Induction Immunochemotherapy Yields a Higher Conversion Rate and Better Overall Survival than Chemotherapy in Initially Unresectable Esophageal Squamous Cell Carcinoma.

INTRODUCTION: This study compared the surgical conversion rate and overall survival (OS) between induction chemotherapy (iC) and induction immunochemotherapy (iIC) for patients with initially unresectable esophageal squamous cell carcinoma (iuESCC). METHODS: In this multicenter, retrospective cohort study, patients from four high-volume institutions with unresectable diseases were included. The primary endpoints were the conversion surgery rate and OS. A multivariate Cox regression analysis was used to identify the independent significant prognostic factors associated with OS. The stabilized inverse probability of treatment weighting was applied to confirm the survival comparison between the iIC and iC cohorts. RESULTS: A total of 309 patients (150 in the iIC cohort and 159 in the iC cohort) were included. A significantly higher conversion surgical rate was observed in the iIC cohort (iIC vs. iC: 127/150, 84.7% vs. 79/159, 49.7%, P < 0.001). The pathological complete response rates were 22.0% and 5.1% in the iIC and the iC cohorts, respectively (P = 0.001). A significant difference in the OS was observed between the iIC (not reached) and iC cohorts (median 95% CI 36.3 [range 27.2-45.5]). The stabilized inverse probability of treatment weighting yielded similar results. Regimen (iIC vs. iC, HR 0.215, 95% CI 0.102-0.454, P < 0.001) and operation (yes vs. no, HR 0.262, 95% CI 0.161-0.427, P < 0.001) were the significant prognostic factors for OS. CONCLUSIONS: Immunochemotherapy plus conversion surgery in the induction setting may be a better treatment option to achieve high pathological responses and improve OS in iuESCC patients.

Validation of the Reichert® Tono-Vera® Vet rebound tonometer in normal ex vivo canine eyes.

OBJECTIVE: To determine the accuracy of the Reichert® Tono-Vera® Vet rebound tonometer for canine intraocular pressure (IOP) measurement. ANIMALS STUDIED: Five normal canine ex vivo globes. PROCEDURES: The anterior chambers of five freshly enucleated normal canine eyes were cannulated and connected to a reservoir of Plasma-Lyte A and a manometer. Starting at a manometric IOP of 5 mmHg, the pressure was progressively increased to 80 mmHg by raising the reservoir. Triplicate IOP measurements were taken with the Tono-Vera® Vet from the central cornea using the dog setting and compared to the manometric pressure by linear regression analysis and Bland-Altman plots. RESULTS: There was a strong positive linear regression trend when comparing central corneal Tono-Vera® Vet IOPs to manometric pressures (r2 = .99) with solid agreement between the two methods. Compared to manometric IOPs, the Tono-Vera® Vet underestimated IOPs at higher pressures ≥70 mmHg. CONCLUSIONS: Measurement of IOPs from the central cornea with the Tono-Vera® Vet provided accurate results over a large range in normal canine globes compared to direct manometry. The mild to moderate underestimation of IOPs at high pressures was not considered clinically relevant.

Serial monitoring of pancreatic lipase immunoreactivity, C-reactive protein, abdominal ultrasonography, and clinical severity in dogs with suspected pancreatitis.

BACKGROUND: Diagnosis of pancreatitis is based on clinical signs, pancreatic lipase immunoreactivity (cPLI), and abdominal ultrasonography (AUS). Diagnostic discrepancies exist between test results which might be related to differences in the timeline for resolution of these abnormalities after pancreatic injury. HYPOTHESIS/OBJECTIVES: To evaluate disease severity, ultrasonographic findings, and serum biomarkers of pancreatitis in dogs over a period of 28-days. ANIMALS: Sixteen client-owned dogs with a clinical suspicion for acute pancreatitis based on history/physical examination, an abnormal SNAP cPLI, and ultrasonographic evidence of pancreatitis. METHODS: Prospective observational study. Clinical severity (modified clinical activity index [MCAI]), cPLI, C-reactive protein (CRP), and AUS were evaluated at days 0, 2, 7, and 28. Owner assessed overall health (OH) was noted. Dogs were stratified into baseline cPLI ≥400 µg/L vs <400 µg/L groups for reporting. RESULTS: The median CRP, MCAI, and OH were 111.9 mg/L, 10, and 4/10 respectively in the cPLI ≥400 µg/L group. The median CRP, MCAI, and OH were 58.0 mg/L, 6, and 6/10 respectively in the cPLI <400 µg/L group. None of these variables were significantly different between groups. Most dogs (4/5) in the cPLI <400 µg/L group had a history of suspected pancreatitis (ie, suspect acute on chronic disease). cPLI and MCAI rapidly decreased in dogs with a baseline cPLI ≥400 µg/L, whereas sonographic evidence of pancreatitis persisted for a longer time period. CONCLUSIONS AND CLINICAL IMPORTANCE: Ultrasonographic evidence of pancreatitis in the absence of overt clinical or biochemical abnormalities might represent a resolving injury rather than active disease.

Treatment-Related Pneumonitis of EGFR Tyrosine Kinase Inhibitors Plus Thoracic Radiation Therapy in Patients With Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Thoracic radiation therapy (RT) for non-small cell lung cancers may overcome resistance to tyrosine kinase inhibitors (TKIs). However, the risk of severe treatment-related pneumonitis (TRP) is a major concern, and the results of the combined treatment remain controversial. Therefore, we aimed to systematically review existing publications and provide a meta-analysis of TRP from a combined therapy of thoracic RT and TKIs. A systematic literature review was performed using the PubMed-MEDLINE and Embase databases to identify eligible publications. The number of severe TRP cases of grade 3 or higher was extracted and then analyzed by fixed or randomized model meta-analysis. Heterogeneity tests were performed using the I² and τ² statistics. Subgroup analyses were conducted on the types of RT and the sequence of the combined treatment. Our literature search identified 37 eligible studies with 1143 patients. Severe TRP occurred in 3.8% (95% CI, 1.8%-6.5%) of patients overall, and fatal pneumonitis occurred rarely in 0.1% (95% CI, 0.0%-0.3%). In the subgroup analysis, the severe TRP proportion was 2.3% (95% CI, 1.0%-4.1%) for patients under definitive (chemo)RT (19 studies, n = 702) versus 2.9% (95% CI, 1.3%-5.1%) for patients who received local stereotactic body RT or palliative RT (15 studies, n = 361). The severe TRP rate was 4.9% (95% CI, 2.4%-8.1%) for concurrent TKI and RT (26 studies, n = 765), which was significantly higher than TRP of 0.4% (95% CI, 0.0%-3.1%) for sequential therapy (6 studies, n = 200). Our meta-analysis showed that combined thoracic RT and epidermal growth factor receptor-TKI therapy has an acceptable risk of severe TRP and rare mortality in patients with non-small cell lung cancers. Concurrent treatment is less tolerable and should be administered with caution. Further investigations using osimertinib are required as the data on its effects are limited.

Ocular pulse amplitude (OPA) in canine ADAMTS10-open-angle glaucoma (ADAMTS10-OAG).

Introduction: The role of ocular rigidity and biomechanics remains incompletely understood in glaucoma, including assessing an individual's sensitivity to intraocular pressure (IOP). In this regard, the clinical assessment of ocular biomechanics represents an important need. The purpose of this study was to determine a possible relationship between the G661R missense mutation in the ADAMTS10 gene and the ocular pulse amplitude (OPA), the difference between diastolic and systolic intraocular pressure (IOP), in a well-established canine model of open-angle glaucoma (OAG). Methods: Animals studied included 39 ADAMTS10-mutant dogs with different stages of OAG and 14 unaffected control male and female dogs between 6 months and 12 years (median: 3.2 years). Dogs were sedated intravenously with butorphanol tartrate and midazolam HCl, and their IOPs were measured with the Icare® Tonovet rebound tonometer. The Reichert Model 30™ Pneumotonometer was used to measure OPA. Central corneal thickness (CCT) was measured via Accutome® PachPen, and A-scan biometry was assessed with DGH Technology Scanmate. All outcome measures of left and right eyes were averaged for each dog. Data analysis was conducted with ANOVA, ANCOVA, and regression models. Results: ADAMTS10-OAG-affected dogs displayed a greater IOP of 23.0 ± 7.0 mmHg (mean ± SD) compared to 15.3 ± 3.6 mmHg in normal dogs (p < 0.0001). Mutant dogs had a significantly lower OPA of 4.1 ± 2.0 mmHg compared to 6.5 ± 2.8 mmHg of normal dogs (p < 0.01). There was no significant age effect, but OPA was correlated with IOP in ADAMTS10-mutant dogs. Conclusion: The lower OPA in ADAMTS10-mutant dogs corresponds to the previously documented weaker and biochemically distinct posterior sclera, but a direct relationship remains to be confirmed. The OPA may be a valuable clinical tool to assess ocular stiffness and an individual's susceptibility to IOP elevation.

Evaluation of combined pathological responses in primary tumor and lymph nodes following neoadjuvant chemoimmunotherapy in non-small cell lung cancer.

BACKGROUND: Inconsistent pathological responses of tumor and lymph nodes (LNs) were frequently observed in non-small cell lung cancer (NSCLC) receiving neoadjuvant chemoimmunotherapy. However, there is a lack of studies to report the prognostic significance and the relevant clinicopathological factors of tumor-nodal inconsistent responses after neoadjuvant immunotherapy or chemoimmunotherapy. Therefore, this study aimed to depict the inconsistent pathological combined tumor-nodal responses in NSCLC patients after neoadjuvant chemoimmunotherapy as well as the underlying clinical significance. METHODS: A total of 81 node-positive NSCLC patients who underwent neoadjuvant chemoimmunotherapy were eligible for inclusion. Demographic, radiologic, and pathological features of patients were recorded. Patients with pathological complete response of both tumor (ypT(pCR)) and LNs (ypN0) were classified into the combined good responder group and the relevant clinicopathological features were evaluated. The event-free survival (EFS) outcome was analyzed using Kaplan-Meier analysis. RESULTS: The ypN0 and ypT(pCR) rates were 74.1 % and 42.0 %, respectively. A significant correlation was observed between ypT(pCR) and ypN0 (P = 0.003), but inconsistent responses remained. The combined responses of the primary tumor and LNs demonstrated a significant association with the prognosis outcome (P = 0.005). Notably,patients who received at least twice of their infusions of immune checkpoint inhibitors after 15:30 had a worse prognosis (P = 0.015). CONCLUSION: A significant but not absolute correlation was observed between good tumor response and good nodal response in NSCLC patients after neoadjuvant chemoimmunotherapy, but inconsistent responses were also found. The combination of tumor and nodal responses is significantly associated with prognosis and combined good responder can be used as a reliable prognosis predictor.

Serum calcium concentrations are inversely correlated with pancreatic lipase concentrations in dogs.

OBJECTIVE: (1) Determine if a relationship exists between ionized calcium (iCa) and pancreatic lipase (cPLI) concentration in dogs, and (2) assess for correlation between resolving hypercalcemia and cPLI concentrations in dogs after treatment for primary hyperparathyroidism (PHPT). SAMPLES: Phase I, 44 residual serum samples (collected April 2023) from client-owned dogs with a clinical indication for cPLI quantification. Phase II, 24 residual serum samples (collected August 2022 through February 2023) from client-owned dogs with PHPT pre- and postcorrection of hypercalcemia. METHODS: Serum cPLI and iCa concentrations were measured via the Spec cPL assay and a spectrophotometric method respectively. Spearman's rank correlation coefficients were used to investigate if there was a correlation between serum calcium and cPLI concentrations. A paired t-test was used to investigate the effect of the resolution of hypercalcemia on serum cPLI concentrations. RESULTS: Phase I, serum cPLI concentrations were negatively correlated with serum iCa concentrations (r = -.429, 95% CI [-.64, -.14], P = .005) in dogs with a clinical indication for cPLI quantification. Phase II, median serum cPLI concentrations were higher before (median: 228.5 µg/L, IQR: 351.3 µg/L) than after (median: 141.0 µg/L, interquartile ranges (IQR): 279.5 µg/L) management of hypercalcemia (PHPT model). However, the decrease in cPLI concentration was not statistically significant (P = .70). CLINICAL RELEVANCE: Calcium depletion may result in an inverse relationship between serum cPLI and iCa concentrations in dogs with a clinical indication for cPLI quantification. Hypercalcemia may be associated with an above reference interval cPLI concentration in some dogs.

Efficacy and safety of immunochemotherapy, immunotherapy, chemotherapy, and targeted therapy as first-line treatment for advanced and metastatic esophageal cancer: a systematic review and network meta-analysis.

Background: The treatment of esophageal cancer has entered a new phase with the development of immunotherapy. The current investigation purpose is to investigate and contrast the efficacy and safety of immunotherapy, immunochemotherapy, chemotherapy, and targeted therapy as first-line treatment for individuals suffering from advanced and metastatic esophageal cancer. Methods: Within the framework of this systematic review and network meta-analysis, clinical trials published or reported in English up until 01 May, 2022, were retrieved from Embase, PubMed, Cochrane Central Register of Controlled Trials, the ClinicalTrials.gov databases, ESMO, and ASCO. The analysis incorporated randomized controlled trials (RCTs) from phase 2 to 3 that evaluated a minimum of two first-line therapeutic regimens for metastatic esophageal cancer were included in the analysis. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary clinical outcomes included the incidence of objective response rate (ORR), and adverse events (AEs) of any grade and ≥3 grade. Relative summary data were extracted from included studies by GZ, HS, WS, and TD. For clear statistical analysis, chemotherapy was divided into two categories of fluorouracil-based chemotherapy (FbCT) and fluorouracil-free chemotherapy (FfCT). Bayesian frequentist approach was employed to conduct the network meta-analysis. The indirect intercomparison between regimens was presented with league tables (HRs and 95% CI for OS and PFS, ORs and 95% CI for ORR and AEs). A greater surface value under the cumulative ranking (SUCRA) indicates a higher potential ranking for the corresponding treatment. A further calculation of relative results about esophageal squamous cell cancer was performed in the subgroup analysis. The current protocol for the systematic review has been properly registered on PROSPERO (registration number: CRD42021241145). Findings: The final analysis comprised 17 trials that involved 9128 patients and 19 distinct treatment regimens. Within the scope of investigated immunotherapy (IO) combinations, toripalimab + FfCT (tori + FfCT) demonstrated the best OS advantages (tori + FfCT vs. FbCT, HR 0.57, 95% CI 0.38-0.85; tori + FfCT vs. FfCT, HR 0.58, 95% CI 0.43-0.78). In terms of PFS, camrelizumab + FfCT (cam + FfCT) demonstrated the best PFS advantages (FbCT vs. cam + FfCT, HR 1.79, 95% CI 1.22-2.63; FfCT vs. cam + FfCT, HR 1.79, 95% CI 1.47-2.17). Nivolumab + FbCT (nivo + FbCT vs. FfCT, OR 3.29, 95% CI 1.43-7.56) showed the best objective responses. Compared to the conventional chemotherapy regimen, the toxicity was observed to be the slightest for the tori + FfCT (FbCT vs. tori + FfCT, OR 3.07, 95% CI 1.22-7.7) and sintilimab + FfCT (FbCT vs. sin + FfCT, OR 2.93, 95% CI 1.16-7.37). The results in this study were evaluated as having a low heterogeneity since the I2 value was ≤25% in all analyses. Interpretation: Compared to foreign IO combinations, sin + FfCT, tori + FfCT, cam + FfCT, and tisle + FbCT are superior first-line treatment options for patients with advanced and metastatic esophageal cancer. Although foreign IO combinations, such as pembro + FbCT and nivo + FbCT obtained better objective response rates than other IO combinations, the addition of chemotherapy to IO worsens the safety profiles. Our findings could provide complementary evidence for current guideline recommendations. Funding: This work was supported by a grant from the Science and Technology Program of Guangzhou, China (202206010103); and Natural Science Foundation of Guangdong Province (2022A1515012469).

Early and Persistent Dysphagia Relief Predicts Tumor Response in Esophageal Squamous Cell Carcinoma Patients Treated with Immunochemotherapy.

BACKGROUND: In this prospective study, we aimed to investigate the role of patient-reported dysphagia relief in predicting pathological tumor responses to neoadjuvant immunochemotherapy (NAIC) in locally advanced esophageal squamous cell carcinoma (ESCC) patients. METHODS: This study was designed as a multi-center, prospective study including ESCC patients who received NAIC in the discovery and validation cohorts. The patients' responses to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-OES 18 and QLQ-C30 were collected at multiple time points. Subsequent time point-intensive esophageal cancer-specific dysphagia trajectories were depicted using growth mixture modeling (GMM) analysis. Furthermore, univariate and multivariate binary logistic regression was used to assess the independent predictors for pathological tumor responses. RESULTS: A total of 120 patients from the discovery cohort and 42 patients from the validation cohort were included in the analysis. In the discovery cohort, 19 (22.9%) of the 83 patients achieved pCR status. In the independent validation cohort, 24 patients underwent surgery, and 9 (37.5%) patients achieved pCR status. Trajectory analysis showed that, in the pCR group, the beginning of rapid declines in the slope occurred on days 3, 6, and 9. Further multivariate analysis showed that the degree of dysphagia relief (△dysphagia%) was the only significant independent predictor for pCR status (OR = 3.267, 95% CI 1.66-6.428, P < 0.001). The AUC value for △dysphagia% was 0.961 (95% CI: 0.922-0.999, P < 0.001). CONCLUSION: The current study demonstrated that a longitudinal patient-reported outcome (PRO) was an easily obtained, cost-effective, and noninvasive tool for predicting tumor responses to neoadjuvant immunochemotherapy.

Unpleasant symptoms of immunotherapy for people with lung cancer: A mixed-method study.

BACKGROUND: Immunotherapy has changed the outlook for lung cancer treatment. A closer look at the accompanying symptoms from the patient's perspective is necessary to improve their tolerance to the treatment, which is also the basis for standardized symptom management. OBJECTIVE: To describe the symptomatic experiences of patients receiving immunotherapy for lung cancer and explore whether symptoms reported during immunotherapy were associated with survival outcomes. DESIGN: Exploratory sequential mixed-method study. SETTINGS: Patients were continuously recruited from the oncology day ward of Guangdong Provincial People's Hospital between October 2019 and January 2020. PARTICIPANTS: 59 patients with advanced lung cancer and receiving immunotherapy (median [IQR] age was 64 [58-69]; 72.9 % pathological stage was IV) were included in the study. METHODS: A sequential qualitative interview on symptom experiences was conducted from the perspective of lung cancer patients in immunotherapy. Summative content analysis was used to develop a standardized symptom reporting checklist. Survival outcome follow-ups of each patient were conducted 2 years after the interview. RESULTS: 47 symptoms were extracted from the 124 interviews of 59 patients, the common symptoms including musculoskeletal pain (52.5 %), itchy skin (45.8 %), fatigue (45.8 %), cough (44.1 %), shortness of breath (32.2 %), lack of appetite (32.2 %), and rashes (32.2 %). The timing, severity, and interference of symptoms were different among patients. The symptoms of shortness of breath, fatigue and chest pain were more common in chemo-immunotherapy, while dry mouth and blurred vision were more frequent with immunotherapy. The symptoms of musculoskeletal pain, shortness of breath, lack of appetite, drowsiness and taste change were more common for those who died two years after the interviews; for those who survived, the symptoms of rash and chill were more common. CONCLUSIONS: We generated a symptom list related to lung cancer immunotherapy from the patients, provided a closer look at symptoms from the patient's perspective, and suggested differences in the presence of symptoms between the group of treatment and survival outcome. This enables clinicians and nurses to better understand and empathize with the patient's experience, so as to truly practice the essence of patient-centered care, and provide a basis for the development of standardized symptom measurement tools in the future. TWEETABLE ABSTRACT: At least 47 unpleasant symptoms were present in immunotherapy from the perspective of lung cancer patients.

Evaluating the release and metabolism of ricinine from castor cake fertilizer in soils using a LC-QTOF/MS coupled with SIRIUS workflow.

Castor cake is a major by-product generated after castor oil extraction and has been widely used as an organic fertilizer. Once applied to soil, a toxic alkaloid ricinine in castor cake may be released into soils and subsequently taken up by crops, which poses a potential threat to food safety and human health. However, the environmental fate of castor cake derived ricinine in agroecosystems remains unclear. In this study, the release and metabolism of ricinine in soils were conducted using soil pot experiments with different castor cake application rates. The analytical methodology of ricinine quantification in soil pore water was first established using solid phase extraction (SPE) coupled with liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF/MS). A non-target screening workflow associated with LC-QTOF/MS and SIRIUS platform was further developed to identify ricinine metabolites in soil pore water. After castor cake application, the ricinine concentrations in soil pore water significantly increased to 297-7990 µg L-1 at 1 day and then gradually decreased to 62.1-3460 µg L-1 at 7 days and 1.70-279 µg L-1 at 14 days for the selected two tested soils with castor cake application rates of 2, 10, and 20 g castor cake/kg soil. In addition, two ricinine metabolites R-194 and R-180 were tentatively identified and one ricinine metabolite N-demethyl-ricinin was confirmed through authentic reference standard for the first time by the developed non-target screening workflow. This study highlights the release and metabolism of toxic alkaloid ricinine in soils once applied castor cake as an organic fertilizer. Ricinine could be released into soil pore water in a short-term after castor cake application and then undergo demethylation, hydroxylation, and hydroxylation followed by methylation metabolisms over time in agroecosystems.

Accuracy of next-generation sequencing for molecular profiling of small specimen of lung cancer: a prospective pilot study of side-by-side comparison.

BACKGROUND: Successful practice of precision medicine in advanced lung cancers relies on therapeutic regimens tailored to individual molecular characteristics. The aim of this study was to investigate the accuracy of small specimens for molecular profiling using next-generation sequencing (NGS). METHODS: Genetic alternations, tumor mutational burden (TMB), status of microsatellite instability (MSI), and expression of programmed death ligand 1 (PD-L1) were compared side-by-side between the concurrently obtained core needle biopsy (CNB) and resection specimens in 17 patients with resectable non-small cell lung cancers. RESULTS: DNA yield and library complexity were significantly lower in CNB specimens (both p < 0.01), whereas the insert size, sequencing depth, and Q30 ratio were similar between the matched specimens (all p > 0.05). The total numbers of genetic alternations detected in resection and CNB specimens were 186 and 211, respectively, with 156 alternations in common, yielding a specific concordance rate of 83.9%. The prevalence of mutations in 8 major driver genes was 100% identical between surgical and CNB specimens, though the allele frequency was lower in CNB specimens, with a median underestimation of 57%. Results of TMB were similar (p = 0.547) and MSI status was 100% matched in all paired specimens. CONCLUSIONS: Pulmonary CNB specimens were suitable for NGS given the satisfactory accuracy when compared to corresponding surgical specimens. NGS results yielding from CNB specimens should be deemed reliable to provide instructive information for the treatment of advanced lung cancers.

Bone Metabolism Discrepancy in Type 2 Diabetes Mellitus Patients With and Without Non-Alcoholic Fatty Liver Disease.

To explore the distribution of several bone metabolic indicators in type 2 diabetes patients (T2DM) with and without non-alcoholic fatty liver disease (NAFLD) and to preliminarily evaluate the relationship of bone metabolism with NAFLD in patients with T2DM. The hospitalized patients with T2DM were divided into the group of T2DM complicated with NAFLD and the group of T2DM alone according to the results of ultrasonic diagnosis. The general information and laboratory test data such as bone metabolism indexes of these patients were collected and the differences of the indexes between the 2 groups were compared. Furthermore, the independent influencing factors of NAFLD in patients with T2DM were analyzed. A total of 186 patients were included in the study. Compared with patients with T2DM only, patients with T2DM combined with NAFLD were characterized with younger age (p < 0.001), higher BMI (p = 0.016), ALT (p = 0.001), TG (p = 0.005), HOMA-IR (p = 0.005), and lower HDL-C (p = 0.031). Significant discrepancy of age (OR 1.052, p = 0.001), ALT (OR 0.964, p = 0.047), HOMA-IR (OR 0.801, p = 0.005), and T-PINP (OR 1.022, p = 0.008) was found using multivariate logistic regression model. Significant discrepancy of T-PINP was found in T2DM patients with and without NAFLD. Further studies are needed to explore whether T-PINP could be used as a predictor of fatty liver disease, osteoporosis, and other related complications in patients with T2DM.