Artificial Intelligence Methods for the Argenta Classification of Deformational Plagiocephaly to Predict Severity and Treatment Recommendation.

INTRODUCTION: Deformational plagiocephaly (DP) can be classified into 5 severity types using the Argenta scale (AS). Patients with type III or higher require referral to craniofacial surgery for management. Primary care pediatricians (PCPs) are often the first to encounter patients with DP, but current screening methods are subjective, increasing the risk of bias, especially for clinicians with little exposure to this population. The authors propose the use of artificial intelligence (AI) to classify patients with DP using the AS and to make recommendations for referral to craniofacial surgery. METHODS: Vertex photographs were obtained for patients diagnosed with unilateral DP from 2019 to 2020. Using the photographs, an AI program was created to characterize the head contour of these infants into 3 groups based on the AS. The program was trained using photographs from patients whose DP severity was confirmed clinically by craniofacial surgeons. To assess the accuracy of the software, the AS predicted by the program was compared with the clinical diagnosis. RESULTS: Nineteen patients were assessed by the AI software. All 3 patients with type I DP were correctly classified by the program (100%). In addition, 4 patients with type II were correctly identified (67%), and 7 were correctly classified as type III or greater (70%). CONCLUSIONS: Using vertex photographs and AI, the authors were able to objectively classify patients with DP based on the AS. If converted into a smartphone application, the program could be helpful to PCPs in remote or low-resource settings, allowing them to objectively determine which patients require referral to craniofacial surgery.

Implementation of Mandibular Distraction Osteogenesis for Patients With Pierre Robin Sequence in a Developing Country Through International Collaboration: A Paradigm for Success.

OBJECTIVE: Though it has made significant strides, Vietnam remains a resource-constrained country of 98 million people. Vietnam National Children's Hospital (VNCH) provides tertiary care to a catchment of 40 million people and is the sole national children's hospital. As such, it is one of the few referral centers in the country equipped to take care of patients diagnosed with Pierre Robin sequence (PRS) as this requires pulmonary, critical care, otolaryngology, and plastic surgery expertise. Before 2015, the only surgical options were tongue lip adhesion or tracheostomy. Only 20% of patients successfully avoided tracheostomy, mechanical ventilation, or death. From 2015 to 2019, mandibular distraction osteogenesis (MDO) was introduced by visiting international surgeons on a short-term basis. Since 2020, local surgeons at VNCH have refined their technique and widely use MDO independently. This report seeks to capitulate their experience and identify factors leading to success. METHODS: A retrospective review was conducted of patients diagnosed with PRS at VNCH from 2015 to 2022. Paper records were digitized, translated, and reviewed for inclusion criteria, including demographics, indications, hospital course, and postoperative outcomes. RESULTS: Complete records satisfying inclusion criteria were available for 53 patients with a diagnosis of PRS who underwent MDO from 2020 to 2022. From 2015 to 2019, there were 19 cases of MDO, though records were incomplete. The median age at the time of MDO was 50 ± 43 days. Forty patients (75.5%) had isolated PRS and 13 (24.5%) were syndromic. Forty-four patients (83%) had a cleft palate. Fifty-one (96.2%) of patients required preoperative supplemental oxygen or mechanical ventilation. The active distraction and consolidation phase was 4.8 ± 1.3 months. The median days to discharge after surgery was 19.0 ± 8.3 days. Median weight at birth, at the time of surgery, and at the time of device removal were 6.8 ± 1.2, 7.7 ± 1.9, and 14.8 ± 2.8 pounds, respectively. Fifty-two patients (98.1%) had obstructive sleep apnea preoperatively with an average Apnea Hypopnea Index of 25.0 ± 10.6. Post-MDO, only 4 (7.5%) had obstructive sleep apnea and the average Apnea Hypopnea Index was 5.2 ± 0.6. No patients (0) required a tracheostomy for a 100% success rate. CONCLUSIONS: The tremendous success of the implementation of MDO by local surgeons in Vietnam after its introduction by visiting international surgeons illustrates a paradigm for capacity-enhancing global surgical endeavors. Mandibular distraction osteogenesis has replaced tongue lip adhesion as the surgical treatment of choice for PRS patients at VNCH. Surgical techniques can be transferred to operating environments with basic infrastructure through collaboration and resource optimization. These results demonstrate that global surgical engagement may be scalable and repeatable with direct benefits for patients in lower-middle-income countries.

Evaluation of Helmeting Therapy Duration After Endoscopic Strip Craniectomy for Metopic and Sagittal Craniosynostosis.

INTRODUCTION: Endoscopic strip craniectomy (ESC) is a minimally invasive option for early surgical treatment of metopic (MC) and sagittal craniosynostosis (SC). For ESC, however, the postoperative duration and compliance of helmet therapy are crucial to correct MC and SC asymmetry. The purpose of this study is to assess the period of postoperative band therapy and determine differences, if any, between MC and SC. METHODS: A single-institution retrospective review was performed for patients with MC and SC who underwent ESC from November 2015 to 2019. Patients received preoperative, postoperative, and post-band 3-dimensional imaging. Factors recorded included patient sex, insurance type, number of helmets needed, age at surgery, time of first helmet, and at time of completion of helmet therapy, cephalic index, interfrontal angle, and cranial vault asymmetry index. RESULTS: Patients with SC and MC had ESC surgery at 3.3 and 3.4 months of age, respectively.Patients with SC were found to have completed banding therapy at a younger age (7.88 versus 10.0 mo), with shorter duration (4.17 versus 6.00 mo), and less number of bands (1.54 versus 2.21) than patients with MC. After regression analysis, suture type was found to be a significant predictor of total time in band therapy (P=0.039) with MC requiring a longer duration of banding therapy when compared with SC. CONCLUSIONS: Suture type directly correlates with duration of helmeting therapy for patients, with patients with MC requiring longer periods of postop helmeting and increased number of bands as compared with SC.

The Skin Necrosis Conundrum: Examining Long-term Outcomes and Risk Factors in Implant-Based Breast Reconstruction.

BACKGROUND: Mastectomy skin flap necrosis (MSFN) is a common complication following mastectomy that causes significant distress to patients and physicians and also compromises oncologic, surgical, and quality-of-life outcomes. OBJECTIVES: We sought to investigate the long-term outcomes of MSFN following implant-based reconstruction (IBR) and determine the rates and predictors of post-MSFN complications. METHODS: This was a 20-year analysis of consecutive adult (>18 years) patients who developed MSFN following mastectomy and IBR from January 2001 to January 2021. Multivariable analyses were performed to identify factors associated with post-MSFN complications. RESULTS: We identified 148 reconstructions, with a mean follow-up time of 86.6 ± 52.9 months. The mean time from reconstruction to MSFN was 13.3 ± 10.4 days, and most cases (n = 84, 56.8%) were full-thickness injuries. Most cases (63.5%) were severe, 14.9% were moderate, and 21.6% were mild. Forty-six percent (n = 68) developed a breast-related complication, with infection being the most common (24%). An independent predictor of overall complications was longer time from reconstruction to MSFN (odds ratio [OR], 1.66; P = .040). Aging was an independent predictor of overall complications (OR, 1.86; P = .038); infection (OR, 1.72; P = .005); and dehiscence (OR, 6.18; P = .037). Independent predictors of dehiscence were longer interval from reconstruction to MSFN (OR, 3.23; P = .018) and larger expander/implant size (OR, 1.49; P = .024). Independent predictors of explantation were larger expander/implant size (OR, 1.20; P = .006) and nipple-sparing mastectomy (OR, 5.61; P = .005). CONCLUSIONS: MSFN is associated with high risk of complications following IBR. Awareness of the timing and severity of MSFN and the predictors of post-MSFN complications is crucial for guiding evidence-based decision-making and improving outcomes.

Decoding the Mastectomy SKIN Score: An Evaluation of Its Predictive Performance in Immediate Breast Reconstruction.

BACKGROUND: The skin ischemia and necrosis (SKIN) score was introduced to standardize the assessment of mastectomy skin flap necrosis (MSFN) severity and the need for reoperation. We evaluated the association between the SKIN score and the long-term postoperative outcomes of MSFN after mastectomy and immediate breast reconstruction (IBR). METHODS: We conducted a retrospective cohort study of consecutive patients who developed MSFN following mastectomy and IBR from January 2001 to January 2021. Primary outcome was breast-related complications following MSFN. Secondary outcomes were 30-day readmission, operating room (OR) debridement, and reoperation. Study outcomes were correlated with the SKIN composite score. RESULTS: We identified 299 reconstructions in 273 consecutive patients with mean follow-up time of 111.8±3.9 months. Most patients had a composite SKIN score of B2 (25.0%, n=13), followed by D2 (17.3%) and C2 (15.4%). We found no significant difference in rates of OR debridement (p=0.347), 30-day readmission (p=0.167), any complication (p=0.492), or reoperation for a complication (p=0.189) based on the SKIN composite score. The composite skin score was a poor predictor of reoperation, with area under the curve (AUC) of 0.56. A subgroup analysis in patients who underwent implant-based reconstruction revealed no difference in rates of OR debridement (p=0.986), 30-day readmission (p=0.530), any complication (p=0.492), or reoperation for a complication (p=0.655) based on the SKIN composite score. CONCLUSION: The SKIN score was a poor predictor for postoperative MSFN outcomes and reoperation. An individualized risk-assessment tool that incorporates both the anatomical appearance of the breast, imaging data, and patient-level risk factors is needed.

Characterization of Regional Morphological Changes in Sagittal Craniosynostosis Following Endoscopic Strip Craniectomy With Post-operative Helmeting: Predictors for Success.

BACKGROUND: Sagittal craniosynostosis (SC) restricts craniofacial growth perpendicular to the sagittal plane resulting in scaphocephaly. The cranium grows in the anterior-posterior dimension causing disproportionate changes, which can be corrected with either cranial vault reconstruction (CVR) or endoscopic strip craniectomy (ESC) combined with post-operative helmet therapy. ESC is performed at an earlier age, and studies demonstrate benefits in risk profile and morbidity compared to CVR, with comparable results if the post-operative banding protocol is strictly upheld. We aim to identify predictors of successful outcome and, using three-dimensional (3D) imaging, assess cranial changes following ESC with post-banding therapy. MATERIALS AND METHODS: A single institution retrospective review was performed from 2015-19 for patients with SC who underwent ESC. Patients received immediate post-operative 3D photogrammetry for helmet therapy planning and implementation as well as post-therapy 3D imaging. Using these 3D images, the cephalic index (CI) for study patients was calculated before and after helmet therapy. In addition, Deformetrica™ was used to measure volume and shape changes of pre-defined anatomic skull regions (frontal, parietal, temporal, & occipital) based on the pre- and post-therapy 3D imaging results. Fourteen institutional raters evaluated the pre- and post-therapy 3D imaging in order to determine the success of the helmeting therapy. RESULTS: Twenty-one SC patients met our inclusion criteria. Using 3D photogrammetry, 14 raters at our institution rated 16 of the 21 patients to have had successful helmet therapy. There was a significant difference in CI following helmet therapy with both groups, but there was no significant difference in CI between the "successful" and "unsuccessful" groups. Furthermore, the comparative analysis demonstrated that the parietal region had a significantly higher change in mean RMS distance when compared to the frontal or occipital regions. CONCLUSION: For patients with SC, 3D photogrammetry may be able to objectively recognize nuanced findings not readily detectable when using CI alone. The greatest changes in volume were observed in the parietal region, which falls in line with treatment goals for SC. Patients deemed to have unsuccessful outcomes were found to be older at time of surgery and initiation of helmet therapy. This suggests that early diagnosis and management for SC may increase the likelihood of success.

Laparoscopic appendectomy in an adult patient with situs inversus totalis.

Left-sided appendicitis is usually caused by situs inversus totalis or midgut malrotation. Clinical and imaging diagnoses have been presented relatively fully in the literature. However, this is a rare condition, and each related case should be further reported to help the day-to-day clinician better investigate and understand. Therefore, in this paper, we present a case of left-sided acute appendicitis in an adult male patient with situs inversus totalis. In addition, we also discuss the laparoscopic technique of the left-sided appendectomy as it is technically more difficult because of the mirror nature of the anatomy.

Area Deprivation Index is Associated with Variation in Quality of Life and Psychosocial Well-being Following Breast Cancer Surgery.

BACKGROUND: Neighborhood-level factors have been shown to influence surgical outcomes through material deprivation, psychosocial mechanisms, health behaviors, and access to resources. To date, no study has examined the relationship between area-level deprivation (ADI) and post-mastectomy outcomes. METHODS: A cross-sectional survey of adult female breast cancer patients who underwent lumpectomy or mastectomy between January 2018 to June 2019 was carried out. Patient-specific characteristics and ADI information were abstracted and correlated with postoperative global- (SF-12) and condition-specific (BREAST-Q) quality-of-life performance via multivariable regression. Patients were classified into three ADI terciles: 0-39 (low deprivation), 40-59 (moderate deprivation), and 60-100 (high deprivation). RESULTS: A total of 564 consecutive patients were identified, being mostly white (75%) with mean age of 60.2 ± 12.4 years, median body mass index of 27.8 [interquartile range (IQR) 24.3-32.2) kg/m2, median Charlson Comorbidity Index of 3 (IQR 2-5), and mean ADI of 42.3 ± 25.7. African American and Hispanic patients and those with high BMI were more likely to reside in highly deprived neighborhoods (p = 0.003 and p < 0.001). In adjusted models, patients in highly deprived neighborhoods had significantly lower mean SF-12 physical (44.9 [95% CI, 43.8-46.0] versus 44.9 [95% CI, 43.7-46.1] versus 46.3 [95% CI, 45.3-47.3], p = 0.03) and BREAST-Q psychosocial well-being scores (63.5 [95% CI, 59.32-67.8] versus 69.3 [95% CI, 65.1-73.6] versus 69.7 [95% CI, 66.4-73.1], p = 0.01) relative to moderate- and low-deprivation groups. CONCLUSIONS: Patients residing in the most deprived neighborhoods were identified to have worse psychological well-being and quality-of-life. The ADI should be incorporated into the shared decision-making process and perioperative counseling to engender value-based and personalized care, especially for vulnerable populations.

Ink Rheology Regulates Stability of Bioprinted Strands.

Three-dimensional (3D) extrusion bioprinting typically requires an ad hoc trial-and-error optimization of the ink composition toward enhanced resolution. The ink solutions are solidified after leaving cone-shaped or cylindrical nozzles. The presence of ink instability not only hampers the extrusion resolution but also affects the behavior of embedded cellular components. This is a key factor in selecting (bio)inks and bioprinting design parameters for well-established desktop and handheld bioprinters. In this work, we developed an analytical solution for the process of ink deposition and compared its predictions against numerical simulations of the deposition. We estimated the onset of ink instability as a function of ink rheological properties and nozzle geometry. Our analytical results suggest that enhancing the shear-thinning behavior of the ink shortens the toe region of the deposition. Such an extrusion process is often desired, as it leads to faster depositions. However, we demonstrated that such conditions increase the possibility of lateral buckling of the strand once touching the substrate defined as instability in this study. The present study serves as a benchmark for detailed simulations of the extrusion process for optimal bioprinting.

[The effect of Shendan Sanjie capsule on angiogenesis in mice with colitis associated cancer and mechanism].

Objective: To investigate the effects and the mechanism of Shendansanjie capsules on angiogenesis of colitis associated cancer(CAC) mice. Methods: Azoxymethane and dextran sulfact sodium were used to construct a mice model with CAC. Ten mice were divided into the normal group, model group, Shendan Sanjie capsule group, MK-2206 group, and Shendan Sanjie capsule + IGF-1 group, respectively. Immunohistochemistry was used to detect the microvessel density (MVD) in the colon tissue of each group of mice. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the mRNA levels of basic fibroblast growth factor (bFGF) and angiopoietin 2 (Ang2) in colon tissue. Western blot was used to detect the expressions of Akt, p-Akt, vascular endothelial growth factor A (VEGFA), hypoxia-inducible factor-1α (HIF-1α). Results: The number of MVD in the colon tissue of mice in the model group, Shendan Sanjie capsule group, MK-2206 group, Shendan Sanjie capsule + IGF-1 group were 63.3±3.3, 36.6±2.3, 36.6±2.2, 50.3±2.5, significantly higher than 2.0±0.1 in the normal group (P<0.05). The number of MVD in Shendan Sanjie capsule group, MK-2206 group and Shendan Sanjie capsule+ IGF-1 group are lower than that in model group (P<0.05), while Shendan Sanjie capsule+ IGF-1 group is higher than Shendan Sanjie Capsule group (P<0.05). The relative expressions of bFGF mRNA in the colon cancer tissue of mice in the model group, Shendan Sanjie capsule group, MK-2206 group and Shendan Sanjie capsule+ IGF-1 group were 4.55±0.31, 2.46±0.37, 2.49±0.33, 3.34±0.21, respectively, and the relative mRNA expressions of Ang2 were 5.78±0.19, 2.21±0.14, 2.26±0.17 and 3.67±0.32, respectively, which were significantly higher than 1.01±0.05 and 0.99±0.07 in the normal group (P<0.05). The mRNA levels of bFGF and Ang2 in Shendan Sanjie capsule group, MK-2206 group and Shendan Sanjie capsule+ IGF-1 group were lower than those in the model group (P<0.05), while Shendan Sanjie capsule+ IGF-1 group is higher than Shendan Sanjie capsule group (P<0.05). The relative expression levels of p-Akt/Akt, VEGFA and HIF-1α in colon cancer tissues of the model group were 4.75±0.18, 4.64±0.22 and 4.84±0.12, respectively, which were significantly higher than 1.01±0.07, 0.95± 0.08 and 0.98±0.05 in the normal group (P<0.05). The relative expressions of p-Akt/Akt, VEGFA and HIF-1α in colon cancer tissues in the Shendan Sanjie capsule group were 2.24±0.22, 3.15±0.26 and 2.07±0.18, respectively, which were significantly lower than those in the model group (P<0.05). However, compared with the MK-2206 group, the difference was not statistically significant (P>0.05). The relative expression levels p-Akt/Akt, VEGFA and HIF-1α in colon cancer tissue of the Shendan Sanjie capsule+ IGF-1 group were 3.37±0.15, 4.02±0.11, 3.52±0.24, respectively, which were significantly higher than those in the Shendan Sanjie capsule group (P<0.05). Conclusion: Shendan Sanjie capsules may inhibit Akt/HIF-1α/VEGFA signaling pathway, and then reduce the expression of microvascular growth factors bFGF and Ang2, thereby inhibit the tumor angiogenesis of CAC.

Diagnostic value of maximum signal intensity on T1-weighted MRI images for differentiating parotid gland tumours along with pathological correlation.

AIM: To investigate the efficacy of the maximum signal intensity of tumour on T1-weighted magnetic resonance imaging (MRI) images for differentiating Warthin's tumours (WTs) from pleomorphic adenomas (PAs) and malignant tumours (MTs). MATERIALS AND METHODS: One hundred and fifty-four histopathologically confirmed parotid tumours, including 76 PAs, 45 WTs, and 33 MTs, were analysed. MRI results were compared with pathological findings. The maximum signal intensity of tumour and the average signal intensity of spinal cord were measured on T1-weighted images, then the tumour-to-spinal cord signal intensity ratio (T1-max-SIR) was calculated. The distribution of T1-max-SIRs among the three groups of tumours was analysed using the Mann-Whitney U-test. Receiver operating characteristic curves were generated to assess the ability of T1-max-SIRs to differentiate parotid tumours. In addition, the interobserver agreement between readers was assessed using interclass correlation coefficient (ICC). RESULTS: T1-max-SIRs were higher in WTs than in PAs (p<0.001) and MTs (p<0.001), and no significant difference was found between PAs and MTs (p=0.151). The area under the curve (AUC) of T1-max-SIRs for differentiating WTs from PAs was 0.901, with a sensitivity of 91.1% and a specificity of 82.9%. The AUC of T1-max-SIRs for differentiating WTs from MTs was 0.851, with a sensitivity of 88.9% and a specificity of 78.8%. Readers had excellent interobserver agreement on T1-max-SIRs (ICC = 0.989; 95% confidence interval, 0.985-0.992). CONCLUSIONS: T1-max-SIRs can be useful for differentiating WTs from PAs and MTs with high diagnostic efficiency.

Streamlined MRM method transfer between instruments assisted with HRMS matching and retention-time prediction.

Multiple reaction monitoring (MRM) mode using liquid-chromatography tandem mass spectrometry (e.g., LC-QqQ-MS/MS) has been extensively employed in the small molecule analysis with trace levels in complex samples owing to its high sensitivity. However, most of the reported MRM methods are developed using authentic standards, which are often costly yet not readily available. To address this question, a practical platform for the MRM method transfer between different LC-QqQ-MS/MS instruments, assisted by the high-resolution mass spectrometry (LC-HRMS) and retention time (RT) prediction, has been developed in this study. The reported platform can take advantage of both the high sensitivity of LC-MRM method and ion transition pairs from the previous publications. LC-HRMS can provide the accurate mass measurement of the compounds, though high-quality MS/MS fragments are usually difficult to obtain for chemicals at trace levels. Retention time matching and peaks matching between both instrumental platforms rule out isobaric candidates. With an additional retention time prediction filter from quantitative structure retention relationship (QSRR) model based on random forest feature selection (Pearson r2 = 0.63), identification of small molecules is achieved at a high confidence level without using authentic standards. The developed platform has been validated with robustness by examining spiked environmental chemicals in sludge water samples, biological urine, and cell extracts.

Cardiac amyloidosis mimicking acute coronary syndrome: a case report and literature review.

BACKGROUND: Cardiac amyloidosis, a progressive cardiac disease, results from the accumulation of undegraded proteinaceous substrates in the extracellular matrix of the heart. It may present as acute coronary syndrome (ACS); therefore, a clear distinction remains challenging in clinical practice. We describe a case of cardiac amyloidosis mimicking ACS. CASE SUMMARY: A 72-year-old man experienced chest discomfort for 2 days. He gradually developed dyspnoea during the preceding month. Electrocardiogram (ECG) showed sinus rhythm with right bundle branch block and low voltage. Echocardiography revealed concentric left ventricular thickening, biatrial dilation, and preserved ejection fraction with predominantly left ventricular basal hypokinesis. Serial testing of the cardiac biomarkers showed persistently increased high-sensitive cardiac troponin T levels and normal serum creatine kinase myocardial band levels. He was diagnosed with ACS with haemodynamic stability. However, coronary angiography demonstrated non-obstructive coronary arteries. Furthermore, significant macroglossia and periorbital purpura were noticed. Laboratory investigations revealed elevated serum immunoglobulin free light chain (FLC) kappa and lambda levels with an increased FLC ratio. Histological analysis of the biopsied abdominal skin confirmed amyloidosis. DISCUSSION: Cardiac amyloidosis often presents as restrictive cardiomyopathy. The usual symptoms include dyspnoea and peripheral oedema. Chest pain may manifest rarely, leading to misdiagnosis as coronary artery disease. Some findings suggestive of cardiac amyloidosis include clinical signs such as amyloid deposits, dyspnoea, low ECG voltage, and basal-predominant hypokinesis with relative apical sparing in echocardiography. Serum FLC test and abdominal skin biopsy can confirm the diagnosis of amyloidosis when a myocardial biopsy is not feasible.

Small-Vessel Vasculopathy Due to Aberrant Autophagy in LAMP-2 Deficiency.

Lysosomal associated membrane protein 2 (LAMP2) is physiologically implicated in autophagy. A genetic LAMP2 defect causes Danon disease, which consists of two major phenotypes of myopathy and cardiomyopathy. In addition, arteriopathy may manifest on rare occasions but the pathological basis remains unknown. We encountered two Danon families that developed small-vessel vasculopathy in the coronary or cerebral arteries. To investigate the underlying mechanisms, we characterized the biological features of LAMP-2-deficient mice and cultured cells. LAMP-2-deficient mice at 9-24 months of age showed medial thickening with luminal stenosis due to proliferation of vascular smooth muscle cells (VSMC) in muscular arteries. Ultrastructural analysis of VSMC revealed various autophagic vacuoles scattered throughout the cytoplasm, suggesting impaired autophagy of long-lived metabolites and degraded organelles (i.e., mitochondria). The VSMC in Lamp2 null mice expressed more vimentin but less α-smooth muscle actin (α-SMA), indicating a switch from contractile to synthetic phenotype. Silencing of LAMP2 in cultured human brain VSMC showed the same phenotypic transition with mitochondrial fragmentation, enhanced mitochondrial respiration, and overproduction of reactive oxygen species (ROS). These findings indicate that LAMP-2 deficiency leads to arterial medial hypertrophy with the phenotypic conversion of VSMC, resulting from age-dependent accumulation of cellular waste generated by aberrant autophagy.

A DNA methylation biomarker of alcohol consumption.

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10-7. Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10-7. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

Phase II trial of cetuximab in patients with metastatic or locally advanced soft tissue or bone sarcoma.

BACKGROUND: The epidermal growth factor receptor (EGFR) tyrosine kinase is overexpressed in many sarcoma subtypes. In vitro studies suggest a role of the EGFR pathway in growth and differentiation in some sarcomas. We conducted a phase II trial of cetuximab, a monoclonal antibody to EGFR, in patients with advanced sarcomas. METHODS: Cetuximab was administered intravenously as a loading dose on 400 mg/m on day 1, cycle 1 and subsequently 250 mg/m on days 1, 8, 15, and 21 of a 28 day cycle. Using a Simon 2-stage design, 21 EGFR patients were to be accrued in the first stage, with an additional 11 patients if >3 patients met the primary endpoint of 4-month progression-free survival (PFS). An exploratory subgroup of EGFR patients was also included. RESULTS: Twenty-one and 15 evaluable patients enrolled in the EGFR and EGFR subgroup, respectively. One of 21 EGFR patients (4.8%) achieved 4-month PFS. Median PFS and overall survival were 1.7 months [95% confidence interval (CI), 1.6-1.8] and 7.7 months (95% CI, 4.2-10.7), respectively. Three of 15 EGFR patients (20%) achieved 4-month PFS. Median PFS and overall survival were 1.8 months (95% CI, 0.8-2.5) and 15.7 months (95% CI, 7.7-25.3), respectively. No responses were seen in either group. There was no correlation between clinical outcomes and expression of MAP-K, PTEN, and phospho-EGFR. CONCLUSIONS: Cetuximab is not an active as a single agent in advanced sarcoma. Further study of anti-EGFR therapy in sarcoma should only be considered after identification of molecular abnormalities predictive of benefit.

A phase II study of imatinib in patients with advanced anaplastic thyroid cancer.

BACKGROUND: Currently, there is no standard treatment for metastatic anaplastic thyroid cancer (ATC). DNA microarray analysis has shown platelet-dervived growth factor receptor (PDGFR) overexpression in ATC relative to well-differentiated thyroid cancer. In p53-mutated/deficient ATC cell lines, cABL is overexpressed, and selective inhibition of cABL results in a cytostatic effect. Imatinib inhibits tyrosine kinase activity of Bcr-ABL and PDGF. We hypothesize that patients with ATC that over-expresses PDGF receptors or cABL will respond to imatinib. METHODS: Patients with histologically confirmed ATC who had measurable disease and whose disease expressed PDGF receptors by immunohistochemistry were eligible for study. Imatinib was administered at 400 mg orally twice daily without drug holiday. Response to treatment was assessed every 8 weeks. Patients with complete response, partial responses, or stable disease were treated until disease progression. The study was terminated early due to poor accrual. RESULTS: From February 2004 to May 2007, 11 patients were enrolled and were started on imatinib. At baseline, 4/11 had locoregional disease, 5/11 had distant metastases, and 2/11 had both. Nine of 11 had prior chemoradiation, and 7/11 had thyroidectomy. Eight of 11 were evaluable for response; 4 were excluded for lack of follow-up with radiologic evaluation. The overall response rates at 8 weeks were complete response 0/8, partial response 2/8, and stable disease 4/8. The median time to follow-up was 26 months (ranges 23-30 months). The rate of 6-month progression-free survival was 36% (95% confidence interval, 9%-65%). The rate of 6-month overall survival was 45% (95% confidence interval, 16%-70%). The most common grade 3 toxicity was edema in 25%; other grade 3 toxicities included fatigue and hyponatremia (12.5% each). There were no grade 4 toxicities or treatment related deaths. CONCLUSIONS: Imatinib appears to have activity in advanced ATC and is well tolerated. Due to difficulty of accruing patients with a rare malignancy at a single institution, further investigation of imatinib in ATC may be warranted in a multi-institutional setting.