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Mutations in APC promote colorectal cancer (CRC) progression through uncontrolled WNT signaling. Patients with desmoplastic CRC have a significantly worse prognosis and do not benefit from chemotherapy, but the mechanisms underlying the differential responses of APC-mutant CRCs to chemotherapy are not well understood. We report that expression of the transcription factor prospero homeobox 1 (PROX1) was reduced in desmoplastic APC-mutant human CRCs. In genetic Ape-mutant mouse models, loss of Prox1 promoted the growth of desmoplastic, angiogenic, and immunologically silent tumors through derepression of Mmp14. Although chemotherapy inhibited Prox1-proficient tumors, it promoted further stromal activation, angiogenesis, and invasion in Prox1-deficient tumors. Blockade of vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2) combined with CD40 agonistic antibodies promoted antiangiogenic and immunostimulatory reprogramming of Prox1-deficient tumors, destroyed tumor fibrosis, and unleashed T cell-mediated killing of cancer cells. These results pinpoint the mechanistic basis of chemotherapy-induced hyperprogression and illustrate a therapeutic strategy for chemoresistant and desmoplastic CRCs., Introduction Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide (1). Patients with stage III or IV CRC have a high risk of recurrence and are [...]

Simple Summary: Sarcopenia is defined as a progressive loss of skeletal muscle strength, mass, and function. Lung cancer patients frequently present with sarcopenia, which may be associated with poorer postoperative outcomes. This study aimed to evaluate the impact of CT-derived preoperative sarcopenia on postoperative outcomes and survival in patients that underwent thoracoscopic anatomical pulmonary resection for non-small cell lung cancer. Sarcopenia was observed in almost one-quarter of patients. Our results showed that CT-derived sarcopenia seems to have a small impact on early postoperative outcomes but no effect on overall survival. Preoperative sarcopenia screening may be a useful tool to include in the surgical risk assessment. We aimed to evaluate whether computed tomography (CT)-derived preoperative sarcopenia measures were associated with postoperative outcomes and survival after video-assisted thoracoscopic (VATS) anatomical pulmonary resection in patients with early-stage non-small cell lung cancer (NSCLC). We retrospectively reviewed all consecutive patients that underwent VATS anatomical pulmonary resection for NSCLC between 2012 and 2019. Skeletal muscle mass was measured at L3 vertebral level on preoperative CT or PET/CT scans to identify sarcopenic patients according to established threshold values. We compared postoperative outcomes and survival of sarcopenic vs. non-sarcopenic patients. A total of 401 patients underwent VATS anatomical pulmonary resection for NSCLC. Sarcopenia was identified in 92 patients (23%). Sarcopenic patients were predominantly males (75% vs. 25%; p < 0.001) and had a lower BMI (21.4 vs. 26.5 kg/m2; p < 0.001). The overall postoperative complication rate was significantly higher (53.2% vs. 39.2%; p = 0.017) in sarcopenic patients and the length of hospital stay was prolonged (8 vs. 6 days; p = 0.032). Two factors were associated with postoperative morbidity in multivariate analysis: BMI and American Society of Anesthesiologists score >2. Median overall survival was comparable between groups (41 vs. 46 months; p = 0.240). CT-derived sarcopenia appeared to have a small impact on early postoperative clinical outcomes, but no effect on overall survival after VATS anatomical lung resection for NSCLC. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES We assessed the accuracy of 3 validated lobectomy scoring systems to predict prolonged air leak (PAL) in patients undergoing video-assisted thoracoscopic surgery (VATS) segmentectomy. METHODS We reviewed all consecutive patients who had a VATS segmentectomy between January 2016 and October 2020. We determined PALs on postoperative day 5. These findings were correlated with the calculated Brunelli (gender, age, body mass index [BMI], forced expiratory volume in 1 s < 80 and pleural adhesion), Epithor (gender, location, dyspnoea score, BMI, type of resection and pleural adhesion) and European Society of Thoracic Surgeons (ESTS) (gender, BMI and forced expiratory volume in 1 s) scores of each patient. RESULTS A total of 453 patients (mean age: 66.5 years, female/male sex ratio: 226/227) underwent a VATS segmentectomy for malignant (n = 400) and non-malignant (n = 53) disease. Postoperative cardiopulmonary complications and in-hospital mortality rates were 19.6% and 0.4%, respectively. Median chest tube drainage duration and hospital stay were 2 (interquartile range: 1-4) and 4 (interquartile range: 3-7) days, respectively. On day 5, the prevalence of PAL was 14.1%. The ESTS, Brunelli and Epithor scores for the treated population were, respectively, class A (6.8%), class B (3.2%), class C (10.8%) and class D (28.2%); very low and low (0%), moderate (5%), high (6.3%) and very high (21%); and class A (7%), class B (13.2%), class C (24%) and class D (27.8%). All scores correlated with PAL (p ≤ 0.001). The areas under the receiver operating characteristic (ROC) curve were 0.686, 0.680 and 0.644, respectively. CONCLUSIONS All 3 scoring systems were correlated with PAL > 5 days following the VATS segmentectomies. ESTS scores seem easier to introduce in clinical practice, but validation by a multicentre cohort is mandatory. [ABSTRACT FROM AUTHOR]

Invasive mold infections (IMIs) are difficult to diagnose. This analysis of histopathologically proven IMIs at our institution (2010–2019) showed that 11/41 (27%) of them were not suspected at the time of biopsy/autopsy (9/17, 53% among autopsies). The rate of missed diagnosis was particularly high (8/16, 50%) among nonhematologic cancer patients. [ABSTRACT FROM AUTHOR]

Pulmonary infection by Mycoplasma hominis (M hominis) in lung transplant (LTx) recipients is an uncommon yet potentially severe complication. Bronchial dehiscence in the context of M hominis infection has not been previously reported. In this report, we discuss a case of donor‐derived M hominis infection in a LTx recipient with bilateral bronchial anastomoses dehiscence and stenosis. The infection was managed using a multidisciplinary approach: repeat surgical revision of the necrotic anastomosis; targeted antibiotic therapy with the combination of oral and inhaled fluoroquinolones, and oral doxycycline and continuous ventilatory support. Response to therapy was monitored through repeat bronchoscopy and serial quantitative PCR assays for M hominis in bronchoalveolar lavage and aspiration. The rare nature of M hominis infection after LTx, its difficult detection in conventional cultures and innate resistance to beta‐lactams make diagnosis and timely treatment of this organism challenging. We recommend that transplant centers have a low threshold for screening for Mycoplasma infection, particularly in patients with unsatisfactory postoperative course and little response to broad‐spectrum antimicrobial and antifungal coverage. Monitoring with PCR may help to adapt the duration of antibiotic therapy. [ABSTRACT FROM AUTHOR]

Introduction: VATS pulmonary segmentectomy is increasingly proposed as a parenchyma‐sparing resection for tumors smaller than 2 cm in diameter. The aim of this study was to compare short‐term oncological results and local control in solid non‐small cell lung cancers (NSCLCs) <2 cm surgically treated by intentional VATS segmentectomy or lobectomy. Methods: This study was a single center retrospective study of consecutive patients undergoing VATS lobectomy (VL) or segmentectomy (VS) for solid <2 cm NSCLC from January 2014 to October 2019. Results In total, 188 patients with a median age of 65 years (male/female: 99/89) underwent VS (n = 96) or VL (n = 92). Segmentectomies in the upper lobes were performed in 57% and as a single segment in 55% of cases. There was no statistically significant difference between VS and VL in terms of demographics, comorbidities, postoperative outcomes, dissected lymph node stations (2.89 ± 0.95 vs. 2.93 ± 1, P = 0.58), rate of pN1 (2.2% vs. 2.1%, P = 0.96) or pN2 upstaging (1.09% vs. 1.06%, P = 0.98). Adjuvant chemotherapy was given in 15% of patients in the VL and 11% in the VS group. During follow‐up (median: 23 months), no patients presented with local nodal recurrence or on the stapler line (VS group). Three patients on VL and two in VS groups presented with recurrence on the remnant operated lung. New primary pulmonary tumors were diagnosed in 3.3% and 6.3% of patients in the VL and VS groups, respectively. Conclusions: Despite the short follow‐up, our preliminary data shows that local control is comparable for VATS lobectomy and VATS segmentectomy for patients with NSCLC <2 cm. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Open in new tab Download slide OBJECTIVES Malignant pleural mesothelioma (MPM) is a deadly disease with limited treatment options. Approaches to enhance patient immunity against MPM have been tested but shown variable results. Previously, we have demonstrated interesting vascular modulating properties of low-dose photodynamic therapy (L-PDT) on MPM. Here, we hypothesized that L-PDT vascular modulation could favour immune cell extravasation in MPM and improve tumour control in combination with immune checkpoint inhibitors. METHODS First, we assessed the impact of L-PDT on vascular endothelial E-selectin expression, a key molecule for immune cell extravasation, in vitro and in a syngeneic murine model of MPM. Second, we characterized the tumour immune cell infiltrate by 15-colour flow cytometry analysis 2 and 7 days after L-PDT treatment of the murine MPM model. Third, we determined how L-PDT combined with immune checkpoint inhibitor anti-CTLA4 affected tumour growth in a murine MPM model. RESULTS L-PDT significantly enhanced E-selectin expression by endothelial cells in vitro and in vivo. This correlated with increased CD8+ T cells and activated antigen-presenting cells (CD11b+ dendritic cells and macrophages) infiltration in MPM. Also, compared to anti-CTLA4 that only affects tumour growth, the combination of L-PDT with anti-CTLA4 caused complete MPM regression in 37.5% of animals. CONCLUSIONS L-PDT enhances E-selectin expression in the MPM endothelium, which favours immune infiltration of tumours. The combination of L-PDT with immune checkpoint inhibitor anti-CTLA4 allows best tumour control and regression. [ABSTRACT FROM AUTHOR]

OBJECTIVES Patients with oligometastatic non-small-cell lung cancer (NSCLC) may benefit from therapy with curative intent. Our goal was to identify prognostic factors related to better prognosis in a multicentre analysis of patients who underwent surgery of primary tumours in combination with radical treatment of all metastatic sites. METHODS We retrospectively reviewed the records of oligometastatic patients who underwent resection of primary tumours at 4 centres (August 2001–February 2018). Oligometastasis was defined as ≤5 synchronous metastases in ≤2 organs. Radical metastatic treatment was surgery, radiotherapy or a combination. The Cox proportional hazards model was used for identification of prognostic factors on overall survival. RESULTS We treated 124 patients; 72 (58%) were men, mean age 60 ± 9.8 years, with 87 (70%) adenocarcinoma. Sixty-seven (54%) patients had positive pathologic-N stage (pN). Brain metastases were most common (n  = 76; 61%) followed by adrenal (n  = 13; 10%) and bone (n  = 12; 10%). Systemic therapy was administered in 101 (82%) patients. Median follow-up was 60 months [95% confidence interval (CI) 41–86]. Thirty- and 90-day mortality rates were 0 and 2.4%, respectively. One-, 2-, and 5-year overall survival were 80%, 58% and 36%, respectively. Cox regression analysis showed that patients ≤60 years [hazard ratio (HR) 0.41, 95% CI 0.24, 0.69; P  = 0.001] and patients with pN0 (HR 0.38, 95% CI 0.21–0.69; P  = 0.002) had a significant survival benefit. The presence of bone metastases negatively affected survival (HR 2.53, 95% CI 1.05–6.09; P  = 0.04). CONCLUSIONS Treatment with curative intent of selected oligometastatic NSCLC, including resection of the primary tumour, can be performed safely and with excellent 5-year survival rates, especially in younger patients with pN0 disease. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Evaluation of complex, acquired, non-malignant tracheo/broncho-oesophageal fistulas (TEF) repaired by extrathoracic pedicled muscle flaps that were, in addition to their interposition between the airways and the gastro-intestinal tract, patched into gastrointestinal or airway defects if primary closure seemed risky. METHODS: A single institution experience of patients treated between 2003 and 2015. Twenty-two patients required TEF repair following oesophageal surgery (18), Boerhaave syndrome (1), chemotherapy for mediastinal lymphoma (1), carinal resection and irradiation (1) and laryngectomy (1); 64% of them underwent prior radio- or chemotherapy and 50% prior airway or oesophageal stenting. RESULTS: Airway defects were closed by muscle flap patch (n = 12), lobectomy (n = 4), airway resection/anastomosis (n = 2), pneumonectomy (n = 1), segmentectomy (n = 2) or primary suture (n = 1). Gastro-intestinal defects were repaired by oesophageal diversion (n = 9), muscle flap patch (n = 8) or primary suture (n = 5). A muscle flap patch was used to close airway and gastro-intestinal defects in 55% and 36% of cases, respectively. The 90-day postoperative mortality and TEF recurrence rates were 18% and 4.5%. Airway healing and breathing without tracheal appliance was obtained in 95% of patients and gastro-intestinal healing in 77% of those without oesophageal diversion. Five of nine patients with oesophageal diversion underwent intestinal restoration by retrosternal colon transplants. CONCLUSIONS: Complex TEF arising after oesophageal surgery, radio-chemotherapy or failed stenting can be successfully closed using extrathoracic muscle flaps that can, in addition to their interposition between the airway and the gastro-intestinal tract, also be patched into gastro-oesophageal or airway defects if primary closure seems hazardous. [ABSTRACT FROM AUTHOR]

Damaged lung grafts obtained after circulatory death (DCD lungs) and warm ischemia may be at high risk of reperfusion injury after transplantation. Such lungs could be pharmacologically reconditioned using ex-vivo lung perfusion (EVLP). Since acute inflammation related to the activation of nuclear factor kappaB (NF-κB) is instrumental in lung reperfusion injury, we hypothesized that DCD lungs might be treated during EVLP by pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB. Rat lungs exposed to 1h warm ischemia and 2 h cold ischemia were subjected to EVLP during 4h, in absence (CTRL group, N = 6) or in presence of PDTC (2.5g/L, PDTC group, N = 6). Static pulmonary compliance (SPC), peak airway pressure (PAWP), pulmonary vascular resistance (PVR), and oxygenation capacity were determined during EVLP. After EVLP, we measured the weight gain of the heart-lung block (edema), and the concentration of LDH (cell damage), proteins (permeability edema) and of the cytokines IL-6, TNF-α and CINC-1 in bronchoalveolar lavage (BAL), and we evaluated NF-κB activation by the degree of phosphorylation and degradation of its inhibitor IκBα in lung tissue. In CTRL, we found significant NF-κB activation, lung edema, and a massive release of LDH, proteins and cytokines. SPC significantly decreased, PAWP and PVR increased, while oxygenation tended to decrease. Treatment with PDTC during EVLP inhibited NF-κB activation, did not influence LDH release, but markedly reduced lung edema and protein concentration in BAL, suppressed TNFα and IL-6 release, and abrogated the changes in SPC, PAWP and PVR, with unchanged oxygenation. In conclusion, suppression of innate immune activation during EVLP using the NF-κB inhibitor PDTC promotes significant improvement of damaged rat DCD lungs. Future studies will determine if such rehabilitated lungs are suitable for in vivo transplantation. [ABSTRACT FROM AUTHOR]

Extracorporeal assistances are exponentially used for patients, with acute severe but reversible heart or lung failure, to provide more prolonged support to bridge patients to heart and/or lung transplantation. However, experience of use of extracorporeal assistance for pulmonary resection is limited outside lung transplantation. Airways management with standard mechanical ventilation system may be challenging particularly in case of anatomical reasons (single lung), presence of respiratory failure (ARDS), or complex tracheo-bronchial resection and reconstruction. Based on the growing experience during lung transplantation, more and more surgeons are now using such devices to achieve good oxygenation and hemodynamic support during such challenging cases. We review the different extracorporeal device and attempt to clarify the current practice and indications of extracorporeal support during pulmonary resection. [ABSTRACT FROM AUTHOR]