Modern Management of Esophageal Cancer: Radio-Oncology in Neoadjuvancy, Adjuvancy and Palliation

The modern management of esophageal cancer is crucially based on a multidisciplinary and multimodal approach. Radiotherapy is involved in neoadjuvant and adjuvant settings; moreover, it includes radical and palliative treatment intention (with a focus on the use of a stent and its potential integration with radiotherapy). In this review, the above-mentioned settings and approaches will be described. Referring to available international guidelines, the background evidence bases will be reviewed, and the ongoing, more relevant trials will be outlined. Target definitions and radiotherapy doses to administer will be mentioned. Peculiar applications such as brachytherapy (interventional radiation oncology), and data regarding innovative approaches including MRI-guided-RT and radiomic analysis will be reported. A focus on the avoidance of surgery for major clinical responses (particularly for SCC) is detailed.

Transcriptomic and Lipidomic Profiles in Nasal Polyps of Glucocorticoid Responders and Non-Responders: Before and After Treatment

Background: The pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) and mechanisms underlying different responses to systemic glucocorticoids (GC) remain unclear. The major aim of this study was to explore the transcriptomic and oxidative lipidomic signatures and the effects of GC in patients with different clinical responses.Methods: Nasal polyp biopsies were obtained before and after 14-day oral GC treatment from 16 patients with CRSwNP, and normal nasal mucosa specimens were collected from 12 control subjects. RNA sequencing and oxidative lipidomics were performed, and differential gene expression analysis was conducted in the Responder and Non-responder groups at baseline and after treatment.Results: In the Responder group, GC significantly improved clinical symptoms and reduced tissue eosinophil infiltration. Meanwhile, GC led to a pronounced transcriptomic reversion with robust suppression of inflammatory responses and abnormal metabolism of extracellular matrix, as well as restoration of cilia function. However, non-responders were mainly characterized by epithelial hyperplasia and keratinization, with much less transcriptomic improvement after GC treatment. Higher expression of type 2 inflammatory molecules (CCL13, IGHE, CCL18, CCL23, CCR3, and CLC) with lower levels of LACRT, PPDPFL, DES, C6, MUC5B, and SCGB3A1 were related to a stronger clinical response to GC. Besides decreased prostaglandins and increased leukotrienes, increased dysregulation in other oxylipid mediators derived from polyunsaturated fatty acids was determined in nasal polyps, which was ameliorated by GC treatment.Conclusion: Systemic GC exert anti-inflammatory effects, improve tissue remodeling, restore cilia function, and ameliorate dysregulation of oxylipid mediator pathway in CRSwNP. GC-responders exhibited different transcriptomic signatures from non-responders.

Serum Cytokine Levels for Predicting Immune-Related Adverse Events and the Clinical Response in Lung Cancer Treated with Immunotherapy

Analyses of the composition of peripheral cytokines hold promise for providing a basis for determining the prognosis of lung cancer treated with immunotherapy. In this study, we assessed correlations between interleukins in peripheral blood and the disease prognosis in patients with lung cancer. We retrospectively collected eligible adult patients with histologically confirmed lung cancer. Patients with immune-related adverse events (AE) from immunotherapy had higher pretreatment levels of IL-2 (p=0.002), IL-17 (p=0.01), and IFN-α (p=0.02) than patients with nonimmune-related adverse events (NAE). Univariate analysis showed that changes in IL-2 (p=0.04), IL-5 (p=0.007), IFN-α (p=0.003), IFN-γ (p=0.012) and TNF-α (p=0.049) levels were significantly increased in patients with AE compared with those with NAE before the second cycle of therapy. Patients with a clinical benefit had higher levels of IL-17 before the third cycle than patients without a clinical benefit. No significant cytokine differences were observed between patients with and without a clinical benefit undergoing ICI pretreatment or in the first two cycles of therapy. Plasma cytokines are related to immune-related adverse events and clinical responses, which are potential predictive markers for anti-PD-1/PD-L1 therapy in lung cancer patients and may play an important role in selecting patients who would benefit from PD-1/PD-L1 inhibitors.

Clinical Characteristics of Macrolide-Refractory Mycoplasma pneumoniae Pneumonia in Korean Children: A Multicenter Retrospective Study

Mycoplasma pneumoniae is a major causative pathogen of community-acquired pneumonia in children, and the treatment of choice is macrolides. There is an increasing trend in reports of refractory clinical responses despite macrolide treatment due to the emergence of macrolide-resistant M. pneumoniae. Early discrimination of macrolide-refractory M. pneumoniae pneumonia (MrMP) from macrolide-sensitive M. pneumoniae pneumonia (MSMP) is vital; however, testing for macrolide susceptibility at the time of admission is not feasible. This study aimed to identify the characteristics of MrMP in Korean children, in comparison with those of MSMP. In this multicenter study, board-certified pediatric pulmonologists at 22 tertiary hospitals reviewed the medical records from 2010 to 2015 of 5294 children who were hospitalized with M. pneumoniae pneumonia and administered macrolides as the initial treatment. One-way analysis of variance and the Kruskal-Wallis test were used to compare differences between groups. Of 5294 patients (mean age, 5.6 years) included in this analysis, 240 (4.5%), 925 (17.5%), and 4129 (78.0%) had MrMP, macrolide-less effective M. pneumoniae pneumonia, and MSMP, respectively. Compared with the MSMP group, the MrMP group had a longer fever duration, overall (13.0 days) and after macrolide use (8.0 days). A higher proportion of MrMP patients had respiratory distress, pleural effusion, and lobar pneumonia. The mean aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and C-reactive protein levels were the highest in the MrMP group, along with higher incidences of extrapulmonary manifestations and atelectasis (during and post infection). Pre-existing conditions were present in 17.4% (n = 725/4159) of patients, with asthma being the most common (n = 334/4811, 6.9%). This study verified that MrMP patients show more severe initial radiographic findings and clinical courses than MSMP patients. MrMP should be promptly managed by agents other than macrolides.

A computational modeling approach for dosing endoscopic intratumoral chemotherapy for advanced non-small cell lung cancer

We recently developed a computational model of cisplatin pharmacodynamics in an endobronchial lung tumor following ultrasound-guided transbronchial needle injection (EBUS-TBNI). The model suggests that it is more efficacious to apportion the cisplatin dose between injections at different sites rather than giving it all in a single central injection, but the model was calibrated only on blood cisplatin data from a single patient. Accordingly, we applied a modified version of our original model in a set of 32 patients undergoing EBUS-TBNI for non-small cell lung cancer (NSCLC). We used the model to predict clinical responses and compared them retrospectively to actual patient outcomes. The model correctly predicted the clinical response in 72% of cases, with 80% accuracy for adenocarcinomas and 62.5% accuracy for squamous-cell lung cancer. We also found a power-law relationship between tumor volume and the minimal dose needed to induce a response, with the power-law exponent depending on the number of injections administered. Our results suggest that current injection strategies may be significantly over- or under-dosing the agent depending on tumor size, and that computational modeling can be a useful planning tool for EBUS-TBNI of cisplatin in lung cancer.

Factors Associated With Clinical Responses to Spinal Manipulation in Patients With Non-specific Thoracic Back Pain: A Prospective Cohort Study

Introduction: The management of musculoskeletal disorders is complex and requires a multidisciplinary approach. Manual therapies, such as spinal manipulative therapy (SMT), are often recommended as an adjunct treatment and appear to have demonstrable effects on pain and short-term disability in several spinal conditions. However, no definitive mechanism that can explain these effects has been identified. Identifying relevant prognostic factors is therefore recommended for people with back pain.Objective: The main purpose of this study was to identify short-term candidate prognostic factors for clinically significant responses in pain, disability and global perceived change (GPC) following a spinal manipulation treatment in patients with non-specific thoracic back pain.Methods: Patients seeking care for thoracic spine pain were invited to participate in the study. Pain levels were recorded at baseline, post-intervention, and 1 week after a single session of SMT. Disability levels were collected at baseline and at 1-week follow-up. GPC was collected post-intervention and at 1-week follow-up. Biomechanical parameters of SMT, expectations for improvement in pain and disability, kinesiophobia, anxiety levels as well as perceived comfort of spinal manipulative therapy were assessed.Analysis: Differences in baseline characteristics were compared between patients categorized as responders or non-responders based on their pain level, disability level, and GPC at each measurement time point. Binary logistic regression was calculated if the statistical significance level of group comparisons (responder vs. non-responders) was equal to, or <0.2 for candidate prognostic factors.Results: 107 patients (62 females and 45 males) were recruited. Mean peak force averaged 450.8 N with a mean thrust duration of 134.9 ms. Post-intervention, comfort was associated with pain responder status (p < 0.05) and GPC responder status (p < 0.05), while expectation of disability improvement was associated with GPC responder status (p < 0.05). At follow-up, comfort and expectation of pain improvement were associated with responder GPC status (p < 0.05). No association was found between responder pain, disability or GPC status and biomechanical parameters of SMT at any time point.Discussion: No specific dosage of SMT was associated with short-term clinical responses to treatment. However, expectations of improvement and patient comfort during SMT were associated with a positive response to treatment.

Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.

Comparative Analysis of Predictive Biomarkers for PD-1/PD-L1 Inhibitors in Cancers: Developments and Challenges

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have dramatically changed the landscape of cancer therapy. Both remarkable and durable responses have been observed in patients with melanoma, non-small-cell lung cancer (NSCLC), and other malignancies. However, the PD-1/PD-L1 blockade has demonstrated meaningful clinical responses and benefits in only a subset of patients. In addition, several severe and life-threatening adverse events were observed in these patients. Therefore, the identification of predictive biomarkers is urgently needed to select patients who are more likely to benefit from ICI therapy. PD-L1 expression level is the most commonly used biomarker in clinical practice for PD-1/PD-L1 inhibitors. However, negative PD-L1 expression cannot reliably exclude a response to a PD-1/PD-L1 blockade. Other factors, such as tumor microenvironment and other tumor genomic signatures, appear to impact the response to ICIs. In this review, we examine emerging data for novel biomarkers that may have a predictive value for optimizing the benefit from anti-PD-1/PD-L1 immunotherapy.

Clinical responses following inspiratory muscle training in exercise-induced laryngeal obstruction

Purpose Exercise-induced laryngeal obstruction (EILO) is relatively common in young people. Treatment rests on poor evidence; however, inspiratory muscle training (IMT) has been proposed a promising strategy. We aimed to assess laryngeal outcomes shortly after IMT, and to compare self-reported symptoms with a control group 4–6 years later. Methods Two groups were retrospectively identified from the EILO-register at Haukeland University Hospital, Norway; one group had received only information and breathing advice (IBA), and another additionally IMT (IBA + IMT). At diagnosis, all participants performed continuous laryngoscopy during exercise (CLE), with findings split by glottic and supraglottic scores, and completed a questionnaire mapping exercise-related symptoms. After 2–4 weeks, the IBA + IMT-group was re-evaluated with CLE-test. After 4–6 years, both groups were re-assessed with a questionnaire. Results We identified 116 eligible patients from the EILO-register. Response rates after 4–6 years were 23/58 (40%) and 32/58 (55%) in the IBA and IBA + IMT-group, respectively. At diagnosis, both groups rated symptoms similarly, but laryngeal scores were higher in the IBA + IMT-group (P = 0.003). After 2–4 weeks, 23/32 in the IBA + IMT-group reported symptom improvements, associated with a decrease of mainly glottic scores (1.7–0.3; P < 0.001), contrasting unchanged scores in the 9/32 without symptom improvements. After 4–6 years, exercise-related symptoms and activity levels had decreased to similar levels in both groups, with no added benefit from IMT; however, full symptom resolution was reported by only 8/55 participants. Conclusion Self-reported EILO symptoms had improved after 4–6 years, irrespective of initial treatment. Full symptom resolution was rare, suggesting individual follow-up should be offered.