Interstitial Lung Disease After Kidney Transplantation and the Role of Everolimus.

BACKGROUND: Kidney transplant recipients are at higher risk of developing pulmonary complications related to immunosuppression, and inhibitor of the mammalian target of rapamycin (mTORi) has been reported as a potential cause. METHODS: Five hundred kidney-transplanted patients were retrospectively analyzed for pulmonary complications on the basis of clinical and instrumental data (chest radiography, high-resolution computed tomography, broncho-alveolar lavage, oximetry). RESULTS: We found 26 interstitial lung diseases (ILD) (16%): 12 cases (46.2%) were from infections (42.8% by Pneumocystis jirovecii) and 14 cases of ILD (53.8%) resulted as drug-induced ILD (DI-ILD). According to anti-rejection protocols, DI-ILD occurred in 8 patients (57%) while on triple regimen including steroids, everolimus (EVL), and cyclosporine (CyA) and in 6 patients on double regimen with steroids and mTORi: EVL or sirolimus (43%). In ILD+ patients, everolimus trough-concentration (EVL(TLC)) and cyclosporine (2nd-hour concentration: CyA(C2)) levels were higher than in patients in the same regimen but with ILD- (EVL(TLC) [ng/mL] 9.84 versus 6.85; CyA(C2) [ng/mL] 303.97 versus 298.56). The formula that used the combined blood levels of both drugs (EVL(TLC) + CyA(C2)/100) resulted in a significant difference between groups of patients (12.88 ± 1.61 versus 9.83 ± 1.91). Applying receiver operator characteristic curve (ROC) analysis to detect risk of developing ILD when on combined protocol with EVL and CyA, we obtained an area under the curve of 0.8622 (P = .0081) and 0.9082 (P = .0028), respectively, when using EVL(TLC) or the combination formula with both drugs. CONCLUSIONS: In renal transplant patients, we obtained a relationship of ILD to specific drug concentration. On the basis of ROC analysis, patients on EVL and CyA combined protocol are at risk of ILD when EVL(TLC) is >9.03 ng/mL or >11.41 when a formula with summation of EVL(TLC) and CyA(C2) is used.

Kidney Transplantation in HIV-Infected Recipients: Therapeutic Strategy and Outcomes in Monocentric Experience.

BACKGROUND: In Human immunodeficiency virus (HIV)-positive patients undergoing kidney transplantation, outcomes and immunosuppression (IS) protocol are not yet established due to infectious and neoplastic risks as well as to pharmacokinetic interactions with antiretroviral therapy (TARV). METHODS: We report a retrospective, 1-center study on 18 HIV+ patients undergoing, between October 2007 and September 2015, kidney transplantation (13 cases) or combined kidney-liver transplant (5 cases). Inclusion criteria for transplant were based on the Italian National Transplant Center protocol. IS regimen was based on quick tapering of steroids and the use of mTOR inhibitors (mTORi) with low dose of calcineurin inhibitors (CNI). In the early post-transplant period, TARV was based on enfuvirtide, raltegravir, plus 1 or more nucleoside analogues. RESULTS: In a mean follow-up of 3.1 years, patient survival rate at 1 and 3 years was, respectively, 86.6% and 84.6%, whereas graft survival was 81.2% and 78.6%. Cumulative rejection rate was 20.0% and 26.6% (1- and 3-year results). Median eGFR (MDRD) was 58.8 mL/min and 51.9 mL/min at 1 and 3 years. We had 9 cases of clinically relevant infections (2 Pneumocystis jirovecii pneumonia, 1 pulmonary aspergillosis, 2 severe sepsis, and 4 HCV reactivation) as well as 1 case (5.5%) of HIV reactivation. CONCLUSIONS: IS therapy based on mTORi and low CNI dose ensures good graft survival, low rate of acute rejection, limited drug toxicity, and control of HIV disease. TARV has no significant interaction with IS therapy.

Bronchoscopic staging of squamous cell carcinoma of the upper thoracic esophagus.

OBJECTIVE: To identify bronchoscopic findings that predict resectability of squamous cell carcinoma of the upper thoracic esophagus. DESIGN: Tracheobronchoscopy was performed in patients with squamous cell carcinoma of the thoracic esophagus to assess the infiltration of the tracheobronchial tree by the tumor and predict the resectability. Bronchoscopic records were matched with clinical outcome and intraoperative findings. SETTING: University hospital, tertiary care referral center. PATIENTS: A total of 113 patients with supracarinal esophageal carcinoma underwent bronchoscopy as part of the preoperative staging. In 47 patients the bronchoscopy was repeated after a regimen of neoadjuvant chemotherapy. INTERVENTION: A total of 160 bronchoscopies performed by the same operator. MAIN OUTCOME MEASURES: Bronchoscopic records matched with clinical outcome and intraoperative findings. RESULTS: Including patients before and after neoadjuvant chemotherapy, 27 of the 46 with no bronchoscopic abnormalities were operated on: in 24 (89%) of them radical surgical resection was possible. Among the 22 patients with a slight compression on the tracheobronchial tree admitted to surgery, a radical surgical resection was possible in 20 cases (91%). In none of the 5 patients with compression/deviation associated with fixation of the tracheobronchial tree but no mucosal infiltration who underwent surgery was a radical surgical resection possible because of tracheobronchial infiltration. CONCLUSIONS: Compression of the tracheobronchial tree does not necessarily mean infiltration by esophageal carcinoma. If the compression is slight and the mobility of the tracheobronchial tree is normal, a radical esophagectomy is possible in 91% of patients.

Pulmonary lobectomy for lung cancer: a prospective study to compare patients with forced expiratory volume in 1 s more or less than 80% of predicted.

OBJECTIVE: To compare post-operative course, lung function and survival of lung cancer patients with a forced expiratory volume in 1 s (FEV1) more or less than 80% of predicted submitted to lobectomy. METHODS: The data of patients undergoing lobectomy for non small cell carcinoma at the Thoracic Surgery Unit of the Ospedale Maggiore Policlinico of Milan, Italy, were prospectively collected. Inclusion criteria were a radical resectable tumor with size less than 2.5 cm, negative mediastinal nodes, capability to complete pulmonary function tests, Exclusion criteria were FEV1 <40% of predicted, pre- or post-operative chemo or radiotherapy, lobe to be resected receiving more than 30% of the perfusion, incapacity to quit smoking. RESULTS: Eighty-eight patients entered the study and were divided into two groups according to their FEV1%: 45 patients were included in control group (mean FEV1: 92.2%) and 42 in chronic obstructive pulmonary disease group (mean FEV1: 64.2%). Post-operative complications, operative mortality and actuarial survival were the same in the 2 groups. Six months after lobectomy, the mean changes in FEV1 were -14.9% for first group and -3.2% for second group (P<0.001). CONCLUSION: Lobectomy for cancer can be performed successfully also in selected patients with chronic obstructive pulmonary disease. Post-operative course and survival of these patients is not different from that of patients with normal FEV1, on the contrary, patients with low FEV1 may lose less pulmonary function or even mend it.

A microcomputer based interactive system for the recording and automatic analysis of esophageal pH-studies.

A microcomputer based system for the recording and automatic analysis of esophageal pH-studies has been developed. It consists of a microcomputer interfaced with a pH-meter, one video display, two disk-drives for five inch diskettes, one printer and a fully interactive program written in BASIC. Every second, the microcomputer records the values of pH measured by the pH-meter. The options available in the program are: 1) Creation of medical records; 2) pH probe calibration; 3) pH-basal value acquisition; 4) Standard Acid Reflux Test (SART); 5) Acid Clearing Test (ACT); 6) 24-hour pH-monitoring test; 7) Summary of patient's current results; 8) Printing and data file management. Each one of these options provides access to other related functions. This system and its software has the following advantages: 1) it achieves a high standard in the execution of esophageal pH-study tests; 2) it provides an objective real-time analysis of the results; 3) it reduces the total cost of the investigation.

Left lung allotransplantation in pig feasibility and transplanted lung function. Experimental Lung Transplant Group of Ospedale Maggiore of Milan.

Changing attitudes to animals in research and practical considerations prompted the authors to evaluate whether the pig might be a suitable substitute for dog and baboons for single left lung transplants. Twenty-nine paired pigs were used. The first transplants on 13 pairs (group 1) were done to adapt the lung transplant technique to pigs; later transplants on 16 pig pairs (group 2) were done to evaluate operative survival, and function and histological modifications of the transplanted lung in the absence of immunosuppressive treatment. Surgical and anesthetic techniques for both donor and recipient are described in detail. The survival rate in group 2 was 68%. Hemodynamic and blood gas changes were assessed during operation. PaO2 did not drop significantly after occluding the right pulmonary artery by an inflatable cuff placed around it; this suggests that the function of the transplanted lung was preserved. The pigs were put down on the third postoperative day. Vascular and bronchial anastomoses were patent and intact, but the transplanted lung was macroscopically and microscopically altered. Lung transplants can be performed in pigs and the transplanted lung seems to be capable of functioning immediately after the operation. Alteration in the lung after 3 days is probably due to rejection.

Single lung transplantation for emphysema. Lessons learned on the field. The Lung Transplant Group of the Ospedale Maggiore of Milan.

Emphysematous patients that were once treated with double lung transplantation can now also be treated with single lung transplantation. However, single lung transplantation in emphysematous patients presents problems in lung size matching, choice of side to transplant and post-operative assistance. Analysing their own experience of three single lung transplants performed on emphysematous patients, the Authors evaluate the effectiveness of the operation, the results and the difficulties encountered. Single lung transplantation is a good therapeutic option for end-stage emphysematous patients. In these patients right lung transplantation is preferable and the donor organ should be oversized. Positive and expiratory pressure in the native emphysematous lung should be applied with extreme caution.

[Transection of the popliteal artery caused by exostosis]. / Trans-sezione dell'arteria poplitea causata da esostosi.

Two cases of post-traumatic transection of the popliteal artery in patients with exostosis of the lower extremities are reported. This complication does not seem to have been previously described in the literature. The pathogenetic, clinical, diagnostic and therapeutic aspects are analysed.

[Right adrenal adenoma: laparoscopic exeresis]. / Adenoma surrenalico destro: exeresi per via laparoscopica.

The authors report the case of a non functioning adrenal adenoma, incidentally diagnosed and excised through a laparoscopic approach. Indications to adrenalectomy for such a pathological condition and surgical technique are reviewed and discussed. In consideration of the relatively rare disease and of the scant literature on minimally-invasive approach to right adrenalectomy, it seemed worth reporting this case and the technical skills performed to ease this operation through laparoscopy.

[Reconstruction of the thoracic wall in neoplasms of the manubrium of sternum]. / Ricostruzione della parete toracica per neoplasia del manubrio sternale.

The case of a voluminous neoplasia originating at the manubrium sterni is described. Given the rapid growth of the mass and its dimensions, the mass was removed surgically together with the manubrium sterni and the sternal extremity of the clavicle and of the first two ribs. The defect in the anterior wall of the thorax was filled by a net of prolene partially covered with the mobilised pectoral muscles. Functional and aesthetic results were very good. Assisted respiration was not necessary in the immediate postoperative period and the net remained stable and firmly in place during respiration. One month after the operation, respiratory function tests were on a par with those done prior to the operation. The positioning of prolene nets for the reconstruction of the thoracic wall is an extremely effective technique which makes it possible to preserve satisfactory respiratory mechanics even after the removal of extensive portions of the thoracic wall.

Diagnosis of complete mainstem bronchus avulsion by 3-dimensional spiral CT scan of the chest.

Tracheobronchial injury (TBI) after blunt trauma of the chest is a rare life-threatening entity that can be successfully managed by surgery if there is an early diagnosis. A 18-year-old man was injured in a motocycle accident. Three consecutive flexible bronchoscopies risulted negative for tracheo-bronchial lesions. Then, the patient was submitted to a spiral CT-scan of the chest with 3-dimensional reconstruction of the tracheobronchial tree that showed a rupture of the right main bronchus from the trachea. The lesion was successfully treated by surgery. Bronchoscopic findings in TBI may be unclear also for an experienced thoracic surgeon.

[Minimal jejunostomy for early postoperative enteral feeding: technic and results]. / Digiunostomia minima per nutrizione enterale post-operatoria precoce: tecnica e risultati.

From March 1980 to December 1982, at the 2nd Surgical Clinic of the University of Milan, 47 jejunostomies were performed at the conclusion of a major gastrointestinal surgery to provide immediate post-operative enteral nutrition. A fine needle catheter jejunostomy technique according to Delaney (10) was employed in all cases, using a polythene catheter with an internal diameter of 2.5 mm. inserted into the proximal jejunum using a stainless-steel needle. An elemental diet (13) was adopted and fed through a volumetric infusion pump. Enteral nutrition was usually initiated on the second postoperative day and on average lasted 12 days. No complications connected to positioning, permanence or removal of the catheter were observed. The only inconvenience was represented by obstruction of the catheter with food concretion thus feeding was discontinued in 3 patients. Collateral effects were observed in 9 patients: diarrhoea (5 cases), hyperperistaltis (2 cases), abdominal distension and nausea (1 case). This method of nutritional intake allowed us to: maintain body weight at pre-operative values; obtain a positive nitrogen balance on average the sixth postoperative day; reduce the volume of parenteral support, early suspension and a significant reduction in complications connected with this method.

Everolimus, cyclosporine, and thrombotic microangiopathy: clinical role and preventive tools in renal transplantation.

INTRODUCTION: Thrombotic microangiopathy (TMA) is characterized by endothelial cell injury and formation of fibrin thrombi within capillary and arterioles. In renal allograft recipients, TMA mainly presents as hemolytic uremic syndrome. Its occurrence is rare, and diagnosis requires a high degree of suspicion. Drug toxicity, in particular from calcineurin inhibitors (CNIs) and mTOR inhibitors (mTORi), is the most common cause posttransplant and has recently been emphasized in the setting of lung transplantation. OBJECTIVE: The goal of this study was to investigate the role of mTORi as an added risk factor in the development of TMA to propose strategies for modulation of immunosuppressive (IS) therapy. PATIENTS AND METHODS: From a database of 496 renal graft recipients, we analyzed 350 renal graft biopsy specimens gathered at our center from 1998 to 2012. In patients undergoing combined therapy with mTORi and CNI, we compared drugs levels in TMA-affected and TMA-free groups, using mTORi and CNI TLC and the summation of [everolimus TLC+(cyclosporine C2/100)] (Σ) as a surrogate marker of combined exposition to 2 drugs. Receiver-operating characteristic analysis of association of EVL TLC+(C2/100) was performed for patients exposed to mTORi. RESULTS: Histologic features of TMA were found in 36 patients (prevalence of 7.3%). The caseload was divided into 2 groups: not drug-related TMA (n=19) and drug-related TMA (n=17). Despite the prevalence of TMA in patients exposed to mTORi being greater (8 of 153; prevalence, 5.3%) compared with therapies without mTORi (9 of 324; prevalence, 2.8%), statistical difference was not reached. Patients treated with mTORi who developed de novo drug-related TMA had higher blood levels of IS drugs compared with those who did not develop TMA. Receiver-operating characteristic analysis found a significant threshold of 12.5 ng/mL (area under the curve, 0.803; P=.006). CONCLUSIONS: Results confirm the pivotal role of IS drugs in the onset of de novo TMA. On the basis of literature, we could speculate a sequence of endothelial damage by CNI, on which everolimus fits hindering the repair of endothelial injury. Therefore, high blood levels of CNI and mTORi seem to predispose patients to posttransplant TMA. Combined monitoring of these 2 drugs might be used to prevent the complication. Σ [everolimus TLC + (cyclosporine C2/100)]>12.5 ng/mL should be avoided as a surrogate risk factor for adverse effects.