Salvage resection of advanced mediastinal tumors

The surgical treatment of locally advanced mediastinal tumors invading the great vessels and other nearby structures still represent a tricky question, principally due to the technical complexity of the resective phase, the contingent need to carry out viable vascular reconstructions and, therefore, the proper management of pathophysiologic issues. Published large-number series providing oncologic outcomes of patients who have undergone extended radical surgery for invasive mediastinal masses are just a few. Furthermore, the wide variety of different histologies included in some of these studies, as well as the heterogeneity of chemo and radiation therapies employed, did not allow for the development of clear oncologic guidelines. Usually in the past, surgical resections of large masses along with the neighbouring structures were not offered to patients because of related morbidity and mortality and limited information available on the prognostic advantage for long term. However, in the last decades, advances in surgical technique and perioperative management, as well as increased oncologic experience in this field, have allowed radical exeresis in selected patients with invasive tumors requiring resections extended to the surrounding structures and complex vascular reconstructions. Such aggressive surgical treatment has been proposed in association or not with adjuvant chemo- or radiotherapy regimens, achieving encouraging oncologic results with limited morbidity and mortality in experienced institutions. Congestive heart failure or impending cardiovascular collapse due to the compression by the large mass are the most frequent immediately lifethreatening problems that some of these patients can experience. In this setting, medical palliation is usually ineffective and an aggressive salvage surgical treatment may remain the only therapeutic option

Activation of NF-kappaB/Rel transcription factors in human primary peripheral blood mononuclear cells by interleukin 7.

Pathways that regulate the activation of NF-kappaB/Rel transcription factors are known to include signaling through a number of cytokine receptors. Interleukin 7 (IL-7), produced by bone marrow and other stromal cells, is a key factor for differentiation and survival in the lymphoid and other compartments. We found that human recombinant IL-7 induced NF-kappaB/Rel activation, analyzed by electrophoretic mobility shift assay (EMSA), in human peripheral blood T lymphocytes from healthy donors. Induced complexes included p65 and p50 NF-kappaB/Rel subunits. These results demonstrate for the first time that IL-7 can participate in signaling leading to NF-kappaB/Rel activation

Severe reperfusion lung injury after double lung transplantation

AIM: To demonstrate the effects of combined inhaled nitric oxide and surfactant replacement as treatment for acute respiratory distress syndrome. This treatment has not previously been documented for reperfusion injury after double lung transplantation. METHOD: A 24-year-old female with cystic fibrosis underwent double lung transplantation. During implantation of the second lung a marked increase in pulmonary artery pressure associated with systemic hypotension, hypoxemia and low cardiac output were observed. Notwithstanding the patient received support from cardiovascular drugs and pulmonary vasodilators cardiopulmonary by-pass was necessary. In the intensive care unit the patient received the same drug support, inhaled nitric oxide and two bronchoscopic applications of bovine surfactant. RESULTS: A rapid improvement in PaO(2)/FiO(2) within 2–3 hours of administration of surfactant was seen. The patient is well at follow-up 1 year post-transplant. CONCLUSION: There is a potential role for a combined therapy with inhaled nitric oxide and surfactant replacement in reperfusion injury after lung transplantation

A challenging upper digestive tract continuity restoration after recurrent esophago-colonic anastomosis complications

Background: Acute and chronic complications in esophago-colonic anastomosis have a significant impact in the postoperative course of patients with colonic transposition. Evidence about their management is poor and surgical treatment is mostly based on tailored approaches, so each new experience could be useful to improve knowledge about this peculiar condition. We report a unique case of an esophago-colonic resection and re-anastomosis without sternal approximation after recurrent anastomosis failure and strictures. Case presentation: A 69-year-old woman was referred to our hospital for worsening dysphagia. The patient had undergone esophago-gastrectomy with right colon interposition 12 years prior due to caustic ingestion. The esophago-colonic anastomosis was initially complicated by an enterocutaneous fistula, which was treated with anastomosis resection and left colon transposition. This was then further complicated by dehiscence and sternal infection treated with resection of the distal portion of the sternum and a new colo-jejunal anastomosis. Finally, a chronic anastomotic stricture occurred, refractory to endoscopic dilatation and prothesis positioning. We planned a new colonic-esophageal resection and re-anastomosis. The main technical challenges were addressing the adhesions resulting from previous surgery and mobilizing an adequate length of the intestinal tract to allow conduit continuity restoration. Blood supply was assessed through Indocyanine Green Fluorescence. To avoid compression of the digestive conduit sternal margins were not re-approximated, and the transposed tube was covered and protected using both pectoralis major muscles flap. We decided to avoid the use of any prosthetic material to reduce the risk of infection. The patient was able to resume oral food intake on the 12th day postoperatively after a barium swallowing test showed an adequate conduit caliber. Conclusion: Esophago-colonic anastomosis complications represent a life-threatening condition. Therefore, reports and sharing of knowledge are important to improve expertise in management of these conditions

Enhancement of cytosine arabinoside-induced apoptosis in human myeloblastic leukemia cells by NFkB/Rel- specific decoy oligodeoxynucleotides

The activity of NF-kB/Rel nuclear factors is known to inhibit apoptosis in various cell types. We investigated whether the subtraction of NF-kB/Rel activity influenced the response of 11 AML (M1, M2 and M4) patients’ cells to AraC. To this end we used a phosphorothioate double-stranded decoy oligodeoxynucleotide (ODN) carrying the NF-kB/Rel- consensus sequence. Cell incubation with this ODN, but not its mutated (scrambled) form used as a control, resulted in abating the NF-kB/Rel nuclear levels in these cells, as verified by electrophoretic mobility shift assay (EMSA) of cells’ nuclear extracts. We incubated the leukemic cells with AraC (32 or 1 mM), in either the absence or presence of the decoy or the scrambled ODN, and analyzed cell apoptosis. The spontaneous cell apoptosis detectable in the absence of AraC (,25%) was not modulated by the oligonucleotide presence in cell cultures. On the other hand, in 10 of the 11 samples tested, the decoy kB, but not the scrambled ODN significantly (P ,0.01 in a Student’s t test) enhanced cell apoptotic response to AraC. Such an effect was particularly remarkable at low AraC doses (1 mM). These findings indicate that NF-kB/Rel activity influences response to AraC in human primary myeloblastic cells, and suggests that the inhibition of NF-kB/Rel factors can improve the effect of chemotherapy in AM

Reconstruction of the heart and the aorta for radical resection of lung cancer

Introduction: We report a single-center experience of resection and reconstruction of the heart and aorta infiltrated by lung cancer in order to prove that involvement of these structures is no longer a condition precluding surgery. Methods: Twenty-seven patients underwent surgery for lung cancer presenting full-thickness infiltration of the heart (n = 6) or the aorta (n = 18) and/or the supra-aortic branches (subclavian n = 3). Cardiac reconstruction was performed in 6 patients (5 atrium, 1 ventricle), with (n = 4) or without (n = 2) cardiopulmonary bypass, using a patch prosthesis (n = 4) or with deep clamping and direct suture (n = 2). Aortic or supra-aortic trunk reconstruction (n = 21) was performed using a heart-beating crossclamping technique in 14 cases (8 patch, 4 conduit, 2 direct suture), or without crossclamping by placing an endovascular prosthesis before resection in 7 (4 patch, 3 omental flap reconstruction). Neoadjuvant chemotherapy was administered in 13 patients, adjuvant therapy in 24. Results: All resections were complete (R0). Nodal staging of lung cancer was N0 in 14 cases, N1 in 10, N2 in 3. No intraoperative mortality occurred. Major complication rate was 14.8%. Thirty-day and 90-day mortality rate was 3.7%. Median follow-up duration was 22 months. Recurrence rate is 35.4% (9/26: 3 loco-regional, 6 distant). Overall 3- and 5-year survival is 60.9% and 40.6%, respectively. Conclusions: Cardiac and aortic resection and reconstruction for full-thickness infiltration by lung cancer can be performed safely with or without cardiopulmonary bypass and may allow long-term survival of adequately selected patients

Mechanisms of endothelial cell dysfunction in cystic fibrosis

Although cystic fibrosis (CF) patients exhibit signs of endothelial perturbation, the functions of the cystic fibrosis conductance regulator (CFTR) in vascular endothelial cells (EC) are poorly defined. We sought to uncover biological activities of endothelial CFTR, relevant for vascular homeostasis and inflammation. We examined cells from human umbilical cords (HUVEC) and pulmonary artery isolated from non-cystic fibrosis (PAEC) and CF human lungs (CF-PAEC), under static conditions or physiological shear. CFTR activity, clearly detected in HUVEC and PAEC, was markedly reduced in CF-PAEC. CFTR blockade increased endothelial permeability to macromolecules and reduced trans‑endothelial electrical resistance (TEER). Consistent with this, CF-PAEC displayed lower TEER compared to PAEC. Under shear, CFTR blockade reduced VE-cadherin and p120 catenin membrane expression and triggered the formation of paxillin- and vinculin-enriched membrane blebs that evolved in shrinking of the cell body and disruption of cell-cell contacts. These changes were accompanied by enhanced release of microvesicles, which displayed reduced capability to stimulate proliferation in recipient EC. CFTR blockade also suppressed insulin-induced NO generation by EC, likely by inhibiting eNOS and AKT phosphorylation, whereas it enhanced IL-8 release. Remarkably, phosphodiesterase inhibitors in combination with a β2 adrenergic receptor agonist corrected functional and morphological changes triggered by CFTR dysfunction in EC. Our results uncover regulatory functions of CFTR in EC, suggesting a physiological role of CFTR in the maintenance EC homeostasis and its involvement in pathogenetic aspects of CF. Moreover, our findings open avenues for novel pharmacology to control endothelial dysfunction and its consequences in CF

BAG3 protein regulates stress- induced apoptosis in normal and neoplastic leukocytes

Co-chaperone proteins that share the Bcl-2-associated athanogene (BAG) domain are characterized by their interaction with a variety of partners, such as heat shock proteins (Hsp), steroid hormone receptors, Bcl-2, Raf-1 and others, involved in regulating protein folding and a number of cellular processes, including proliferation and apoptosis. Among BAG family members there is BAG3, also known as CAIR-1 or Bis. BAG3 forms a complex with Hsp70,1,2,4,6 a protein able to modulate apoptosis by interfering with cytochrome c release, apoptosome assembly and other events in the death process. In addition, BAG3 polypeptide binds to phospholipase C-g (PLC-g)4 or Bcl-2 protein.3,5 Due to such interaction with more than one apoptosis-modulating factor, BAG3 can participate in apoptosis regulation. Indeed, its hyperexpression can decrease apoptosis induced via Bax or Fas in the human epithelial cell line HeLa3 or by IL-3 deprivation in the murine hematopoietic cell line 32D.5 Furthermore, we recently showed that BAG3 downmodulation enhances the apoptotic response to chemotherapy in human primary B chronic lymphocytic leukemia cell

Thyroid Cancer and Fibroblasts

Thyroid cancer is the most common type of endocrine cancer, and its prevalence continue to rise. Non-metastatic thyroid cancer patients are successfully treated. However, looking for new therapeutic strategies is of great importance for metastatic thyroid cancers that still lead to death. With respect to this, the tumor microenvironment (TME), which plays a key role in tumor progression, should be considered as a new promising therapeutic target to hamper thyroid cancer progression. Indeed, thyroid tumors consist of cancer cells and a heterogeneous and ever-changing niche, represented by the TME, which contributes to establishing most of the features of cancer cells. The TME consists of extracellular matrix (ECM) molecules, soluble factors, metabolites, blood and lymphatic tumor vessels and several stromal cell types that, by interacting with each other and with tumor cells, affect TME remodeling, cancer growth and progression. Among the thyroid TME components, cancer-associated fibroblasts (CAFs) have gained more attention in the last years. Indeed, recent important evidence showed that thyroid CAFs strongly sustain thyroid cancer growth and progression by producing soluble factors and ECM proteins, which, in turn, deeply affect thyroid cancer cell behavior and aggressiveness. Hence, in this article, we describe the thyroid TME, focusing on the desmoplastic stromal reaction, which is a powerful indicator of thyroid cancer progression and an invasive growth pattern. In addition, we discuss the origins and features of the thyroid CAFs, their influence on thyroid cancer growth and progression, their role in remodeling the ECM and their immune-modulating functions. We finally debate therapeutic perspectives targeting CAFs