Autologous micro-fragmented adipose tissue for the treatment of diabetic foot minor amputations: A randomized controlled single-center clinical trial (MiFrAADiF)

Background: The diabetic foot ulcer (DFU) is one of the most prevalent complications of diabetes mellitus and often develops severe effects that can lead to amputation. A non-healing "minor" amputation often precedes a major amputation resulting in a negative impact on the function and quality of life of the patients. Stem cell-based therapies have emerged as a promising option to improve healing, and the adipose tissue is an abundant and easy to access source. The injection of autologous micro-fragmented adipose tissue at the amputation stump of a diabetic population undergoing a lower limb minor amputation was evaluated and compared with the standard care. Methods: In this randomized controlled trial with two arms (parallel assignment) and no masking, 114 patients undergoing a lower limb minor amputation were randomized to standard of care or to micro-fragmented adipose tissue injection prepared using a minimal manipulation technique (Lipogems®) in a closed system. Clinical outcomes were determined monthly up to 6 months. Primary endpoint of the study was the evaluation of the healing rate and time after the minor amputation. Secondary endpoints included the assessment of safety, feasibility, technical success, relapse rate, skin tropism, and intensity of pain. Results: At 6 months, 80% of the micro-fragmented adipose tissue-treated feet healed and 20% failed as compared with the control group where 46% healed and 54% failed (p = 0.0064). No treatment-related adverse events nor relapses were documented, and technical success was achieved in all cases. The skin tropism was improved in the treatment group, and the pain scale did not differ between the two groups. Conclusion: The results of this randomized controlled trial suggest that the local injection of autologous micro-fragmented adipose tissue is a safe and valid therapeutic option able to improve healing rate following minor amputations of irreversible DFU. The technique overcomes several stem cell therapy-related criticisms and its potential in wound care should be better evaluated and the therapeutic indications could be expanded. Trial registration: ClinicalTrials.gov number: NCT03276312. Date of registration: September 8, 2017 (retrospectively registered)

A RANDOMIZED, DOUBLE-BLIND, CROSS-OVER STUDY COMPARING A LEVOSULPIRIDE-BASED AND A METOCLOPRAMIDE-BASED COMBINATION IN THE PREVENTION OF PROMECE-CYTABOM-INDUCED EMESIS

Background. To test two different antiemetic regimens for preventing nausea and vomiting in patients with non-Hodgkin's lymphoma (NHL) undergoing systemic chemotherapy (CT) with ProMECE-CytaBOM (P-C). Patients and Methods. Twenty consecutive untreated adult outpatients with histologically confirmed NHL and scheduled to receive P-C chemotherapy were registered in a randomized, double-blind, cross-over study to compare the antiemetic efficacy of a levosulpiride (LS)-based and metoclopramide (MTC)-based regimen. Results. Complete protection from vomiting was recorded in 93% (62/67) of courses with the LS-regimen and in 89% (62/70) with the MTC-regimen (p = 0.428). No nausea was observed in 84% (56/67) of courses with the LS-regimen and in 74% (52/70) with the MTC-regimen (p = 0.183). No differences in prevention of emesis were recorded when patients crossed to the other regimen. Both regimens were well tolerated; however, on day 8 of chemotherapy, when both antiemetic regimens were administered at a higher dose, the LS-based combination showed significantly lower toxicity (p = 0.035). Conclusions. ProMECE-CytaBOM-induced emesis can be prevented in most cases with appropriate, specifically designed antiemetic therapy. Both the LS- and MTC-based combinations resulted in a high percentage of complete protection from emesis, but the higher incidence of side effects observed with MTC makes the LS-based regimen preferable for patients receiving P-C chemotherapy

Hybrid rescue technique after failure of a standard multibranched stent graft

A 78-year-old woman presented with type IIIC and IIID endoleaks after endovascular treatment for a thoracoabdominal aortic aneurysm. Mating between the ruptured segments of superior mesenteric artery stent graft was performed. After failed attempts at relining the right renal artery stent graft, a hybrid approach was used to connect the side branch to the target vessel: a stent graft was deployed into the side branch of the main graft and it was temporarily occluded with a balloon. After opening the sac, a stent graft was deployed into the right renal artery and the two stent grafts were connected with a running suture. Follow-up examination performed 1 month postoperatively by computed tomography imaging confirmed the effectiveness of this treatment

Midterm Outcomes of the Nellix Endovascular Aneurysm Sealing System: A Dual-Center Experience

Purpose: To report midterm outcomes of the Nellix Endovascular Aneurysm Sealing (EVAS) System in the treatment of abdominal aortic aneurysm (AAA). Methods: Between September 2013 and July 2014, 64 AAA patients (mean age 76.6±6.8 years; 61 men) were treated with the EVAS system at 2 centers (only procedures performed at least 12 months prior to the analysis were included). Most patients were treated for a stable AAA, while 1 patient was treated for a ruptured aneurysm. Mean aneurysm diameter was 57.3±9.3 mm. The proximal neck measured a mean 21.5±3.3 mm in diameter and 27.0±12.1 mm long; the neck angle was 16.9°±19.3°. Eleven (17.2%) patients were treated outside the instructions for use (IFU). Results: Technical success was achieved in 63 (98.4%) of 64 patients; 1 type Ia endoleak was treated intraoperatively. One (1.6%) aneurysm-related death occurred at 4 months due to a secondary aortoenteric fistula. Overall, endoleaks occurred in 3 (4.7%) patients (2 type Ia, 1 type II). The estimated rates for 18-month overall survival, freedom from aneurysm-related death, and freedom from secondary interventions were 92.7%, 98.4%, and 95.0%, respectively. Patients treated outside the IFU had a significantly higher incidence of device-related complications (p=0.03). Conclusion: The use of the Nellix device in everyday clinical practice is safe and offers promising midterm results. The risk of secondary aortoenteric fistula requires further analysis. Longer follow-up is needed to assess the actual efficacy of the device, although the risk of migration with late endoleak seems low

Selective Disruption of Perineuronal Nets in Mice Lacking Crtl1 is Sufficient to Make Fear Memories Susceptible to Erasure

The ability to store, retrieve, and extinguish memories of adverse experiences is an essential skill for animals' survival. The cellular and molecular factors that underlie such processes are only partially known. Using chondroitinase ABC treatment targeting chondroitin sulfate proteoglycans (CSPGs), previous studies showed that the maturation of the extracellular matrix makes fear memory resistant to deletion. Mice lacking the cartilage link protein Crtl1 (Crtl1-KO mice) display normal CSPG levels but impaired CSPG condensation in perineuronal nets (PNNs). Thus, we asked whether the presence of PNNs in the adult brain is responsible for the appearance of persistent fear memories by investigating fear extinction in Crtl1-KO mice. We found that mutant mice displayed fear memory erasure after an extinction protocol as revealed by analysis of freezing and pupil dynamics. Fear memory erasure did not depend on passive loss of retention; moreover, we demonstrated that, after extinction training, conditioned Crtl1-KO mice display no neural activation in the amygdala (Zif268 staining) in comparison to control animals. Taken together, our findings suggest that the aggregation of CSPGs into PNNs regulates the boundaries of the critical period for fear extinction

Negative effects of ant-plant interaction on pollination: costs of a mutualism

The mutualism of ants and extrafloral nectary (EFN)-bearing plants is known to reduce rates of herbivory. However, ants may have negative impacts on other mutualisms such as pollination, constituting an indirect cost of a facultative mutualism. For instance, when foraging on or close to reproductive plant parts ants might attack pollinators or inhibit their visits. We tested the hypothesis that ants on EFN-bearing plants may negatively influence pollinator behavior, ultimately reducing plant fitness (fruit set). The study was done in a reserve at Brazilian savannah using the EFN-bearing plant Banisteriopsis malifolia (Malpighiaceae). The experimental manipulation was carried out with four groups: control (free visitation of ants), without ants (ant-free branches), artificial ants (isolated branches with artificial ants on flowers) and plastic circles (isolated branches with plastic circles on flowers). We made observations on flower visitors and their interactions, and measured fruit formation as a proxy for plant fitness. Our results showed that pollinators hesitated to visit flowers with artificial ants, negatively affecting pollination, but did not hesitate to visit flowers with plastic circles, suggesting that they recognize the specific morphology of the ants. Pollinators spent more time per flower on the ant-free branches, and the fruiting rate was lower in the group with artificial ants. Our results confirm an indirect cost in this facultative mutualism, where the balance between these negative and positive effects of ants on EFN-bearing plants are not well known

Hodgkin's disease presenting below the diaphragm. The experience of the Gruppo Italiano Studio Linfomi (GISL)

Background and Objective. Infradiaphragmatic Hodgkin\ub4s disease is rare, making up 5-12% of cases in clinical stages I and II; consequently, several questions concerning prognosis and treatment strategy remain to be answered. The aim of this study was to analyze the clinical and prognostic characteristics and outcome of his condition. Methods. A series of 282 patients with CS I-II Hodgkin\ub4s disease (HD) was investigated. In 31 patients the disease was confined below the diaphragm (BDHD), and in the remaining above the diaphragm (ADHD). The presenting features and outcomes were compared in the two groups. Results. The BDHD group was older (p < 0.0002), had a higher frequency of males (p < 0.08) and a different histological subtype group distribution (p < 0.0001). Stage II BDHD patients had a worse overall survival rate (OS) than stage II ADHD patients (68.8% vs 86.6% at 8 years, p < 0.01) if age is not considered; patients with more than 40 years of age, in fact, had the same survival rates as those with ADHD. BDHD patients with intra-abdominal disease alone had worse prognostic factors and OS (p = 0.12) than patients with inguinal-femoral nodes. Interpretation and Conclusions. Although BDHD patients present distinct features, they have the same OS and relapse-free survival rate as age-adjusted ADHD patients. According to our experience patients with stage I peripheral BDHD respond well to radiotherapy-based regimens. Those with stage II and or intra-abdominal disease are more challenging; chemotherapy or a combined therapy seem to be more suitable approaches for these patients

CCNU, vinblastine, procarbazine and prednisone (CVPP) with extended-field radiotherapy in the treatment of early unfavorable Hodgkin's disease - A prospective study on behalf of the Gruppo Italiano per lo Studio dei Linfomi (GISL)

Purpose. To test the adequacy of the CVPP four-drug regimen as ancillary chemotherapy associated with extended-field radiotherapy in the treatment of early, unfavorable, clinically staged Hodgkin's disease. Patients and Methods. The population of this prospective, multicenter study consisted of 49 patients with stage I-II disease, associated with bulky involvement or unfavorable histology (lymphocyte-depleted nodular sclerosis or lymphocyte depletion), systemic symptoms or extranodal involvement, or presenting with stage III A favorable-histology disease, with or without extranodal involvement. Results. Complete remission was achieved in 39 patients, partial remission in 2, while 8 patients did not respond. Four patients have relapsed so far (median follow-up: 43 months), all of whom were subsequently rescued with different salvage treatments. Dose intensity (mean+/-SD: 0.83+/-0.12) and hematological toxicity (including 2 deaths from infection) were higher when RT followed CT than when it was interposed in the middle of the 6 cycles. No growth factors were used. Nonhematological toxicity was very low and fully tolerable. Conclusions. Results confirmed the mild neurological and gastroenteric side effects of CVPP that make it an interesting MOPP-variant regimen. This combination seems most indicated when a regimen devoid of cardiac and pulmonary toxicity is required for association with full-dosage mediastinal radiotherapy, as is often the case in early, unfavorable Hodgkin's disease. The optimal sequence consists of radiotherapy administered after completion of the chemotherapy program. The use of growth factors for correction (or prevention) of marked leukopenia seems appropriate

Midterm results on a new self-expandable covered stent combined with branched stent grafts: Insights from a multicenter Italian registry

Objective: To investigate the technical periprocedural and midterm outcomes of endovascular repairs with multibranched endovascular repair or iliac branch devices combined with a new self-expanding covered stent. Methods: The COvera in BRAnch registry is a physician-initiated, multicenter, ambispective, observational registry (ClinicalTrials.gov Identifier: NCT04598802) enrolling patients receiving a multibranched endovascular repair or iliac branch devices procedure mated with Bard Covera Plus (Tempe, AZ) covered stent, designed to evaluate the outcomes of the covered stent mated with patient-specific and off-the-shelf branched stent graft. Primary end points were technical success, branch instability, and freedom from aortic and branch-related reintervention within 30 days and at follow-up. Preoperative characteristics, comorbidities, and outcomes definitions were graded according to the Society for Vascular Surgery reporting standards. Results: Two hundred eighty-four patients (76 years; range, 70-80 years; 79% males) in 24 centers were enrolled for a total of 708 target vessels treated. The covered stents were mated with an off-the-shelf graft in 556 vessels (79%) and a custom-made graft in 152 (21%). Three hundred seven adjunctive relining stents in 277 vessels (39%) were deployed, of which 116 (38%) were proximal, 66 (21%) intrastent, and 125 (41%) distal. Adjunctive relining stent placement was more frequent when landing in a vessel branch instead of the main trunk (59% vs 39%; P = .031), performing a percutaneous access (49% vs 35%; P < .001), using a stent with a diameter of 8 mm or greater (44% vs 36%; P = .032) and a length of 80 mm or greater (65% vs 55%; P = .005), when a post-dilatation was not performed (45% vs 29%; P < .001) and when an inner branch configuration was used (55% vs 35%; P < .001). Perioperative technical bridging success was 98%. Eight patients (3%) died in the perioperative period. Two deaths (1%) were associated with renal branch occlusion followed by acute kidney injury and paraplegia. Follow-up data were available for 638 vessels (90%) at a median of 32 months (Q1, Q3, 21, 46). Branch instability was reported in 1% of branches. Forty-six patients (17%) died during follow-up, nine (3%) of them owing to aortic-related causes. Primary patency rates at 1, 2, and 3 years were 99% (581/587), 99% (404/411), and 97% (272/279), respectively. Branch instability was associated with patient-specific devices (9% vs 4%; P = .014) and intrastent adjunctive stent placement (12% vs 2%; P = .003), especially when a bare metal balloon-expandable stent was used (25% vs 3%; P < .001). Conclusions: The use of this new self-expanding covered stent mated with branched endografts proved to be safe and feasible with high technical procedural success rates. Low rates of branch instability were observed at midterm follow-up. Comparative studies with other commercially available covered stents are warranted