Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP).

Acquired aplastic anemia (AA) is a rare heterogeneous disorder characterized by pancytopenia and hypoplastic bone marrow. The incidence is 2-3 per million population per year in the Western world, but 3 times higher in East Asia. Survival in severe aplastic anemia (SAA) has improved significantly due to advances in hematopoietic stem cell transplantation (HSCT), immunosuppressive therapy, biologic agents, and supportive care. In SAA, HSCT from a matched sibling donor (MSD) is the first-line treatment. If a MSD is not available, options include immunosuppressive therapy (IST), matched unrelated donor, or haploidentical HSCT. The purpose of this guideline is to provide health care professionals with clear guidance on the diagnosis and management of pediatric patients with AA. A preliminary evidence-based document prepared by a group of pediatric hematologists of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Hemato-Oncology (AIEOP) was discussed, modified and approved during a series of consensus conferences that started online during COVID 19 and continued in the following years, according to procedures previously validated by the AIEOP Board of Directors.

Cost-effectiveness analysis of the temporary percutaneous ileostomy for faecal diversion after colorectal resection in elderly.

BACKGROUND: Conventional loop ileostomy (CLI) is a suitable procedure for transitory faecal diversion after colorectal anastomosis, but it causes relevant morbidities (dehydration, discomfort, peristomal infections) and requires a second operation to be closed. We already described an alternative technique of temporary percutaneous ileostomy (TPI), which can be removed without surgery. AIMS: We analyse the outcomes and the costs of the TPI in protecting low colorectal anastomosis in elderly, compared to the CLI. METHODS: Data of patients underwent elective anterior rectal resection for rectal cancer with extra-peritoneal colorectal anastomosis protected by ileostomy from January 2011 to December 2015 were reviewed. Sixty-one out of 132 patients were older than 70; 35 underwent faecal diversion by TPI and 26 by CLI. RESULTS: The two groups resulted homogenous about age, sex, operative time, short-term post-operative complications. None of the patients reported anastomotic leakage. The hospital stay and the cost for the first surgical procedure did not show statistically significant differences between TPI and CLI. When comparing the overall hospital stay and costs the differences are statistically significant: the TPI showed a shorter hospital stay (12.4 vs 19.3 days, -35.7%) and a lower cost of hospitalization (7954.0 vs 14,372.1€, -44.7%), compared to CLI. DISCUSSION: The limited duration of the faecal diversion and the uselessness of a second surgical procedure to remove the TPI are the most important advantages of TPI, especially in elderly. CONCLUSION: The TPI not only improved the post-operative outcome of the patients, but also allowed a remarkable saving for the National Health System.

Hyaluronan scaffold supports osteogenic differentiation of bone marrow concentrate cells.

Osteochondral lesions are considered a challenge for orthopedic surgeons. Currently, the treatments available are often unsatisfactory and unable to stimulate tissue regeneration. Tissue engineering offers a new therapeutic strategy, taking into account the role exerted by cells, biomaterial and growth factors in restoring tissue damage. In this light, Mesenchymal Stem Cells (MSCs) have been indicated as a fascinating tool for regenerative medicine thanks to their ability to differentiate into bone, cartilage and adipose tissue. However, in vitro-cultivation of MSCs could be associated with some risks such as de-differentiation/reprogramming, infection and contaminations of the cells. To overcome these shortcomings, a new approach is represented by the use of Bone Marrow Concentrate (BMC), that could allow the delivery of cells surrounded by their microenvironment in injured tissue. For this purpose, cells require a tridimensional scaffold that can support their adhesion, proliferation and differentiation. This study is focused on the potentiality of BMC seeded onto a hyaluronan-based scaffold (Hyaff-11) to differentiate into osteogenic lineage. This process depends on the specific interaction between cells derived from bone marrow (surrounded by their niche) and scaffold, that create an environment able to support the regeneration of damaged tissue. The data obtained from the present study demonstrate that BMC grown onto Hyaff-11 are able to differentiate toward osteogenic sense, producing specific osteogenic genes and matrix proteins.

Cognitive impairment is a negative short-term and long-term prognostic factor in elderly patients with hip fracture.

BACKGROUND: Subjects with severe cognitive impairment (CI) have a high-risk of hip fractures with increased rate of adverse postoperative functional outcomes and mortality. AIM: To evaluate the impact of different degrees of CI on functional recovery and mortality after hip fracture. DESIGN: Prospective observational study. SETTING: Two orthopedic surgery units. POPULATION: Two hundred twenty-eight consecutive patients after a hip surgery. METHODS: Patients were assessed at baseline through the Short Portable Mental Status Questionnaire (SPMSQ), an instrument that allows to categorize subjects as follows: cognitively intact (SPMSQ≥8) or with mild (SPMSQ=6-7), moderate (SPMSQ=3-5) and severe CI (SPMSQ<3). Barthel Index (BI) was used to assess functional disability. All patients underwent rehabilitation from the day after surgery to discharge (mean length of stay =10.2±3.4). Outcome measures were: (1) overall mortality up to 12 months after surgery; (2) motor ability achieved at discharge from the orthopedic ward (sitting, standing, walking); (3) BI and SPMSQ at 1, 3, 6 and 12 months postoperatively. RESULTS: All degrees of severity of CI were inversely correlated to the ability to walk at hospital discharge. At one year from surgery, the majority of patients with CI were functionally severely dependent, whereas about half of the cognitively intact ones gained a functional independence status. CI and the level of premorbid disability influenced the risk of death. CONCLUSION: CI for all degrees of severity is a negative prognostic factor in elderly patients with hip fracture. CLINICAL REHABILITATION IMPACT: We suggest evaluating the cognitive status of patients with hip fracture as it affects both the short and long-term functional recovery at any degree of severity.

Robot-assisted or conventional laparoscoic rectopexy for rectal prolapse? Systematic review and meta-analysis.

AIM: The use of robotic technology has proved to be safe and effective, arising as a helpful alternative to standard laparoscopy in a variety of surgical procedures. However the role of robotic assistance in laparoscopic rectopexy is still not demonstrated. METHODS: A systematic review of the literature was carried out performing an unrestricted search in MEDLINE, EMBASE, the Cochrane Library, and Google Scholar up to 30th June 2014. Reference lists of retrieved articles and review articles were manually searched for other relevant studies. We meta-analyzed the data currently available regarding the incidence of recurrence rate of rectal prolapse, conversion rate, operative time, intra-operative blood loss, post-operative complications, re-operation rate and hospital stay in robot-assisted rectopexy (RC) compared to conventional laparoscopic rectopexy (LR). RESULTS: Six studies were included resulting in 340 patients. The meta-analysis showed that the RR does not influence the recurrence rate of rectal prolapse, the conversion rate and the re-operation rate, whereas it decreases the intra-operative blood loss, the post-operative complications and the hospital stay. Yet, the RR resulted to be longer than the LR. Post-operative ano-rectal and the sexual functionality and procedural costs could not meta-analyzed because the data from included studies about these issues were heterogeneous and incomplete. CONCLUSION: The meta-analysis showed that the RR may ensure limited improvements in post-operative outcomes if compared to the LR. However, RCTs are needed to compare RR to LR in terms of short-term and long-term outcomes, specially investigating the functional outcomes that may confirm the cost-effectiveness of the robotic assisted rectopexy.

Temporary percutaneous ileostomy for faecal diversion after intestinal resection for acute abdomen in elderly: how to avoid the conventional loop ileostomy.

Conventional loop ileostomy (CLI) is a suitable procedure for transitory faecal diversion after colocolic or colorectal anastomosis, but it causes relevant morbidities (dehydration, discomfort, peristomal infections) and requires a second operation to be closed. We already described an alternative technique of temporary percutaneous ileostomy (TPI), which can be removed without surgery, as faecal diversion in low colorectal anastomosis. Now we report our experience with the TPI in protecting colocolic and colorectal anastomosis in urgency in elderly. From January 2012 to June 2014, 45 patients underwent urgent surgical procedures for acute abdomen with colonic and/or rectal resections and colocolic or colorectal anastomosis with faecal diversion by TPI. Nineteen out of 45 patients were older than 70. Four low colorectal anastomoses, 10 intra-peritoneal colorectal anastomosis and 4 colocolic anastomosis were performed. Neither intra-operative complications nor post-operative deaths were observed. None of the 19 patients treated had evidence of clinical or radiological leakage of the anastomosis. Post-operative complications occurred in 7 patients and nobody required re-intervention. No intestinal obstruction was reported in the early (30 days) post-operative period. The TPI seems to be a valid alternative to standard ileostomy, ensuring an optimal faecal diversion both in elective surgery and in urgency. The TPI also ensures less patient discomfort and it can be easily removed without surgery, unlike the CLI. The limited duration of the faecal diversion and the uselessness of a second surgical procedure to remove the TPI are the most important advantages of this new technique, especially in elderly.

Traditional lateral ileostomy versus percutaneous ileostomy by exclusion probe for the protection of extraperitoneal colo-rectal anastomosis: the ALPPI (Anastomotic Leak Prevention by Probe Ileostomy) trial. A randomized controlled trial.

BACKGROUND: Low colo-rectal anastomoses have a relevant risk of leakage. The protective stomas (ileostomy or colostomy) have always been utilized to reduce the complications due to anastomotic leakage. The stoma not only causes relevant morbidity but also needs a second operation to be closed, with an added risk of complications. PURPOSE: For this reason we planed and carried out a temporary percutaneous ileostomy by a jejunal probe introduced in the distal ileum, that can be removed without a surgical procedure and with negligible complications. METHODS: The ALPPI trial is a randomized controlled, open, parallel, equivalence multicenter study. Patients undergoing elective laparoscopic or laparotomic surgery for rectal cancer with extraperitoneal anastomosis, will be randomly allocated to undergo either lateral ileostomy or percutaneous ileostomy by exclusion probe. RESULTS: The primary endpoint is the protection of the extraperitoneal colo-rectal anastomosis in terms of incidence of symptomatic and asymptomatic anastomotic leakages. The secondary endpoints are the evaluation of complications due to the placement and the removal of the exclusion probe for percutaneous ileostomy. CONCLUSIONS: The ALPPI trial is designed to provide the surgical community with an evidence based new technique in the protection of low colo-rectal anastomosis, alternative to the conventional stomas. TRIAL REGISTRATION: The ALPPI trial was approved by the Ethical Committee of Regional Public Health System of Umbria, Italy, (Protocol Number 28657/11/AV, study code RO-MA 01) and it is registered in the International Standard Randomised Controlled Trial Number (ISRCTN) Register with identification number ISRCTN99356919.

To drain or not to drain extraperitoneal colorectal anastomosis? A systematic review and meta-analysis.

AIM: Anastomotic leakage is the one of the most serious complications in rectal cancer surgery and is associated with high mortality, morbidity and an increased incidence of local recurrence. Although many studies have compared drained and undrained colorectal anastomoses, to date the role of pelvic drainage in extraperitoneal colorectal anastomosis remains undefined. METHOD: We carried out a systematic review of the literature, performing an unrestricted search in MEDLINE and Embase up to 30 October 2012. Reference lists of retrieved articles and review articles were manually searched for other relevant studies. We performed a meta-analysis of the data currently available on the incidence of extraperitoneal anastomotic leakage, according to the presence or absence of pelvic drainage. RESULTS: Overall, eight studies - three randomized clinical trials (RCTs) and five non-RCTs, comprising a total of 2277 patients - were included in the meta-analysis. Pelvic drainage was demonstrated to reduce both the leak rate and the rate of reintervention in patients who underwent anterior rectal resection with extraperitoneal colorectal anastomosis (OR = 0.51, 95% CI: 0.36-0.73; and OR = 0.29, 95% CI: 0.18-0.46, respectively) compared with patients without drainage. Overall mortality and infection rates were also evaluated, but a nonsignificant correlation was found with the presence of drainage. CONCLUSION: The meta-analysis shows that the presence of a pelvic drain reduces the incidence of extraperitoneal colorectal anastomotic leakage and the rate of reintervention after anterior rectal resection.

Association among 1267 A/G HSP70-2, -308 G/A TNF-α polymorphisms and pro-inflammatory plasma mediators in old ZincAge population.

Proinflammatory cytokines and heat shock proteins play relevant roles in the pathogenesis of inflammatory diseases. We investigated whether Hsp70 1267 A/G and TNF-α -308 G/A polymorphisms are associated with proinflammatory mediators, zinc status and laboratory parameters in 1,078 healthy elderly from ZincAge study. Hsp70 1267 A/G genotype and allele distribution were similar among various European countries, while a TNF-α genetic heterogeneity was observed between the Northern and the Southern European populations, with a major frequency of the -308 A variant in France, Germany and Poland. We used linear regression models to test additive, dominant or recessive associations of each SNP with proinflammatory mediators, laboratory parameters, metallothioneins and zinc status. Hsp70 1267 A/G SNP, but not TNF-α -308 G/A SNP, influences TNF-α and IL-6 plasma levels under additive, dominant and recessive models (for TNF-α only). An association between Hsp70 1267 A/G SNP and zinc plasma levels was observed in the dominant model. In particular, G allele carriers showed increased circulating pro-inflammatory cytokines and zinc. Moreover, both these SNPs affect creatinine levels suggesting a possible influence on renal function. In conclusion, Hsp70 1267 A/G SNP is associated with pro-inflammatory cytokine production in healthy elderly and might represent a possible determinant of individual susceptibility to inflammatory diseases.

Gamma rays induce a p53-independent mitochondrial biogenesis that is counter-regulated by HIF1α.

Mitochondrial biogenesis is an orchestrated process that presides to the regulation of the organelles homeostasis within a cell. We show that γ-rays, at doses commonly used in the radiation therapy for cancer treatment, induce an increase in mitochondrial mass and function, in response to a genotoxic stress that pushes cells into senescence, in the presence of a functional p53. Although the main effector of the response to γ-rays is the p53-p21 axis, we demonstrated that mitochondrial biogenesis is only indirectly regulated by p53, whose activation triggers a murine double minute 2 (MDM2)-mediated hypoxia-inducible factor 1α (HIF1α) degradation, leading to the release of peroxisome-proliferator activated receptor gamma co-activator 1ß inhibition by HIF1α, thus promoting mitochondrial biogenesis. Mimicking hypoxia by HIF1α stabilization, in fact, blunts the mitochondrial response to γ-rays as well as the induction of p21-mediated cell senescence, indicating prevalence of the hypoxic over the genotoxic response. Finally, we also show in vivo that post-radiotherapy mitochondrial DNA copy number increase well correlates with lack of HIF1α increase in the tissue, concluding this may be a useful molecular tool to infer the trigger of a hypoxic response during radiotherapy, which may lead to failure of activation of cell senescence.

Temporary percutaneous ileostomy versus conventional loop ileostomy in mechanical extraperitoneal colorectal anastomosis: a retrospective study.

AIM: Loop ileostomy is a suitable procedure for transitory faecal diversion after low colorectal anastomosis, but it causes relevant morbidities (discomfort, peristomal infections, dehydration) and requires a second operation to be closed. We already described an alternative technique of temporary percutaneous ileostomy (TPI) that can be removed without surgery. METHOD: The data of 143 consecutive patients, undergoing elective laparoscopic anterior resection of the rectum for adenocarcinoma and low mechanical colorectal anastomosis, 68 with conventional loop ileostomy (CLI) and 75 with TPI, were analyzed. RESULTS: Neither intra-operative complications nor deaths occurred during the follow-up period. Clinical anastomotic leakage occurred in 4 patients with CLI and in 1 with TPI (p = 0.191). The median time required for the emission of gases and faeces through the stoma was respectively 1 and 2.5 days in the CLI group, and 1 and 2 days in the TPI group (p = 0.259 and p = 0.126). The median post-operative stay was 8 days in the CLI group and 11 days in the TPI group (p < 0.001). PTIs were removed on the median of 9 days after surgery without major complications, whereas the CLIs were re-canalized in 79.4% of patients on an average of 106 days, with 2 major complications. CONCLUSION: The temporary percutaneous ileostomy seems to be a valid alternative to conventional ileostomy, ensuring optimal faecal diversion and less patient discomfort. It can be easily removed without surgery, allowing patients a better outcome.

Is laparoscopic right colectomy more effective than open resection? A meta-analysis of randomized and nonrandomized studies.

AIM: The aim of this systematic review was to compare laparoscopic and/or laparoscopic-assisted right colectomy (LRC) with open right colectomy (ORC). Many randomized clinical trial have shown that laparoscopic colectomy benefits patients with improved short-term outcomes and comparable overall survival in respect to the open approach. These results, however, could not be applied to right colectomy owing to its wide range of resection and more complicated vascular regional anatomy. METHOD: We performed a meta-analysis of the literature in order to compare LRC vs ORC by examining 21 end-points including operative and recovery outcomes, early postoperative mortality and morbidity, and oncological parameters. A subgroup analysis of patients undergoing right colectomy for cancer was carried out. The meta-analysis was conducted following all aspects of the Cochrane Handbook for systematic reviews and Preferred Reporting Items for Systematic Reviews and Metanalysis (PRISMA) statement. The search strategies were developed using the following electronic databases: PubMed, EMBASE, OVID, Medline, Cochrane Database of Systematic Reviews, EBM reviews and CINAHL until March 2011. We included randomized and non randomized studies that compared the LRC vs ORC for benign disease and malignant neoplasm irrespective of publication status. Only studies in English, French, German, Spanish and Italian languages were considered for inclusion. Emergency right colectomies were excluded. To perform the statistical analysis we used the odds ratio (OR) for categorical variables and the weighted mean difference (WMD) for continuous variables. An intention-to-treat analysis was performed. RESULTS: Seventeen studies, 15 nonrandomized clinical trials and two randomized clinical trials, involving a total of 1489 patients, were identified. The mean operative time was longer in the group of patients undergoing LRC [weighted mean difference (WMD) = 37.94, 95% CI: 25.01 to 50.88; P < 0.00001]. Intra-operative blood loss (WMD = -96.61; 95% CI: -150.68 to -42.54; P = 0.0005), length of hospital stay (WMD = -2.29; 95% CI: -3.96 to -0.63; P = 0.007) and short-term postoperative morbidity (OR = 0.64; 95% CI: 0.49 to 0.83; P = 0.0009) were significantly in favour of LRC. CONCLUSION: Laparoscopic-assisted right colectomy results in less blood loss, a shorter length of hospital stay and lower postoperative short-term morbidity compared with ORC.

Clinical applications and biosafety of human adult mesenchymal stem cells.

Mesenchymal Stem Cells (MSCs) are a population of adherent cells that can differentiate into mesenchymal lineage populations (cartilage, bone and fat tissue). In addition, they seem to be able to differentiate also into a broader type of lineages other than the original mesodermal germ layer. Bone marrow MSCs are a standard in the field of adult stem cell biology and clinical applications; however adipose-derived MSCs are becoming an attractive alternative due to their minimally invasive accessibility and availability in the body. MSCs modulate several effector immune functions by interacting both with innate and adoptive immune responses. Several local signals from the tissue microenvironment, together with cytokine and soluble factors released by MSCs influence anti-inflammatory and tissue repair properties of infused MSCs. Therefore, cellular therapies utilizing ex vivo expanded MSCs may be an interesting approach for inflammatory and autoimmune diseases. Biosafety is still one of the most important aspects; therefore the production of clinical-grade MSCs requires the careful identification and control of all the phases of cell manipulation and release. Many clinical applications of adult MSCs are in progress and are using bone marrow or adipose tissue-derived MSCs for the treatment of Graft Versus Host Disease (GVHD), inflammatory joint diseases and osteocartilagineous defects, digestive tract, cardiovascular and neurological diseases.

Rectal washout and local recurrence in rectal resection for cancer: a meta-analysis.

AIM: The effectiveness of rectal washout was compared with no washout for the prevention of local recurrence after anterior rectal resection for rectal cancer. METHOD: The following electronic databases were searched: PubMed, OVID Medline, Cochrane Database of Systematic Reviews, EBM Reviews, CINAHL and EMBASE. RESULTS: Five nonrandomized studies including a total of 5012 patients were identified. Meta-analysis suggested that rectal washout significantly reduced the local recurrence rate (P < 0.0001; OR 0.57; 95% CI 0.43-0.74). It was also significantly lower after washout in patients having radical resection only (P = 0.0004; OR 0.54; 95% CI 0.39-0.76), patients treated by a curative resection (P < 0.0001; OR 0.55; 95% CI 0.42-0.72) and those undergoing preoperative radiotherapy (P = 0.04; OR 0.62; 95% CI 0.39-0.98). CONCLUSION: Taking into account the limitations of the design of the included studies the meta-analysis showed that rectal washout is associated with reduced local recurrence and therefore should be routine during anterior resection for rectal cancer.

Oxidative imbalance in different neurodegenerative diseases with memory impairment.

BACKGROUND: Byproducts of oxidative metabolic reactions could play a role in the pathogenesis of several neurodegenerative diseases (ND) including Alzheimer's disease (AD). We designed a study aimed at investigating a large set of oxidative and antioxidant markers in a sample of patients affected by different forms of dementia or memory impairment. METHODS: Serum levels of coenzyme Q(10), malondialdehyde (MDA), the total, oxidized and reduced forms of glutathione (GStot, GSSG and GSH, respectively), reactive oxygen species, anti-oxidized low-density lipoprotein antibodies and antioxidant power (PAO) were investigated in patients affected by AD, mild cognitive impairment, dementia with Lewy bodies and Parkinson's disease with dementia. The patient sample (n = 66) was compared with healthy subjects (HC; n = 62), and a comparison across pathological subgroups was also performed. A multivariate logistic regression model was implemented in order to calculate an algorithm model for predicting the risk of developing a neurodegenerative disorder. RESULTS: The comparison between the memory deficit (MD) group and HC showed a significant difference for MDA (MD: 6.3 ± 2.8 µg/l; HC: 9.1 ± 4.9 µg/l; p = 1.7 × 10(-6)), GStot (MD: 260.4 ± 62.6 mg/l; HC: 306.5 ± 60.7 mg/l; p = 2.2 × 10(-5)), GSH (MD: 208.9 ± 68.4 mg/l; HC: 295.3 ± 101.3 mg/l; p = 2.2 × 10(-7)) and PAO (MD: 1,066.5 ± 247.7 µmol; HC: 954.9 ± 200.4 µmol; p = 0.8 × 10(-3)). By contrast, no differences in the levels of the studied markers were detected across the different forms of ND. An older age, higher levels of PAO, lower levels of GSH and MDA and the use of cardiovascular or antidepressant drugs were the most important factors associated with the carrier ship of neurodegenerative disorder. CONCLUSION: To our knowledge, this is the first study reporting similar oxidative imbalance in different forms of memory impairment, regardless of the specific etiology. Low GSH levels could be considered as a favorable factor in ND; at the same time it could be suggested that higher levels of PAO represent a counteracting mechanism against an increased oxidative stress. The association between vascular risk factors, depressive status and cognitive impairment is in line with findings in the literature.

Malignant small-bowel neoplasms: spectrum of disease on MR imaging.

Malignant neoplasms of the small bowel are among the rarest types of cancer, accounting for only 2% of all gastrointestinal neoplasms. Owing both to the intrinsic difficulty of common radiographic and endoscopic methods in visualising the entire small bowel and the lack of typical physical findings, a delay in diagnosis is common. Recently, magnetic resonance (MR) imaging has become a widely accepted imaging modality in the study of suspected small-bowel neoplasms due to its ability to depict, without exposure to ionising radiation and with excellent soft-tissue contrast, intraluminal disorders in conjunction with mural, extraparietal and regional abnormalities. The aim of this pictorial review is to illustrate the MR appearance of malignant small-bowel neoplasms.

Preliminary report of a new technique for temporary faecal diversion after extraperitoneal colorectal anastomosis.

AIM: Loop ileostomy is a suitable procedure for transitory faecal diversion after colorectal or coloanal anastomosis. We describe here an easy alternative technique for ileostomy construction that does not require reintervention for the closure. METHOD: In twenty patients undergoing anterior resection of the extraperitoneal rectum with colorectal and/or coloanal anastomosis, loop ileostomy was performed using a modified jejunotomy tube inflated with 10 ml of normal saline. The tube was deflated on the eighth post-operative day and removed on day 11 after a radiological contrast enema of the anastomosis. RESULTS: Radiological control carried out on day 11 evidenced a premature dislocation of the jejunostomy tube in 1 patient, thus the tube was correctly removed without any complications. In another patient a delayed closure of the ileo cutaneous fistula was recorded that required simple medication over 15 days in the out patient clinic. No signs of anastomotic leakage, either clinical or radiological were evidenced. CONCLUSION: We have described here a safe alternative technique for loop ileostomy with negligible complications related to construction as demonstrated in our results.