting for <0.1% of ovarian neoplasms. Extraovarian steroid cell tumors are exceptionally rare, often androgensecreting, and pose significant diagnostic challenges. Early recognition is essential to prevent prolonged morbidity from hyperandrogenism. Case: A 60-year-old female, 15 years after total hysterectomy and bilateral salpingo-oophorectomy for a large ovarian mass with massive ascites, presented with deranged liver function tests on routine follow-up. Ultrasonography and computed tomography imaging revealed multiple hypervascular lesions in the liver, retroperitoneum, and peritoneum, suggestive of metastatic disease, with normal-appearing adrenal glands. Biopsy of a liver lesion demonstrated a metastatic neoplasm with morphology and immunoprofile favoring a steroid cell tumor. However, metastasis from the adrenal cortex or an ovarian primary could not be excluded. Given the prior bilateral oophorectomy, metastatic adrenocortical carcinoma was initially suspected, prompting endocrine evaluation. Further history revealed a 1-year history of progressive virilization, including increased facial hair and frontal balding. Hormonal studies demonstrated elevated testosterone (12.2 mmol/L and reference range 0.1–1.42) and dehydroepiandrosterone sulfate (15.9 µmol/L and reference range 0.510–5.560) and the adrenocorticotropic hormone level of 11.7 pmol/L (reference range 1.60–13.9) with suppressed gonadotrophins. Additional workup for catecholamine, cortisol, and aldosterone excess was unremarkable. The discordance between androgen excess and normal adrenal imaging, despite absent ovarian tissue, suggested an extraadrenal androgen-secreting steroid cell tumor. A second histopathology review and multidisciplinary discussion with radiology, gynecologic oncology, and pathology teams were undertaken. As the disease was deemed inoperable, repeat retroperitoneal lesion biopsy confirmed metastatic steroid cell tumor and guided palliative chemotherapy. She was subsequently referred to gynecologic oncology for systemic chemotherapy. Conclusion Extra-adrenal steroid cell tumors, though rare, should be considered in patients with hyperandrogenism long after bilateral oophorectomy, especially when adrenal imaging is normal. Multidisciplinary evaluation and repeat biopsy are often crucial for establishing the diagnosis and guiding treatment.
Hyperandrogenism ; Ovariectomy ; Steroids ; Neoplasms

Introduction: Atypical parathyroid adenoma (APA) constitutes approximately 0.5–4.0% of all cases of primary hyperparathyroidism (pHPT). Here, we report a case of APA presenting with severe hypercalcemia, complicated with renal impairment, bilateral medullary nephrocalcinosis, and multiple fragility fractures. Case: A 45-year-old male initially presented with a 6-month history of constipation, polyuria, lethargy, bone pain, and difficulty in initiating micturition. Laboratory investigations revealed impaired renal function with an estimated glomerular filtration rate of 41.4 mL/min, severe hypercalcemia (4.07 mmol/L), and an elevated intact parathyroid hormone (iPTH) level of 104.0 pmol/L (reference range: 1.58–6.03 pmol/L), confirming the diagnosis of pHPT. He was also found to have vitamin D deficiency, with a serum total 25-hydroxyvitamin D level of 46 nmol/L. Ultrasound of the abdomen demonstrated bilateral medullary nephrocalcinosis, while neck ultrasound and Tc-99 m sestamibi parathyroid scintigraphy revealed a concordant lesion in the posterior aspect of the left thyroid lobe, suggestive of a parathyroid adenoma. He returned 3 months later with closed fractures of the right subtrochanteric femur and the right humerus following a fall from standing height. In view of persistent hypercalcemia despite hyperhydration and treatment with zoledronic acid, subcutaneous denosumab (60 mg) was administered, resulting in an improvement in serum calcium levels. A left inferior parathyroidectomy was then performed concurrently with internal fixation of the right femur. The surgery was uneventful. Histopathological examination confirmed an atypical parathyroid adenoma. Postoperatively, the serum calcium and iPTH levels normalized, and the patient remained asymptomatic and normocalcemic during regular follow-up. Conclusion APA remains a diagnostic and therapeutic challenge due to its clinical, biochemical, and histopathological features of equivocal malignancy. Surgical resection remains the mainstay of management of APA, and long-term surveillance is essential in view of its uncertain malignant potential and risk of recurrence.
Hypercalcemia ; Parathyroid Neoplasms

Introduction: Giant prolactinomas represent 2–3% of prolactin-secreting pituitary adenomas and show a male predominance. They present with mass effect symptoms and hypogonadism, but may be overlooked, leading to delayed diagnosis. Although dopamine agonists are first-line therapy, management remains challenging due to the large size and invasive behavior. This study aims to describe the clinical and radiological features, treatment modalities, and outcomes of three cases of giant prolactinomas. We retrospectively reviewed three men with giant prolactinomas, including their clinical, biochemical, and radiological features, along with treatment and outcomes. Cases: Three male patients aged 35–59 years with giant prolactinomas were included. Two patients presented with visual disturbances, headache, and features of hypogonadism, while one patient had acute confusion and visual loss secondary to obstructive hydrocephalus requiring ventriculoperitoneal shunt insertion. Imaging in all cases demonstrated large invasive pituitary macroadenomas with extensive local extension. Baseline serum prolactin levels were markedly elevated, ranging from 86,568 to 441,116 uIU/mL (86–324 uIU/mL). All patients had secondary hypogonadism, while secondary hypothyroidism and hypocortisolism were each identified in two patients. One patient also had poorly controlled diabetes mellitus at presentation. Dopamine agonist therapy was initiated as the primary therapy for all the patients. Two patients developed cerebrospinal fluid leak following initiation of low-dose dopamine agonist therapy (one patient received cabergoline 0.25 mg weekly, while another received 0.5 mg weekly), which resolved spontaneously with conservative management. Serum prolactin levels decreased markedly, with significant improvement in symptoms related to mass effect following treatment. Conclusion Giant prolactinomas may present with significant mass effect and multiple pituitary hormone deficiencies. Dopamine agonists remain the cornerstone of management and can result in substantial biochemical and clinical improvement even in large invasive tumors. However, rapid tumor shrinkage may lead to complications such as cerebrospinal fluid leak, highlighting the importance of close monitoring during treatment initiation.
Prolactinoma

Introduction: Arginine vasopressin (AVP) deficiency is an uncommon but important presentation of infiltrative hypothalamic– pituitary disorders. In adults, isolated AVP deficiency with pituitary stalk thickening is diagnostically challenging, especially in the absence of systemic disease. Langerhans cell histiocytosis (LCH) is a rare cause and may precede systemic involvement by several years. Case: We report a 42-year-old male who presented in 2017 with polyuria and polydipsia, with urine output of up to 10 L/ day. AVP deficiency was confirmed by the water deprivation test, and desmopressin was initiated. Initial pituitary magnetic resonance imaging (MRI) was normal, baseline anterior pituitary hormonal evaluation was unremarkable, and contrast-enhanced computed tomography (CECT) of the thorax and abdomen showed no abnormalities. Repeat pituitary MRI 1 year later demonstrated loss of the posterior pituitary bright spot with pituitary stalk thickening. In the absence of systemic involvement, a presumptive diagnosis of lymphocytic hypophysitis was made, and pituitary biopsy was deferred due to the high procedural risk. Serial pituitary MRIs over the following years showed persistent infundibular thickening and continued absence of the posterior pituitary bright spot, without interval progression or development of additional hormonal deficiencies. The patient remained clinically stable until June 2024, when new-onset left hip pain prompted MRI, revealing a heterogeneous mass involving the femoral neck and intertrochanteric region with a pathological fracture. Histopathological examination following wide resection confirmed LCH, with negative BRAF V600 mutation. Postoperative PET scan revealed a multisystem disease involving the skeleton, lymph nodes, spine, and gastrointestinal tract, with no bone marrow involvement. He subsequently completed six cycles of intravenous methotrexate and cytarabine. Conclusion Adult-onset AVP deficiency may be the earliest manifestation of occult multisystem Langerhans cell histiocytosis. This case highlights the importance of longterm follow-up and reconsideration of the initial diagnosis when new systemic features emerge.
Histiocytosis, Langerhans-Cell

Introduction: Insulinoma is a rare functioning pancreatic neuroendocrine tumor and the most common cause of endogenous hyperinsulinemic hypoglycemia. Although biochemical confirmation is usually straightforward, tumor localization may be difficult when lesions are small and not detected on conventional cross-sectional imaging. In such cases, endoscopic ultrasound (EUS) plays an important role in identifying occult lesions and facilitating definitive treatment. Case: A 52-year-old female was admitted in April 2025 with recurrent seizures secondary to hypoglycemia for 3 years, with increasing frequency over time. She fulfilled Whipple’s triad, with documented capillary glucose of 1.8 mmol/L during an episode and symptom resolution following glucose administration. A supervised prolonged fasting test confirmed endogenous hyperinsulinemic hypoglycemia, with plasma glucose 1.4 mmol/L, insulin 122 pmol/L, and C-peptide 1,010 pmol/L. Short Synacthen test demonstrated adequate adrenal reserve. Due to persistent hypoglycemia, she required high-dose diazoxide. Contrast-enhanced computed tomography abdomen did not reveal a pancreatic lesion but incidentally detected a right ovarian teratoma. She underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy in June 2025, with histopathology confirming a mature cystic teratoma without malignancy. However, hypoglycemic episodes persisted. Further evaluation with EUS in July 2025 identified a highly vascular isoechoic 8 × 8 mm lesion in the pancreatic body. Fine-needle biopsy confirmed a well-differentiated neuroendocrine tumor (WHO grade 1) with Ki-67 index of 2%. She subsequently underwent EUSguided radiofrequency ablation in August 2025. Follow-up EUS in December 2025 showed post-ablation change, and her hypoglycemic episodes resolved completely, allowing diazoxide to be discontinued. Conclusion This case highlights the diagnostic challenge of occult insulinoma in the presence of negative conventional imaging. EUS was pivotal for tumor localization and tissue diagnosis, while EUS-guided radiofrequency ablation provided effective minimally invasive treatment in a carefully selected patient.
Insulinoma ; Tomography, X-Ray Computed