Integrated endoscopic treatment of primitive unresectable tracheal tumor: the INTACT retrospective cohort study.

Background: Primitive tracheal tumors represent a rare entity whose management, when unresectable, remains challenging. Primary aim of this study was to explore the survival and the factors influencing prognosis of patients with unresectable primitive tracheal tumor undergoing multimodal treatment integrating interventional bronchoscopy and radiotherapy. Methods: This retrospective cohort study was conducted at the University Hospital of Modena (Italy) over a 12-year period (January 2010 to January 2022) analyzing patients with unresectable primary tracheal tumor receiving interventional bronchoscopy treatment followed by radiotherapy. Survival analysis was conducted for the whole population and according to histology, development of metastasis, stent placement and the onset of disease relapse. The raw and independent association between potential risk factor and 5-year mortality and the reported complications were investigated. Results: A total of 12 patients were included. Five-year survival rate was 42% with a median survival time of 26.7 (interquartile range, 4.1-82) months. Survivors showed a higher prevalence of cystic-adenoid histology (80% vs. 14%), while patients who were dead at 5 years were those with a more advanced T (prevalence of T2: 71% vs. 0%) and a lower response to first line treatment (57% vs. 0%). Treatment complications accounted for stent dislocation (33%) and the onset of granuloma (18%), while no major side effects were reported. The presence of cystic-adenoid histology resulted in significantly improved 5-year survival rate (80% vs. 14%). The onset of distal metastasis, the occurrence of disease relapse and the placement of tracheal stent did not result significantly associated with lower survival. Among analysed variables, only the presence of cystic-adenoid histology resulted independently associated with survival (odds ratio =0.1, P=0.04). Conclusions: Multimodal treatment including interventional bronchoscopy and associated radiotherapy for unresectable primary tracheal tumors seems not burdened by significant complications and may provide benefits in terms of survival for those patients with cystic-adenoid histology.

Targeting the conserved active site of splicing machines with specific and selective small molecule modulators.

The self-splicing group II introns are bacterial and organellar ancestors of the nuclear spliceosome and retro-transposable elements of pharmacological and biotechnological importance. Integrating enzymatic, crystallographic, and simulation studies, we demonstrate how these introns recognize small molecules through their conserved active site. These RNA-binding small molecules selectively inhibit the two steps of splicing by adopting distinctive poses at different stages of catalysis, and by preventing crucial active site conformational changes that are essential for splicing progression. Our data exemplify the enormous power of RNA binders to mechanistically probe vital cellular pathways. Most importantly, by proving that the evolutionarily-conserved RNA core of splicing machines can recognize small molecules specifically, our work provides a solid basis for the rational design of splicing modulators not only against bacterial and organellar introns, but also against the human spliceosome, which is a validated drug target for the treatment of congenital diseases and cancers.

Lipoaspirate Injection in Relapsing Idiopathic Subglottic Stenosis: Preliminary Results.

OBJECTIVES: The management of idiopathic subglottic stenosis (iSGS) poses a clinical challenge due to high recurrence rates following both endoscopic and open approaches, often leading to tracheostomy. The activation of abnormal T-cells and cytokine pathways has been linked to iSGS pathogenesis. Autologous adipose tissue centrifugation yields lipoaspirate, offering optimal anti-inflammatory effects and biocompatibility widely utilized in various medical settings. This report presents the first 3 cases employing endoscopic dilation (ED) in combination with local lipoaspirate injection to address recurrent iSGS. METHODS: A prospective observational study was conducted, involving multidisciplinary evaluation by the Tracheal Team at the University of Modena. Patients meeting specific criteria were directed to undergo ED + lipoaspirate injection. RESULTS: Three patients fulfilled the inclusion criteria. The mean number of prior endoscopic procedures performed was 8. Endoscopic examination revealed 90% stenosis in patient A, 60% stenosis in patient B, and 60% stenosis in patient C. All patients presented inflammatory tissue or incipient granulations at the stenotic site, with an average time of 6 months between previous procedures. After 15 months, none of the patients required further procedures, and endoscopic examination revealed a significant reduction or disappearance of inflammatory tissue with a stable airway lumen. CONCLUSIONS: The observed results are encouraging in terms of reducing local inflammation and halting stenosis progression, especially in cases of short-term relapsing iSGS.

Use of blood flow restriction for increasing the strength of the ischiocrural muscles in anterior cruciate ligament rehabilitation: A case report.

BACKGROUND: The hamstring muscles have a key function in the stability of the knee, limiting the anterior translation of the tibia. Therefore, to better perform rehabilitation after anterior cruciate ligament (ACL) surgery, it is important to develop a specific program based on hamstring strength recovery. It is possible to increase strength and muscle hypertrophy through high load exercises (HL); the recommended load is about 60%-80% of a maximum repetition (MR). Although low-load resistance training (LL) is ineffective at reproducing these values, the use of Blood Flow Restriction (BFR) with LL exercises appears to allow athletes to increase strength and muscle hypertrophy. This could limit functional decline and mitigate muscle atrophy allowing to optimize the recovery path and load management in post-operative patients. Recent scientific evidence, as far as the increasingly frequent use of BFR in rehabilitation and sports rehabilitation is concerned, suggests that these devices could represent one of the most significant innovations in the physiotherapy field. The aim of this study was to increase the strength of the hamstrings in the early phases of ACL rehabilitation with an LL-BFR training protocol for speeding up the development of adequate muscle strength. CASE DESCRIPTIONS: The patient, a 25-year-old male professional footballer, suffered from ACL injury during a football match, and after three months, he underwent a reconstruction ACL surgery with medial Hamstring tendon autograft. The athlete engaged a pre-operative program to restore a full active and passive knee range of motion and increase muscular strength. The first rehabilitation phase was supported by the adoption of BFR for hamstring strengthening, starting from the sixth week post-surgery (T0). A complete assessment of posterior hamstring muscles was performed through a hand-held dynamometer and load detection platforms. Three different types of exercises, focusing on the hamstring muscles, were chosen. Two further assessments were performed over time (T1 ant T2), highlighting different changes that occurred. RESULTS: Interesting results showed a significant increase between T0 and T1 for all the assessed outcomes; in this case an average increase in strength of 59.87% between the beginning and the end of 4 weeks rehabilitation protocol was obtained in the first interval (T0-T1), while only 25.26% resulted in the second interval (T1-T2). However, the collected data should be considered with caution due to some limitations: the single experience of a single patient can hardly be generalized. Moreover, the reliance on isometric measurement of maximal strength and the absence of a direct strength measurement of the hamstrings during squat remain questionable. CONCLUSION: The final results suggest the capacity of the LL-BFR exercises to recreate a condition of a high intensity muscular effort with respect to load management, especially after surgery. This highlights the need to further investigate BFR adoption as it allows the patients to speed up their rehabilitation goals in developing adequate muscle strength.

Molecular Biology and Therapeutic Targets of Primitive Tracheal Tumors: Focus on Tumors Derived by Salivary Glands and Squamous Cell Carcinoma.

Primary tracheal tumors are rare, constituting approximately 0.1-0.4% of malignant diseases. Squamous cell carcinoma (SCC) and adenoid cystic carcinoma (ACC) account for about two-thirds of these tumors. Despite most primary tracheal cancers being eligible for surgery and/or radiotherapy, unresectable, recurrent and metastatic tumors may require systemic treatments. Unfortunately, the poor response to available chemotherapy as well as the lack of other real therapeutic alternatives affects the quality of life and outcome of patients suffering from more advanced disease. In this condition, target therapy against driver mutations could constitute an alternative to chemotherapy, and may help in disease control. The past two decades have seen extraordinary progress in developing novel target treatment options, shifting the treatment paradigm for several cancers such as lung cancer. The improvement of knowledge regarding the genetic and biological alterations, of major primary tracheal tumors, has opened up new treatment perspectives, suggesting the possible role of biological targeted therapies for the treatment of these rare tumors. The purpose of this review is to outline the state of knowledge regarding the molecular biology, and the preliminary data on target treatments of the main primary tracheal tumors, focusing on salivary-gland-derived cancers and squamous cell carcinoma.

Case report: Endoscopic closure with double stenting and autologous fascia lata graft of large tracheo-esophageal fistula.

Introduction: Radiotherapy and esophageal stenting are usually employed to manage esophageal localization of distant cancer. However, they are also related to the occurrence of an increased risk of tracheoesophageal fistula. Tracheoesophageal fistula management in these patients involves dealing with poor general conditions and short-term prognosis. This paper presents the first case in literature of bronchoscopic fistula closure through an autologous fascia lata graft placement between two stents. Case report and aim: A 67-years-old male patient was diagnosed with pulmonary squamous cell carcinoma in the inferior lobe of the left lung with mediastinal lymph node metastasis. After a multidisciplinary discussion, bronchoscopic repair of tracheoesophageal fistula with autologous fascia lata was decided without the removal of the esophageal stent due to the high risk on the esophagus possibly related to such a procedure. Oral feeding was progressively introduced without the development of aspiration symptoms. Videofluoroscopy and esophagogastroduodenoscopy were performed at 7 months showing no signs of tracheoesophageal fistula patency. Conclusion: This technique might represent a low risks viable option for patients unsuitable for open surgical approaches.

Hydroxylated cyclopamine analogues from Veratrum californicum and their hedgehog pathway inhibiting activity.

Cyclopamine (1), the teratogenic steroidal alkaloid isolated from corn lily (Veratrum californicum), has recently gained renewed interest due to its anticancer potential, that has been translated into the FDA approval of three Hedgehog (Hh) pathway inhibiting antitumor drugs. A chemical analysis of mother liquors obtained from crystallization of cyclopamine, extracted from roots and rhizomes of V. californicum, resulted in the isolation of two unprecedented cyclopamine analogues, 18-hydroxycyclopamine (2) and 24R-hydroxycyclopamine (3), the first compounds of this class to show modifications on rings D-F. The stereostructures of these new natural compounds have been established based on a detailed MS and 1D/2D NMR investigation. The isolated compounds were evaluated with the dual-luciferase bioassay for their inhibition of the hedgehog pathway in comparison to cyclopamine, providing new insights into the structure-activity relationships for this class of compounds.

Neoplastic malignant cord compression mimicking low back pain: A case report.

BACKGROUND: The point prevalence of Cauda Equina Syndrome (CES) as a cause of Low Back Pain (LBP) is estimated at 0.04% in primary care, and it is reported as a complication in about 2% of patients with disc herniation. Compression of the cauda equina usually occurs as a result of disc prolapse. However, CES may be caused by any space-occupying lesion, including spinal stenosis, neoplasms, cysts, infection, and osteophytes. First contact physiotherapists may encounter patients with early CES, as the clinical presentation of CES can mimic non-specific LBP. CASE PRESENTATION: This case report presents the medical history, diagnostic tests and relevant clinical data of a 52-year-old man complaining of LBP. The patient's medical history, his symptoms and the clinical findings led to the identification of a number of red flags (i.e. risk factors) suggestive of a non-musculoskeletal condition. The patient was referred to the emergency department for further investigation. Having undergone several diagnostic tests, the patient was diagnosed with CES due to malignancy. CONCLUSIONS: This case report highlights the importance of differential screening throughout the treatment period, in order to identify red flags that warrant further investigation and a referral to an appropriate specialist. Physiotherapy screening should include clinical reasoning, careful analysis of clinical presentation and symptom progression, in addition to appropriate referral for medical assessment and diagnostic imaging, if necessary.

Stenting versus balloon dilatation in patients with tracheal benign stenosis: The STROBE trial.

Background: It is well known that benign tracheal stenosis represents an obstacle to open surgery, and that its treatment could be challenging. Two endoscopic techniques have so far been adopted to restore tracheal patency: balloon dilatation (BA) through laryngoscopy, and tracheal stenting (ST) with rigid bronchoscopy. The main objective of this study was to compare the efficacy of BA and ST to treat benign tracheal stenosis not eligible for surgery. We also compared the rate of adverse events in the two treatment groups. Methods: A retrospective, observational cohort study was carried out at the University Hospital of Modena (Italy) from November 2012 to November 2017 in two separate departments. Patients were considered to be "stabilized" (primary outcome) if they did not report significant respiratory symptoms, or restenosis in the long-term (2 years) following the endoscopic procedure. Results: Sixty-six patients were included in the study (33 in the BA and 33 in the ST group, respectively). Unadjusted Kaplan-Meier estimates showed a greater therapeutic effect of ST compared to BA at 2 years (hazard ratio = 3.9 95%CI [1.5-9.8], p = .01). After adjusting for confounders, stratified analyses showed that this effect was significant in patients with complex stenosis, idiopathic etiology, and degree of stenosis >70%. Compared with BA, ST showed a higher rate of adverse events (p = .01). Conclusions: Compared to BA, ST seems to be more effective in achieving stabilization of tracheal patency in complex benign tracheal stenosis, although burdened with a significantly higher number of adverse effects. These findings warrant future prospective study for confirmation. Level of evidence: 3.

The burden of words in shoulder pain: A case report of a water polo player.

BACKGROUND AND PURPOSE: Shoulder pain is one of the most common musculoskeletal problems of the world's population. In particular, in water polo athletes, the frequency of injuries or pain to this joint is very high. The incidence of psychosocial factors in musculoskeletal pain is well recognized, even if they seem to be more present in chronic pain, rather than in acute pain. CASE DESCRIPTION: The patient was a semi-professional water polo player with acute shoulder pain which occurred during a game. At first, the pain was very mild, but it progressively got worse after the visit to the casualty department where, even in the absence of any confirmed structural lesions, the patient is ordered to refrain from any active movements. The patient became worried, so his anxiety levels increased which worsened his symptoms. The physiotherapist opted for a "hands-off/hands-on approach". OUTCOMES: Significative improvements were observed in all the considered outcome measures, the patient obtained complete recovery in a very short period of time and then he was able to return to his sport. DISCUSSIONS: Psychosocial factors such as anxiety, fear and catastrophizing can modulate pain responses in a subject without structural problems. Thus, counseling and education in pain science can be an effective therapeutic method, especially with conditions of acute, as well as chronic, pain. LEVEL OF EVIDENCE: 4.

Molecular Mechanisms and Physiological Changes behind Benign Tracheal and Subglottic Stenosis in Adults.

Laryngotracheal stenosis (LTS) is a complex and heterogeneous disease whose pathogenesis remains unclear. LTS is considered to be the result of aberrant wound-healing process that leads to fibrotic scarring, originating from different aetiology. Although iatrogenic aetiology is the main cause of subglottic or tracheal stenosis, also autoimmune and infectious diseases may be involved in causing LTS. Furthermore, fibrotic obstruction in the anatomic region under the glottis can also be diagnosed without apparent aetiology after a comprehensive workup; in this case, the pathological process is called idiopathic subglottic stenosis (iSGS). So far, the laryngotracheal scar resulting from airway injury due to different diseases was considered as inert tissue requiring surgical removal to restore airway patency. However, this assumption has recently been revised by regarding the tracheal scarring process as a fibroinflammatory event due to immunological alteration, similar to other fibrotic diseases. Recent acquisitions suggest that different factors, such as growth factors, cytokines, altered fibroblast function and genetic susceptibility, can all interact in a complex way leading to aberrant and fibrotic wound healing after an insult that acts as a trigger. However, also physiological derangement due to LTS could play a role in promoting dysregulated response to laryngo-tracheal mucosal injury, through biomechanical stress and mechanotransduction activation. The aim of this narrative review is to present the state-of-the-art knowledge regarding molecular mechanisms, as well as mechanical and physio-pathological features behind LTS.

Extensive Tracheal Injuries: A Reasoned Multistep Approach to Guarantee Mechanical Ventilatory Support Developed During the COVID-19 Pandemic.

The COVID-19 pandemic has notably increased the need for prolonged mechanical ventilation (MV) in patients with respiratory failure. This has increased the risk of extensive tracheal injury (ETI) associated with life-threatening complications in complex cases. Furthermore, tracheal injury treatment in patients with COVID-19 has not been described yet. Three patients with COVID-19 and ETI who required MV between April and November 2020 were included. A multistep approach was performed to restore tracheal integrity with a custom-remodeled stent and tracheostomy tube placement to allow ventilatory support. Efficient MV with no residual air leaks was obtained in all cases. One patient died 6 weeks after the procedure due to COVID-19 lung damage. Two patients have completely been weaned from MV. This multistep procedure could be used to maintain ventilatory support in the case of ETI, working as a bridge to subsequent surgery when clinical conditions improve.

Endoscopic Bronchopleural Fistula Repair Using Autologous Fat Graft.

Bronchopleural fistulas (BPFs) represent a rare catastrophic complication of pulmonary resection and carry a high mortality rate. Surgical treatments of BPF are often technically difficult and can be tolerated only by a limited number of patients, while less invasive endoscopic approaches show variable success rates, mainly related to the size of the fistula. In this report, we describe the successful treatment of a large BPF by means of endoscopic autologous fat implantation; we also discuss the technical details of this surgical procedure.

Endobronchial valve positioning for alveolar-pleural fistula following ICU management complicating COVID-19 pneumonia.

BACKGROUND: The main clinical consequences of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection are pneumonia and respiratory failure even requiring mechanical ventilation. In this context, the lung parenchyma is highly prone to ventilator-related injury, with pneumothorax and persistent air leak as the most serious adverse events. So far, endobronchial valve (EBV) positioning has proved efficacious in treating air leaks with a high success rate. CASE PRESENTATION: We report, for the first time, two cases of patients affected by SARS-CoV-2-related pneumonia complicated with bacterial super-infection, experiencing pneumothorax and persistent air leaks after invasive mechanical ventilation. Despite the severity of respiratory failure both patients underwent rigid interventional bronchoscopy and were successfully treated through EBV positioning. CONCLUSIONS: Persistent air leaks may result from lung tissue damage due to a complex interaction between inflammation and ventilator-related injury (VILI), especially in the advanced stages of ARDS. EBV positioning seems to be a feasible and effective minimally invasive therapeutic option for treating this subset of patients.

Pulmonary Stretch and Lung Mechanotransduction: Implications for Progression in the Fibrotic Lung.

Lung fibrosis results from the synergic interplay between regenerative deficits of the alveolar epithelium and dysregulated mechanisms of repair in response to alveolar and vascular damage, which is followed by progressive fibroblast and myofibroblast proliferation and excessive deposition of the extracellular matrix. The increased parenchymal stiffness of fibrotic lungs significantly affects respiratory mechanics, making the lung more fragile and prone to non-physiological stress during spontaneous breathing and mechanical ventilation. Given their parenchymal inhomogeneity, fibrotic lungs may display an anisotropic response to mechanical stresses with different regional deformations (micro-strain). This behavior is not described by the standard stress-strain curve but follows the mechano-elastic models of "squishy balls", where the elastic limit can be reached due to the excessive deformation of parenchymal areas with normal elasticity that are surrounded by inelastic fibrous tissue or collapsed induration areas, which tend to protrude outside the fibrous ring. Increasing evidence has shown that non-physiological mechanical forces applied to fibrotic lungs with associated abnormal mechanotransduction could favor the progression of pulmonary fibrosis. With this review, we aim to summarize the state of the art on the relation between mechanical forces acting on the lung and biological response in pulmonary fibrosis, with a focus on the progression of damage in the fibrotic lung during spontaneous breathing and assisted ventilatory support.

Spontaneous Breathing and Evolving Phenotypes of Lung Damage in Patients with COVID-19: Review of Current Evidence and Forecast of a New Scenario.

The mechanisms of acute respiratory failure other than inflammation and complicating the SARS-CoV-2 infection are still far from being fully understood, thus challenging the management of COVID-19 patients in the critical care setting. In this unforeseen scenario, the role of an individual's excessive spontaneous breathing may acquire critical importance, being one potential and important driver of lung injury and disease progression. The consequences of this acute lung damage may impair lung structure, forecasting the model of a fragile respiratory system. This perspective article aims to analyze the progression of injured lung phenotypes across the SARS-CoV-2 induced respiratory failure, pointing out the role of spontaneous breathing and also tackling the specific respiratory/ventilatory strategy required by the fragile lung type.

Integrated intErventional bronchoscopy in the treatment of locally adVanced non-small lung cancER with central Malignant airway Obstructions: a multicentric REtrospective study (EVERMORE).

OBJECTIVES: Despite new therapeutic perspectives, the presence of central airways occlusion (CAO) in patients with locally advanced non-small cell lung cancer (NSCLC) is associated with poor survival. There is no clear evidence on the clinical impact of interventional bronchoscopy as a part of an integrated treatment to cure these patients. MATERIALS AND METHODS: This retrospective cohort study was conducted in two teaching hospitals over a 10 years period (January 2010-January 2020) comparing patients with NSCLC at stage IIIB and CAO at disease onset treated with chemotherapy/radiotherapy (standard therapy-ST) with those receiving interventional bronchoscopy plus ST (integrated treatment-IT). Primary outcome was 1-year survival. The onset of respiratory events, symptoms-free interval, hospitalization, need for palliation, and overall mortality served as secondary outcomes. RESULTS: A total of 100 patients were included, 60 in the IT and 40 in the ST group. Unadjusted Kaplan-Meier estimates showed greater effect of IT compared to ST on 1-year survival (HR = 2.1 95%CI[1.1-4.8], p = 0.003). IT showed a significantly higher survival gain over ST in those patients showing KRAS mutation (7.6 VS 0.8 months,<0.0001), a lumen occlusion >65% (6.6 VS 2.9 months,<0.001), and lacking the involvement of left bronchus (7 VS 2.3 months,<0.0001). Compared to ST, IT also showed a favorable difference in terms of new hospitalizations (p = 0.03), symptom-free interval (p = 0.02), and onset of atelectasis (p = 0.01). CONCLUSIONS: In patients with NSCLC stage IIIB and CAO, additional interventional bronchoscopy might impact on 1-year survival. Genetic and anatomic phenotyping might allow identifying those patients who may gain life expectancy from the endoscopic intervention.

Incidence, Etiology, and Clinicopathologic Features of Endobronchial Benign Lesions: A 10-Year Consecutive Retrospective Study.

BACKGROUND: Airways can be affected by non-neoplastic lesions leading to critical stenosis of the lumen. Incidence, etiology, and clinical significance of endobronchial benign lesions are not systematically characterized.This study aimed to assess the epidemiology of nonmalignant processes involving the bronchial tree on clinical, pathologic, endoscopic, and radiologic grounds. METHODS: We retrospectively analyzed bronchoscopy procedures over 10 years at the Bronchoscopy Unit of Modena University Hospital. All the endoscopically growing benign lesions with histologic confirmation were considered. For each lesion, we evaluated demographics, clinical features and outcome, the endoscopic aspect and radiologic characteristics by means of computed tomography as assessed by 2 experienced radiologists blinded with regard to the diagnosis. RESULTS: Over the study period, we analyzed 10,431 bronchoscopies and identified 2075 cases of tracheobronchial alterations. Among these, 11.2% had a benign etiology with an average annual incidence of 23 new cases/year and a general incidence of 2.2%. Anthrachosis was the most prevalent bronchial lesion. In total, 22% of benign lesions presented airway stenosis >50% and required bronchoscopic treatment. Bronchial stenosis was most frequently observed in tuberculosis (P=0.031) and aspergillosis (P=0.020) when compared with sarcoidosis. Immunosuppressive status was significantly associated with endobronchial aspergillosis (P=0.0001) and the 1-year survival from diagnosis resulted significantly lower irrespectively to the immune system condition. CONCLUSIONS: A consistent proportion of endobronchial benign lesions are reported. One fifth of these are associated with critical stenosis of the airway lumen, requiring rigid bronchoscopy. Among these, aspergillosis is characterized by the poorest prognosis, regardless of host immunity status.