Signet ring cells and conditional survival after trimodality therapy for esophageal adenocarcinoma.

BACKGROUND AND METHODS: Although signet ring cell (SRC) histology is associated with resistance to neoadjuvant chemoradiotherapy and worse overall survival (OS) in esophageal adenocarcinoma (EAC), its prognostic relationship among patients who survive the early period following resection is unknown. EAC patients who underwent trimodality therapy at a single institution (2006-2018) were identified. Bayesian multivariable regression (BMR) analyses of OS and additional OS from a 3-year landmark were performed. RESULTS: Of 631 patients, SRCs were present in 16.0% (N = 101). SRC was associated with shorter median OS (45.8 [95% confidence interval: 31.0-96.7] vs. 79.8 [63.0-107.2] months; p = 0.014). In BMR analysis, the absence of an SRC component was moderately associated with improved OS (probability of beneficial effect, PBE = 0.879). Three-year conditional BMR analysis of additional OS (N = 357) showed that SRC status no longer had a prognostic effect (PBE = 0.546); higher pathological stage was strongly associated with worse additional OS (PBE < 0.001). CONCLUSIONS: The presence of SRC portends worse OS following trimodality therapy for EAC. However, this prognostic impact is dynamic and abates by 3 years postoperatively. In contrast, a higher pathological stage is strongly associated with poor overall and 3-year conditional survival. DISCUSSION: These findings may inform postoperative patient counseling and surveillance protocols.

Is the third molar the most frequently extracted tooth? A population-based study utilizing dental panoramic radiographs in adults.

OBJECTIVES: The study aimed to examine the authenticity of the often-mentioned statement that the third molar is the most frequently extracted tooth. This finding has not been shown previously in a large population-based sample. MATERIALS AND METHODS: Data comprised a nationally representative sample of 6082 panoramic radiographs taken from adults in the cross-sectional Health 2000 Survey. From the radiographs, all missing teeth were recorded. Information on congenital agenesis of individual teeth was retrieved from two published meta-analyses. Primary outcome was the frequency of missing teeth by tooth type. Explanatory variables were age, sex, and the jaw (maxilla/mandible). Statistical analyses included χ2 test and binomial logistic regression. RESULTS: Mean age of participants (46% men, 54% women) was 53 years (SD 14.6; range 30‒97 years). Missing teeth occurred more often in women than in men (P < 0.001). The third molar was most frequently missing and the canine least frequently. In the maxilla and mandible, the third molar was missing more often than each of the other tooth types up to the age of 80 years (P < 0.01). CONCLUSIONS: When considering the rates of congenital agenesis of individual teeth, it is concluded that the third molar remained the most common tooth extracted up till the age of 80 years. CLINICAL RELEVANCE: The third molar is the most common target for extraction, but also the most common tooth associated with malpractice claims, and therefore, calls for skills, adequate equipment, and other resources for a successful extraction.

High incidence and geographic distribution of cleft palate cases in Finland are associated with a regulatory variant in IRF6.

In Finland the frequency of isolated cleft palate (CP) is higher than that of isolated cleft lip with or without cleft palate (CL/P). This trend contrasts to that in other European countries but its genetic underpinnings are unknown. We performed a genome-wide association study for orofacial clefts, which include CL/P and CP, in the Finnish population. We identified rs570516915, a single nucleotide polymorphism that is highly enriched in Finns and Estonians, as being strongly associated with CP ( P = 5.25 × 10 -34 , OR = 8.65, 95% CI 6.11-12.25), but not with CL/P ( P = 7.2 × 10 -5 ), with genome-wide significance. The risk allele frequency of rs570516915 parallels the regional variation of CP prevalence in Finland, and the association was replicated in independent cohorts of CP cases from Finland ( P = 8.82 × 10 -28 ) and Estonia ( P = 1.25 × 10 -5 ). The risk allele of rs570516915 disrupts a conserved binding site for the transcription factor IRF6 within a previously characterized enhancer upstream of the IRF6 gene. Through reporter assay experiments we found that the risk allele of rs570516915 diminishes the enhancer activity. Oral epithelial cells derived from CRISPR-Cas9 edited induced pluripotent stem cells demonstrate that the CP-associated allele of rs570516915 concomitantly decreases the binding of IRF6 and the expression level of IRF6 , suggesting impaired IRF6 autoregulation as a molecular mechanism underlying the risk for CP.

A Phase 2 Multicenter Clinical Trial of Intraoperative Molecular Imaging of Lung Cancer with a pH-Activatable Nanoprobe.

PURPOSE: Intraoperative molecular imaging (IMI) uses tumor-targeted optical contrast agents to improve identification and clearance of cancer. Recently, a probe has been developed that only fluoresces when activated in an acidic pH, which is common to many malignancies. We report the first multicenter Phase 2 trial of a pH-activatable nanoprobe (pegsitacianine, ONM-100) for IMI of lung cancer. METHODS: Patients with suspected or biopsy-confirmed lung cancer scheduled for sublobar resection were administered a single intravenous infusion of pegsitacianine (1 mg/kg) one to three days prior to surgery. Intraoperatively, the patients underwent a white light thoracoscopic evaluation, and then were imaged with an NIR thoracoscope to detect tumor fluorescence. The primary study endpoint was the proportion of patients with a clinically significant event (CSE) which was defined as an intraoperative discovery during IMI that led to a change in the surgical procedure. Possible CSEs included (i) localizing the index lung nodule that could not be located by white light, (ii) identifying a synchronous malignant lesion, or (iii) recognizing a close surgical margin (< = 10 mm). Secondary endpoints were sensitivity, specificity, NPV, and PPV of pegsitacianine in detecting tumor-containing tissue. The safety evaluation was based on adverse event reporting, clinical laboratory parameters, and physical examinations. RESULTS: Twenty patients were confirmed as eligible and administered pegsitacianine. Most of the patients were female (n = 12 [60%]), middle-aged (mean age 63.4 years), and former smokers (n = 13 [65%], 28.6 mean pack years). Mean lesion size was 1.9 cm, and most lesions (n = 17 [85%]) were malignant. The most common histologic subtype was adenocarcinoma (n = 9). By utilizing IMI with pegsitacianine, one patient had a CSE in the detection of a close margin and another had localization of a tumor not detectable by traditional surgical means. Six of 19 (31.6%) malignant lesions fluoresced with mean tumor-to-background ratio (TBR) of 3.00, as compared to TBR of 1.20 for benign lesions (n = 3). Sensitivity and specificity of pegsitacianine-based IMI for detecting malignant tissue was 31.6% and 33.3%, respectively. Positive predictive value (PPV) and negative predictive value (NPV) of pegsitacianine-based IMI was 75% and 7.1%, respectively. Pegsitacianine-based imaging was not effective in differentiating benign and malignant lymph nodes. From a safety perspective, no drug-related serious adverse events occurred. Four patients experienced mild pegsitacianine-related infusion reactions which required discontinuing the study drug with complete resolution of symptoms. CONCLUSIONS: Pegsitacianine-based IMI, though well tolerated from a safety perspective, does not consistently label lung tumors during resection and does not provide significant clinical benefit over existing standards of surgical care. The biology of lung tumors may not be as acidic as other solid tumors in the body thereby not activating the probe as predicted.

Pulmonary Surgical Margins for Metastatic Osteosarcoma: Is Negative Margin Enough?

BACKGROUND: In advanced osteosarcoma, the lung is the most frequent site of distant metastasis, with metastasectomy often used for local disease control. The influence of pulmonary resection margin length on outcomes for osteosarcoma has not been well explored. This study sought to evaluate the impact of margin length relative to tumor size on local recurrence and survival in lung-limited metastatic osteosarcoma. METHODS: Patients with metastatic osteosarcoma who underwent lung resection between 2000 and 2020 were identified from a single institution. Clinicopathologic variables were collected. The margin length-to-tumor size ratio (MTR) was calculated per nodule and classified relative to an MTR of 0.5. The primary outcome was development of local recurrence per nodule. Multivariate logistic regression was used to investigate covariates. RESULTS: A total of 142 patients with 689 nodules met inclusion criteria, with mean age of 35.6 years (interquartile range [IQR], 20.9-46.6 years). Patients were predominantly male (n = 87; 61.3%) and White (n = 106; 72.5%). Most nodules (n = 644; 93.5%) were resected through thoracotomy. The mean tumor size was 0.8 cm (IQR, 0.5-1.70 cm), with an average margin length of 0.3 cm (IQR, 0.1-0.7 cm). Among all nodules, 299 (43.4%) had an MTR >0.5. Systemic therapy was received by 94 patients (66.2%) preoperatively and by 100 patients (70.4%) postoperatively. Importantly, the study found that an MTR >0.5 conferred a protective effect against disease recurrence (hazard ratio, 0.67; 95% CI, 0.52-0.87; P = .003). CONCLUSIONS: In resected pulmonary metastatic osteosarcoma, a margin length greater than one-half the size of the pulmonary nodule is associated with a lower incidence of local disease recurrence. This finding has implications for the subsequent need for additional therapy and disease-free status, thus meriting attentive intraoperative consideration.

The physical and psychosocial benefits of a family judo program for parents of children with Autism Spectrum Disorder: A pilot study.

BACKGROUND: Parents of children with Autism Spectrum Disorder (ASD) tend to have high levels of stress and poor health habits. There is a lack of interventions that focus on improving health outcomes in parents of children with ASD. OBJECTIVE: To examine the physical and psychosocial effects of a family-based judo program on parents of children diagnosed with ASD. METHODS: This study utilized a pre-post single group design. Eighteen parent-child dyads participated in a 14-week judo program for families of children with ASD. Judo sessions were held once a week for 45 min. Parents wore wrist accelerometers to assess physical activity/sleep quality, and completed surveys regarding self-reported stress levels pre- and post-judo. Parents also completed open-ended questions regarding their experience in the program. Paired sample t-tests were conducted to examine changes in stress, physical activity, and sleep quality from pre-to post-program. RESULTS: Both a decrease in parental stress (47.77 vs. 41.61, p < 0.01) and an increase in minutes per day of physical activity (35.49 vs 45.94, p = 0.002) were observed from baseline to post-program. Fourteen of the 18 parents (78 %) reported at least one psychosocial benefit (e.g. increased self-confidence) or physical health benefit (e.g. increased physical activity) from participation in the program. CONCLUSIONS: A family judo program may provide health benefits, such as reducing stress levels and increasing physical activity in parents of children with ASD. Further research involving larger sample sizes is necessary to better determine the effects of judo on both parents and their children with ASD.

Patient-reported outcome measures in surgical patients with upper gastrointestinal cancers: A qualitative interview study.

BACKGROUND AND OBJECTIVES: Patients with pancreatic and gastroesophageal (PGE) cancers experience high symptom burden, but patient experience throughout multimodality treatment remains unclear. We aimed to delineate the experience and symptom burden of patients throughout their perioperative course. METHODS: Qualitative interviews were performed with 17 surgical patients with PGE cancer. Interview transcripts were analyzed and symptoms were ranked by frequency. An expert panel assessed the relevance of these symptom inventory items. RESULTS: Of the 17 patients included, 35% (n = 6) underwent gastrectomy, 30% (n = 5) underwent esophagectomy, and 35% (n = 6) underwent pancreatectomy; 76% (n = 13) received neoadjuvant systemic chemotherapy and/or chemoradiation. Overall, 32 symptoms were reported, and 19 were reported by over 20% of patients. An expert panel rated nine symptoms to be relevant or very relevant to PGE surgical patients. These symptoms (difficulty swallowing, heartburn/reflux, diarrhea, constipation, flushing/sweating, stomach feeling full, malaise, dizziness, or feeling cold) were added to the core MD Anderson Symptom Inventory (MDASI) if they were commonly reported or reached a threshold relevancy score. CONCLUSIONS: In this qualitative study, we developed a provisional symptom inventory for patients undergoing surgery for PGE cancer. This symptom inventory module of the MDASI for PGE surgical patients will be psychometrically tested for validity and reliability.

The International Association for the Study of Lung Cancer Pleural Mesothelioma Staging Project: Proposal for Revision of the TNM Stage Groupings in the Forthcoming (Ninth) Edition of the TNM Classification for Pleural Mesothelioma.

INTRODUCTION: The eighth edition of the TNM classification of pleural mesothelioma (PM) saw substantial changes in T and N components and stage groupings. The International Association for the Study of Lung Cancer collected data into a multinational database to further refine this classification. This ninth edition proposal incorporates changes proposed in the clinical (c)T component but not the pathologic T component, to include size criteria, and further refines TNM stage groupings for PM. METHODS: Data were submitted through electronic data capture or batch transfer from institutional databases. Survival was measured from diagnosis date. Candidate stage groups were developed using a recursive partitioning and amalgamation algorithm applied to all cM0 cases for clinical stage and subsequently for pathologic stage. Cox models were developed to estimate survival for each stage group. RESULTS: Of 3598 submitted cases, 2192 were analyzable for overall clinical stage and 445 for overall pathologic stage. Recursive partitioning and amalgamation generated survival tree on overall survival outcomes restricted to cM0, with newly proposed (ninth edition) cT and cN component-derived optimal stage groupings of stage I (T1N0), II (T1N1; T2N0), IIIA (T1N2; T2N1/2; any T3), IIIB (any T4), and IV (any M1). Although cT and pathologic T descriptors are different in the ninth edition, aligning pathologic stage groupings with clinical stage produced better discrimination than did retaining eighth edition pathologic stage groupings. CONCLUSIONS: To our knowledge, this revision of the clinical TNM classification for PM is the first to incorporate the measurement-based proposed changes in cT category. The pathologic TNM aligns with clinical TNM.

The International Association for the Study of Lung Cancer Mesothelioma Staging Project: Proposals for the "N" Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Pleural Mesothelioma.

INTRODUCTION: The International Association for the Study of Lung Cancer developed an international database to inform potential revisions in the ninth edition of the TNM classification of diffuse pleural mesothelioma (PM). This study analyzed the clinical and pathologic N categories to determine whether revisions were indicated relative to the eighth edition staging system. METHODS: Of 7338 PM cases diagnosed from 2013 to 2022 and 3598 met all inclusion criteria for planned analyses. Data on 2836 patients without metastases were included in this study. Overall survival (OS) was measured from date of diagnosis. Patients were included regardless of whether they received neoadjuvant treatment. For the pathologic N analysis, patients who underwent resection (extrapleural pneumonectomy or pleurectomy/decortication) were included. N subgroups were analyzed and OS assessed by the Kaplan-Meier method. RESULTS: The existing eighth edition N categories were performed adequately in the ninth edition data set. A median OS advantage was noted for clinical and pathologic N0 versus N1 patients: 23.2 versus 18.5 and 33.8 versus 25.0 months, respectively. Patients with resected pN0 had a 3-year OS of 48%. No difference in OS was noted for single- versus multiple-station nodal metastases. The number of nodal stations sampled at the time of resection was not associated with a difference in OS. CONCLUSIONS: Data regarding clinical and pathologic N categories corroborate those used in the eighth edition. No changes in the N categories are recommended in the ninth edition of PM staging system.

Early Interventional Treatment of High Output Chyle Leak After Esophagectomy is Associated With Improved Survival.

OBJECTIVE: To investigate overall survival and length of stay (LOS) associated with differing management for high output (>1 L over 24 hours) leaks (HOCL) after cancer-related esophagectomy. BACKGROUND: Although infrequent, chyle leak after esophagectomy is an event that can lead to significant perioperative sequelae. Low-volume leaks appear to respond to nonoperative measures, whereas HOCLs often require invasive therapeutic interventions. METHODS: From a prospective single-institution database, we retrospectively reviewed patients treated from 2001 to 2021 who underwent esophagectomy for esophageal cancer. Within that cohort, we focused on a subgroup of patients who manifested a HOCL postoperatively. Clinicopathologic and operative characteristics were collected, including hospital LOS and survival data. RESULTS: A total of 53/2299 patients manifested a HOCL. These were mostly males (77%), with a mean age of 62 years. Of this group, 15 patients received nonoperative management, 15 patients received prompt (<72 hours from diagnosis) interventional management, and 23 received late interventional management. Patients in the late intervention group had longer LOSs compared with early intervention (slope = 9.849, 95% CI: 3.431-16.267). Late intervention (hazard ratio: 4.772, CI: 1.384-16.460) and nonoperative management (hazard ratio: 4.731, CI: 1.294-17.305) were associated with increased mortality compared with early intervention. Patients with early intervention for HOCL had an overall survival similar to patients without chyle leaks in survival analysis. CONCLUSIONS: Patients with HOCL should receive early intervention to possibly reverse the prognostic implications of this potentially detrimental complication.

The International Association for the Study of Lung Cancer Mesothelioma Staging Project: Proposals for Revisions of the "T" Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Pleural Mesothelioma.

INTRODUCTION: The primary tumor (T) component in the eighth edition of pleural mesothelioma (PM) staging system is based on pleural involvement and extent of invasion. Quantitative assessment of pleural tumor has been found to be prognostic. We explored quantitative and qualitative metrics to develop recommendations for T descriptors in the upcoming ninth edition of the PM staging system. METHODS: The International Association for the Study of Lung Cancer prospectively collected data on patients with PM. Sum of maximum pleural thickness (Psum) was recorded. Optimal combinations of Psum and eighth edition cT descriptors were assessed using recursive binary splitting algorithm, with bootstrap resampling to correct for the adaptive nature of the splitting algorithm, and validated in the eighth edition data. Overall survival (OS) was calculated by the Kaplan-Meier method and differences in OS assessed by the log-rank test. RESULTS: Of 7338 patients submitted, 3598 were eligible for cT analysis and 1790 had Psum measurements. Recursive partitioning identified optimal cutpoints of Psum at 12 and 30 mm, which, in combination with extent of invasion, yielded four prognostic groups for OS. Fmax greater than 5 mm indicated poor prognosis. cT4 category (based on invasion) revealed similar performance to eighth edition. Three eighth edition descriptors were eliminated based on low predictive accuracy. Eighth edition pT descriptors remained valid in ninth edition analyses. CONCLUSION: Given reproducible prognostication by Psum, size criteria will be incorporated into cT1 to T3 categories in the ninth edition. Current cT4 category and all pT descriptors will be maintained, with reclassification of fissural invasion as pT2.

Endobronchial ultrasound: A novel screening test for pulmonary hypertension prior to major pulmonary surgery.

Objectives: Pulmonary hypertension (PH) is an important physiologic variable in the assessment of patients undergoing major thoracic operations but all too often neglected because of the need for right heart catheterization (RHC) due to the inaccuracy of transthoracic echocardiography. Patients with lung cancer often require endobronchial ultrasound (EBUS) as part of the staging of the cancer. We sought to investigate whether EBUS can be used to screen these patients for PH. Methods: Patients undergoing a major thoracic operation requiring EBUS for staging were included prospectively in the study. All patients had also a RHC (gold standard). We aimed to compare the pulmonary artery pressure measurements by EBUS with the RHC values. Results: A total of 20 patients were enrolled in the study. The prevalence of abnormal pulmonary artery pressure was 65% based on RHC. All patients underwent measurement of the pulmonary vascular acceleration time (PVAT) by EBUS with no adverse events. Linear regression analysis comparing PVAT and RHC showed a correlation (r = -0.059, -0.010 to -0.018, P = .007). A receiver operator characteristic curve (area under the curve = 0.736) was used to find the optimal PVAT threshold (140 milliseconds) to predict PH; this was used to calculate a positive and negative likelihood ratio following a positive diagnosis of 2.154 and 0.538, respectively. Conclusions: EBUS interrogation of pulmonary artery hemodynamic is safe and feasible. EBUS may be used as a screening test for PH in high-risk individuals.

Octreotide's role in the management of post-esophagectomy chylothorax.

The use of octreotide in managing intrathoracic chyle leak following esophagectomy has gained popularity in the adult population. While the benefits of octreotide have been confirmed in the pediatric population, there remains limited evidence to support its use in the adults post-esophagectomy. Thus, we performed a single-institution cohort study to characterize its efficacy. The study was performed using a prospective, single-center database, from which clinicopathologic characteristics were extracted of patients who had post-esophagectomy chyle leaks. Kaplan-Meier and multivariable Cox regression analyses were performed to investigate the effect of octreotide use on chest tube duration (CTD), hospital length of stay (LOS), and overall survival (OS). In our cohort, 74 patients met inclusion criteria, among whom 27 (36.5%) received octreotide. Kaplan-Meier revealed no significant effect of octreotide on CTD (P = 0.890), LOS (P = 0.740), or OS (P = 0.570). Multivariable Cox regression analyses further corroborated that octreotide had no effect on CTD (HR = 0.62, 95% confidence interval [CI]: 0.32-1.20, P = 0.155), LOS (HR = 0.64, CI: 0.34-1.21, P = 0.168), or OS (1.08, CI: 0.53-2.19, P = 0.833). Octreotide use in adult patients with chyle leak following esophagectomy lacks evidence of association with meaningful clinical outcomes. Level 1 evidence is needed prior to further consideration in this population.