Thymic Stromal Lymphopoietin (TSLP) Is Cleaved by Human Mast Cell Tryptase and Chymase.

Thymic stromal lymphopoietin (TSLP), mainly expressed by epithelial cells, plays a central role in asthma. In humans, TSLP exists in two variants: the long form TSLP (lfTSLP) and a shorter TSLP isoform (sfTSLP). Macrophages (HLMs) and mast cells (HLMCs) are in close proximity in the human lung and play key roles in asthma. We evaluated the early proteolytic effects of tryptase and chymase released by HLMCs on TSLP by mass spectrometry. We also investigated whether TSLP and its fragments generated by these enzymes induce angiogenic factor release from HLMs. Mass spectrometry (MS) allowed the identification of TSLP cleavage sites caused by tryptase and chymase. Recombinant human TSLP treated with recombinant tryptase showed the production of 1-97 and 98-132 fragments. Recombinant chymase treatment of TSLP generated two peptides, 1-36 and 37-132. lfTSLP induced the release of VEGF-A, the most potent angiogenic factor, from HLMs. By contrast, the four TSLP fragments generated by tryptase and chymase failed to activate HLMs. Long-term TSLP incubation with furin generated two peptides devoid of activating property on HLMs. These results unveil an intricate interplay between mast cell-derived proteases and TSLP. These findings have potential relevance in understanding novel aspects of asthma pathobiology.

TSLP is localized in and released from human lung macrophages activated by T2-high and T2-low stimuli: relevance in asthma and COPD.

BACKGROUND: Macrophages are the predominant immune cells in the human lung and play a central role in airway inflammation, including asthma and chronic obstructive pulmonary disease (COPD). Thymic stromal lymphopoietin (TSLP), a pleiotropic cytokine mainly expressed by bronchial epithelial cells, plays a key role in asthma and COPD pathobiology. TSLP exists in two variants: the long form (lfTSLP) and a shorter TSLP isoform (sfTSLP). We aimed to localize TSLP in human lung macrophages (HLMs) and investigate the mechanisms of its release from these cells. We also evaluated the effects of the two variants of TSLP on the release of angiogenic factor from HLMs. METHODS: We employed immunofluorescence and Western blot to localize intracellular TSLP in HLMs purified from human lung parenchyma. HLMs were activated by T2-high (IL-4, IL-13) and T2-low (lipopolysaccharide: LPS) immunological stimuli. RESULTS: TSLP was detected in HLMs and subcellularly localized in the cytoplasm. IL-4 and LPS induced TSLP release from HLMs. Preincubation of macrophages with brefeldin A, known to disrupt the Golgi apparatus, inhibited TSLP release induced by LPS and IL-4. lfTSLP concentration-dependently induced the release of vascular endothelial growth factor-A (VEGF-A), the most potent angiogenic factor, from HLMs. sfTSLP neither activated nor interfered with the activating property of lfTSLP on macrophages. CONCLUSIONS: Our results highlight a novel immunologic circuit between HLMs and TSLP. Given the central role of macrophages in airway inflammation, this autocrine loop holds potential translational relevance in understanding innovative aspects of the pathobiology of asthma and chronic inflammatory lung disorders.

Oligo-metastatic neoPlasms from the gastro-intestinal tract: iDentIfiCaTIon of cliNical and molecular drivers: the PREDICTION study.

BACKGROUND: Metastatic disease in tumors originating from the gastrointestinal tract can exhibit varying degrees of tumor burden at presentation. Some patients follow a less aggressive disease course, characterized by a limited number of metastatic sites, referred to as "oligo-metastatic disease" (OMD). The precise biological characteristics that define the oligometastatic behavior remain uncertain. In this study, we present a protocol designed to prospectively identify OMD, with the aim of proposing novel therapeutic approaches and monitoring strategies. METHODS: The PREDICTION study is a monocentric, prospective, observational investigation. Enrolled patients will receive standard treatment, while translational activities will involve analysis of the tumor microenvironment and genomic profiling using immunohistochemistry and next-generation sequencing, respectively. The first primary objective (descriptive) is to determine the prevalence of biological characteristics in OMD derived from gastrointestinal tract neoplasms, including high genetic concordance between primary tumors and metastases, a significant infiltration of T lymphocytes, and the absence of clonal evolution favoring specific driver genes (KRAS and PIK3CA). The second co-primary objective (analytic) is to identify a prognostic score for true OMD, with a primary focus on metastatic colorectal cancer. The score will comprise genetic concordance (> 80%), high T-lymphocyte infiltration, and the absence of clonal evolution favoring driver genes. It is hypothesized that patients with true OMD (score 3+) will have a lower rate of progression/recurrence within one year (20%) compared to those with false OMD (80%). The endpoint of the co-primary objective is the rate of recurrence/progression at one year. Considering a reasonable probability (60%) of the three factors occurring simultaneously in true OMD (score 3+), using a significance level of α = 0.05 and a test power of 90%, the study requires a minimum enrollment of 32 patients. DISCUSSION: Few studies have explored the precise genetic and biological features of OMD thus far. In clinical settings, the diagnosis of OMD is typically made retrospectively, as some patients who undergo intensive treatment for oligometastases develop polymetastatic diseases within a year, while others do not experience disease progression (true OMD). In the coming years, the identification of true OMD will allow us to employ more personalized and comprehensive strategies in cancer treatment. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05806151.

One-way endobronchial valves in the management of complex persistent air leaks in a soft tissue sarcoma patient.

Complex persistent air leak (PAL) is a clinical condition which is difficult to treat. Herein, we report the clinical case of an 18-year-old woman with lung and bone metastases due an ultrarare sarcoma: "round cell sarcoma non-Ewing". She developed persistent air leaks due to an alveolopleural fistula which developed following two cycles of chemotherapy with doxorubicin. Chest drainage with suction failed to resolve the air leaks, while surgical treatment was unfeasible due to the poor clinical condition of the patient. Thus, she was reviewed for endoscopic treatment with one-way endobronchial valves. A small valve was sequentially inserted within each segment of the right upper bronchus to occlude the entire upper lobe. Two days after the procedure, resolution of the air leaks were obtained. Chest drainage was removed 5 days later and the patient was discharged. Chemotherapy was resumed. The patient died 7 months later because of disease progression.

Oligo-Metastatic Cancers: Putative Biomarkers, Emerging Challenges and New Perspectives.

Some cancer patients display a less aggressive form of metastatic disease, characterized by a low tumor burden and involving a smaller number of sites, which is referred to as "oligometastatic disease" (OMD). This review discusses new biomarkers, as well as methodological challenges and perspectives characterizing OMD. Recent studies have revealed that specific microRNA profiles, chromosome patterns, driver gene mutations (ERBB2, PBRM1, SETD2, KRAS, PIK3CA, SMAD4), polymorphisms (TCF7L2), and levels of immune cell infiltration into metastases, depending on the tumor type, are associated with an oligometastatic behavior. This suggests that OMD could be a distinct disease with specific biological and molecular characteristics. Therefore, the heterogeneity of initial tumor burden and inclusion of OMD patients in clinical trials pose a crucial methodological question that requires responses in the near future. Additionally, a solid understanding of the molecular and biological features of OMD will be necessary to support and complete the clinical staging systems, enabling a better distinction of metastatic behavior and tailored treatments.

Risk Management Activities in a Lung Cancer Multidisciplinary Team at a Comprehensive Cancer Center: Results of a Prospective Analysis.

PURPOSE: The objective of the study was to highlight sources of harm that could negatively affect the lung cancer multidisciplinary team (MDT) activities to reduce the level of risk of each factor. METHODS: A modified Delphi approach was used by a board of multi-health care professionals of the lung cancer MDT to identify the main processes, subprocesses, and risk factors of the multidisciplinary pathway of patients with lung cancer. A semiquantitative matrix was built with a five-point scale for probability of harm (likelihood) and severity of harm (consequences) according to the international risk management standards (ISO 31000-2018). The risk level was calculated by multiplying likelihood × consequences. Mitigation strategies have been identified and applied by the MDT to reduce risks to acceptable levels. RESULTS: Three main processes (outpatient specialist visit, MDT discussion, and MDT program implementation), eight related subprocesses, and 16 risk factors were identified. Four risk factors (25%) were related to outpatient specialist visit, seven (43.75%) to case discussion, and five (31.25%) to program implementation. Overall, two risk factors were assigned a low-risk level (12.5%), 11 a moderate-risk level (68.75%), one (6.25%) a high-risk level, and two (12.5%) a very high-risk level. After the implementation of mitigation measures, the new semiquantitative risk analysis showed a reduction in almost all hazardous situations: two risk factors (12.5%) were given a very low level, six (37.5%) a low level, seven (43.75%) a moderate level, and one (6.25%) a very high level. CONCLUSION: An interdisciplinary risk assessment analysis is applicable to MDT activities by using an ad hoc risk matrix: if the hazard is identified and monitored, the risk could be reduced and managed in a short time.

Early experience with uniportal robotic thoracic surgery lobectomy.

Background: Invasiveness is considered one of the cornerstones of every field of surgery, and video-assisted thoracoscopic (VATS) approaches are now routinely used worldwide to perform pulmonary resections. Recently, robotic-assisted thoracic surgery (RATS) has become the preferred technique in many centers; it is routinely performed using three or four ports with at least one service incision, contrasting with the real concept of invasiveness, especially when compared to uniportal VATS (U-VATS). Hereby, we present our early experience with uniportal RATS (U-RATS) pulmonary resections for early-stage lung cancer. Technical details of surgical steps are accurately described and commented on. Results: Twenty-four consecutive patients with lung cancer underwent U-RATS anatomical pulmonary resections at our institute. All procedures were completed with the uniportal approach. The mean operative time was 210 min (range 120-350); in the last 10 cases, the operative time was significantly reduced (180 min) compared to the first 10 cases (232 min) (p < 0.02), showing a very fast learning curve. The postoperative pain score was comparable to that for U-VATS and was constantly low. Conclusions: U-RATS is a safe and feasible technique, combining the advantages of U-VATS with the well-known advantages of robotic surgery.

Lurbinectedin in small cell lung cancer.

Few treatment options are available for patients with small cell lung cancer (SCLC) in progression after a first-line therapy. A novel therapeutic approach is represented by lurbinectedin, a synthetic derivative of trabectedin that works by inhibiting oncogenic transcription and promoting apoptosis in tumor cells. A phase II basket trial demonstrated the activity of lurbinectedin at the dose of 3.2 mg/m2 in patients with SCLC who had failed a previous chemotherapy, with a response rate of 35.2%, a median progression-free survival (mPFS) of 3.5 months, and a median overall survival (mOS) of 9.3 months. Common severe adverse events (grades 3-4) were hematological disorders, including anemia (9%), leukopenia (29%), neutropenia (46%), and thrombocytopenia (7%). On the basis of the positive results of this phase II study, on June 2020, lurbinectedin was approved by the Food and Drug Administration as second line for SCLC patients in progression on or after platinum-based therapy. The subsequent phase III trial comparing the combination of lurbinectedin plus doxorubicin vs. CAV (cyclophosphamide, Adriamycin, and vincristine) or topotecan did not demonstrate an improvement in overall survival, although the experimental arm showed a superior safety profile. Combinations of lurbinectedin with other drugs, cytotoxic agents and immune checkpoint inhibitors, are currently under investigation. The results of these studies should better define the optimal clinical application of lurbinectedin.

Nodal Upstaging Evaluation After Robotic-Assisted Lobectomy for Early-Stage Non-small Cell Lung Cancer Compared to Video-Assisted Thoracic Surgery and Thoracotomy: A Retrospective Single Center Analysis.

Introduction: The standard surgical procedures for patients with early-stage NSCLC is lobectomy-associated radical lymphadenectomy performed by using the thoracotomy approach. In the last few years, minimally invasive techniques have increasingly strengthened their role in lung cancer treatment, especially in the early stage of the disease. Although the lobectomy technique has been accepted, controversy still surrounds lymph node dissection. In our study, we analyze the rate of upstaging early non-small cell lung cancer patients who underwent radical surgical treatment using the robotic and the VATS techniques compared to the standard thoracotomy approach. Methods and Materials: We retrospectively reviewed patients who underwent a lobectomy and radical lymphadenectomy at our Institute between 2010 and 2019. We selected 505 patients who met the inclusion criteria of the study: 237 patients underwent robotic surgery, 158 patients had thoracotomy, and 110 patients were treated with VATS. We analyzed the demographic features between the groups as well as the nodal upstaging rate after pathological examination, the number of dissected lymph nodes and the ratio of dissected lymph nodes to metastatic lymph nodes of the three groups. Results: The patients of the three groups were homogenous with respect to age, sex, and histology. The postoperative major morbidity rate was significantly higher in the thoracotomy group, and hospital stay was significantly longer. The percentage of the mediastinal nodal upstaging rate and the number of dissected lymph nodes was significantly higher in the robotic group compared with the VATS group. The ratio of dissected lymph nodes to metastatic lymph nodes was significantly lower compared with the VATS group and the thoracotomy group. Discussion: The prognostic impact of the R(un) status is still highly debated. A surgical approach that allows better results in terms of resection has still not been defined. Our results show that robotic surgery is a safe and feasible approach especially regarding the accuracy of mediastinal lymphadenectomy. These findings can lead to defining a more precise pathological stage of the disease and, if necessary, to more accurate postoperative treatment.

Uniportal thoracoscopic left main bronchus resection with new lobar carina reconstruction.

Isolated endobronchial tumors of the left main bronchus are quite rare. They are treated by surgical resection, preferably using lung-sparing techniques, when possible. These procedures are technically challenging and are usually performed through a standard thoracotomy.  This video tutorial shows a left main bronchus sleeve resection with distal lobar carina reconstruction, performed through a uniportal thoracoscopic approach, for a typical carcinoid tumor of the distal left main bronchus.

COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study.

BACKGROUND: Early reports on patients with cancer and COVID-19 have suggested a high mortality rate compared with the general population. Patients with thoracic malignancies are thought to be particularly susceptible to COVID-19 given their older age, smoking habits, and pre-existing cardiopulmonary comorbidities, in addition to cancer treatments. We aimed to study the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with thoracic malignancies. METHODS: The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry is a multicentre observational study composed of a cross-sectional component and a longitudinal cohort component. Eligibility criteria were the presence of any thoracic cancer (non-small-cell lung cancer [NSCLC], small-cell lung cancer, mesothelioma, thymic epithelial tumours, and other pulmonary neuroendocrine neoplasms) and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms. Patients of any age, sex, histology, or stage were considered eligible, including those in active treatment and clinical follow-up. Clinical data were extracted from medical records of consecutive patients from Jan 1, 2020, and will be collected until the end of pandemic declared by WHO. Data on demographics, oncological history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes were collected. Associations between demographic or clinical characteristics and outcomes were measured with odds ratios (ORs) with 95% CIs using univariable and multivariable logistic regression, with sex, age, smoking status, hypertension, and chronic obstructive pulmonary disease included in multivariable analysis. This is a preliminary analysis of the first 200 patients. The registry continues to accept new sites and patient data. FINDINGS: Between March 26 and April 12, 2020, 200 patients with COVID-19 and thoracic cancers from eight countries were identified and included in the TERAVOLT registry; median age was 68·0 years (61·8-75·0) and the majority had an Eastern Cooperative Oncology Group performance status of 0-1 (142 [72%] of 196 patients), were current or former smokers (159 [81%] of 196), had non-small-cell lung cancer (151 [76%] of 200), and were on therapy at the time of COVID-19 diagnosis (147 [74%] of 199), with 112 (57%) of 197 on first-line treatment. 152 (76%) patients were hospitalised and 66 (33%) died. 13 (10%) of 134 patients who met criteria for ICU admission were admitted to ICU; the remaining 121 were hospitalised, but were not admitted to ICU. Univariable analyses revealed that being older than 65 years (OR 1·88, 95% 1·00-3·62), being a current or former smoker (4·24, 1·70-12·95), receiving treatment with chemotherapy alone (2·54, 1·09-6·11), and the presence of any comorbidities (2·65, 1·09-7·46) were associated with increased risk of death. However, in multivariable analysis, only smoking history (OR 3·18, 95% CI 1·11-9·06) was associated with increased risk of death. INTERPRETATION: With an ongoing global pandemic of COVID-19, our data suggest high mortality and low admission to intensive care in patients with thoracic cancer. Whether mortality could be reduced with treatment in intensive care remains to be determined. With improved cancer therapeutic options, access to intensive care should be discussed in a multidisciplinary setting based on cancer specific mortality and patients' preference. FUNDING: None.

Primary pulmonary hodgkin lymphoma simulating a mediastinal tumour: an uncommon occurrence.

The case of a patient with primary pulmonary Hodgkin Lymphoma simulating a mediastinal tumour is reported for its rarity and the diagnostic concerns encountered by us.

[Laparoscopic splenectomy in haematological diseases: short- and medium-term results in thirty initial cases]. / La splenectomia laparoscopica nelle patologie ematologiche: risultati a breve e medio terrnine in trenta casi iniziali.

In 1991 Delaitre and Maignien described the first laparoscopic splenectomy, since when a rapid spread of this technique has been observed and the procedure has become the gold standard in the surgical management of benign and malignant haematological diseases. In the present study, the results of the first 30 laparoscopic splenectomies performed at the Division of General Surgery of the S. Eugenio Hospital of Rome are reported. The operations were performed in patients with benign (27 cases) and malignant (3 cases) haematological diseases, treated in the Regional Haematological Centre of the same hospital. The procedures were carried out according to criteria corresponding to those recently described in the guidelines of the European Association for Endoscopic Surgery. As regards the results, two procedures (6.7%) were converted to open surgery. One postoperative haemorrhage was observed, requiring a laparoscopic reoperation for haemostasis. No other major local or general complications were observed. Mortality was nil. The mean postoperative hospital stay was 4.2 days (range: 4-8 days). Medium-term surgical and haematological results were excellent. Laparoscopic splenectomy is the surgical gold standard, but should be performed in advanced centres in close cooperation with a haematology centre. The procedure is indicated in all patients who are candidates for splenectomy, with the sole exception of those affected by portal hypertension or with general contraindications to laparoscopy. In advanced centres, better early and late results can be achieved, in addition to the well-known benefits of the minimally invasive technique, particularly in aesthetic terms, which in younger patients affected by benign haematological pathologies are very important.

Giant symptomatic myelolipoma of the right adrenal gland: a case report.

Adrenal myelolipoma is an uncommon tumour of the adrenal gland, usually unilateral, frequently associated with hypertension and obesity, with a benign biological behaviour and without hormonal activity, first described in 1905. The neoplasm consists of adipose tissue and myelopoietic cells of the bone marrow. These tumours have a very slow but continued growth and their volume and weight vary significantly from small lesions of a few grams to huge masses weighing up to several kilograms. If symptoms occur, surgery should be performed without delay, especially for large myelolipomas that are at high risk of spontaneous rupture with haemorrhage and life-threatening shock. In this report a case of a 43-year-old male with a 22 x 18 x 9 cm giant myelolipoma, weighing 3500 g and originating from the right adrenal gland is described. The large mass dislocating and compressing the inferior vena cava, was removed surgically. The early postoperative course and the late outcome were favourable without recurrence after 30 months. The different aetiological hypotheses of this rare neoplasm and its clinical features, diagnosis and treatment are discussed.

[Incidental thyroid microcarcinoma in benign thyroid disease. Incidence in a total of 100 consecutive thyroidectomies]. / I microcarcinoma incidentale della tiroide nelle tireopade benigne. Incidenza su 100 tiroidectomie totali consecutive.

Over the past few years, incidental thyroid microcarcinoma has become a frequent disease and its incidence in some reports is considerable. Discovering new cases depends on the extended indications for total thyroidectomy for benign disease, on progress in the field of diagnostic instruments (ultrasound, scintigram, fine needle biopsy for cytology, CT scan, MRI), and on the pathology examination of very thin slices of specimens. In spite of the high incidence reported in some autopsy series, suggesting that this tumour may have a good prognosis, some Authors report an overall incidence of up to 11% of local recurrence, metastasis or mortality. For all these reasons the surgical treatment of incidental thyroid microcarcinoma is still controversial. The aim of this study was to estimate the incidence and examine the clinical-pathological findings of incidental thyroid microcarcinoma in a series of 100 consecutive thyroidectomies and to evaluate whether complete removal of the gland should be adopted in all cases. In the present series the incidence of incidental thyroid microcarcinoma was 21.6% (19/88). Total thyroidectomy was considered the treatment of choice for diffuse benign disease and appeared to be necessary for both the diagnosis and treatment of incidental thyroid microcarcinoma.

Catamenial Bernard-Horner's syndrome related to thoracic endometriosis.

We describe the case of a young woman with a recurrent right Bernard-Horner's syndrome associated with the onset of intermittent supraclavicular mass. Surgical excision of the mass revealed the endometrial pattern of the tumor and the close relationship between Bernard-Horner's syndrome and thoracic endometriosis. No other case of this syndrome has been reported in the literature.

Major iatrogenic tracheal injury during pneumonectomy: conservative treatment.

We hereby present the case of a 55-year-old woman with an iatrogenic tracheal laceration that occurred during double lumen intubation for left pneumonectomy. Conservative treatment was performed and the patient was discharged 12 days after surgery. No major sequelae after 3 months of follow-up were observed.