Children and adolescents with haematological malignancies (PedHM) are characterized by a severe loss of exercise ability during cancer treatment, lasting throughout their lives once healed and ...impacting their social inclusion prospects. The investigation of the effect of a precision-based exercise program on the connections between systems of the body in PedHM patients is the new frontier in clinical exercise physiology. This study is aimed at evaluating the effects of 11 weeks (3 times weekly) of combined training (cardiorespiratory, resistance, balance and flexibility) on the exercise intolerance in PedHM patients. Two-hundred twenty-six PedHM patients were recruited (47% F). High or medium frequency participation (HAd and MAd) was considered when a participant joined; > 65% or between 30% and < 64% of training sessions, respectively. The "up and down stairs'' test (TUDS), "6 min walking" test (6MWT), the "5 Repetition Maximum strength" leg extension and arm lateral raise test (5RM-LE and 5RM-ALR), flexibility (stand and reach), and balance (stabilometry), were performed and evaluated before and after training. The TUDS, the 5RM-LE and 5RM-ALR, and the flexibility exercises showed an increase in HAd and MAd groups (P < 0.05), while the 6MWT and balance tests showed improvement only in HAd group (P < 0.0001). These results support the ever-growing theory that, in the case of the treatment of PedHM, 'exercise is medicine' and it has the potential to increase the patient's chances of social inclusion.
Flow cytometric analysis of leukemia-associated immunophenotypes and polymerase chain reaction-based amplification of antigen-receptor genes rearrangements are reliable methods for monitoring minimal ...residual disease. The aim of this study was to compare the performances of these two methodologies in the detection of minimal residual disease in childhood acute lymphoblastic leukemia.
Polymerase chain reaction and flow cytometry were simultaneously applied for prospective minimal residual disease measurements at days 15, 33 and 78 of induction therapy on 3565 samples from 1547 children with acute lymphoblastic leukemia enrolled into the AIEOP-BFM ALL 2000 trial.
The overall concordance was 80%, but different results were observed according to the time point. Most discordances were found at day 33 (concordance rate 70%) in samples that had significantly lower minimal residual disease. However, the discordance was not due to different starting materials (total versus mononucleated cells), but rather to cell input number. At day 33, cases with minimal residual disease below or above the 0.01% cut-off by both methods showed a very good outcome (5-year event-free survival, 91.6%) or a poor one (5-year event-free survival, 50.9%), respectively, whereas discordant cases showed similar event-free survival rates (around 80%).
Within the current BFM-based protocols, flow cytometry and polymerase chain reaction cannot simply substitute each other at single time points, and the concordance rates between their results depend largely on the time at which they are used. Our findings suggest a potential complementary role of the two technologies in optimizing risk stratification in future clinical trials.
Leukemias bearing CRLF2 and JAK2 gene alterations are characterized by aberrant JAK/STAT signaling and poor prognosis. The HDAC inhibitor givinostat/ITF2357 has been shown to exert anti-neoplastic ...activity against both systemic juvenile idiopathic arthritis and myeloproliferative neoplasms through inhibition of the JAK/STAT pathway. These findings led us to hypothesize that givinostat might also act against CRLF2-rearranged BCP-ALL, which lack effective therapies. Here, we found that givinostat inhibited proliferation and induced apoptosis of BCP-ALL CRLF2-rearranged cell lines, positive for exon 16 JAK2 mutations. Likewise, givinostat killed primary cells, but not their normal hematopoietic counterparts, from patients carrying CRLF2 rearrangements. At low doses, givinostat downregulated the expression of genes belonging to the JAK/STAT pathway and inhibited STAT5 phosphorylation. In vivo, givinostat significantly reduced engraftment of human blasts in patient-derived xenograft models of CRLF2-positive BCP-ALL. Importantly, givinostat killed ruxolitinib-resistant cells and potentiated the effect of current chemotherapy. Thus, givinostat in combination with conventional chemotherapy may represent an effective therapeutic option for these difficult-to-treat subsets of ALL. Lastly, the selective killing of cancer cells by givinostat may allow the design of reduced intensity regimens in CRLF2-rearranged Down syndrome-associated BCP-ALL patients with an overall benefit in terms of both toxicity and related complications.
The supra-molecular assembly of the main respiratory chain enzymatic complexes in the form of “supercomplexes” has been proved by structural and functional experimental evidence. This evidence ...strongly contrasts the previously accepted Random Diffusion Model stating that the complexes are functionally connected by lateral diffusion of small redox molecules (i.e. Coenzyme Q and cytochrome c).
This review critically examines the available evidence and provides an analysis of the functional consequences of the intermolecular association of the respiratory complexes pointing out the role of Coenzyme Q and of cytochrome c as channeled or as freely diffusing intermediates in the electron transfer activity of their partner enzymes.
Heart rate, measured as beat-to-beat intervals, is not constant and varies in time. This property is known as heart rate variability (HRV) and it has been investigated in several diseases, including ...myocardial infarction (MI). The main hypothesis is that HRV embed some physiological processes that are characteristics of regulatory systems acting on cardiovascular system. It is possible to quantify such a complex behaviour starting from RR intervals properties itself with the idea that any event affecting the cardiac regulatory system significantly will disrupt and change HRV. In this article, we first review different methodologies previously published to calculate HRV indexes. We then searched literature for studies published on HRV and MI and we derive a metanalysis where published data allow calculation of composite outcomes.
Articles considered eligible for metanalysis were original retrospective/prospective studies investigating HRV after myocardial infarction, reporting follow up for mortality or significant cardiac complications. Random effect model was used to assessed for homogeneity and calculate composite outcome and its 95% confidence interval (CI).
21 studies were identified as eligible for subsequent analysis. Among these studies 5 large trials were eligible for metanalysis: "they included 3489 total post-MI patient with an overall mortality of 125/577 (21.7%) in patients with standard deviation of RR intervals (SDNN) less than 70 msec compared to 235/2912 (8.1%) in patients with SDNN > 70 msec". Metanalysis demonstrates that, after a MI, patients with SDNN below 70 msec on 24 hours ECG recording have almost 4 times more chance to die in the next 3 years.
Results from metanalysis and other studies considered (but not included in the analysis) are consistent with the final finding, that a disrupted HRV dynamic (low SDNN) is associated with higher adverse outcome. In this perspective, although data are strongly positive for a direct relationship between SDNN and mortality after MI, SDNN value must be considered carefully on a single patient. The primary purpose of the metanalysis was to address whether studies conducted on HRV and MI were consistent rather than established a cut-off for SDNN. HRV is simple, non invasive and relatively not expensive to obtain.
The outcome of infants with KMT2A-germline acute lymphoblastic leukaemia (ALL) is superior to that of infants with KMT2A-rearranged ALL but has been inferior to non-infant ALL patients. Here, we ...describe the outcome and prognostic factors for 167 infants with KMT2A-germline ALL enrolled in the Interfant-06 study.
Univariate analysis on prognostic factors (age, white blood cell count at diagnosis, prednisolone response and CD10 expression) was performed on KMT2A-germline infants in complete remission at the end of induction (EOI; n = 163). Bone marrow minimal residual disease (MRD) was measured in 73 patients by real-time quantitative polymerase chain reaction at various time points (EOI, n = 68; end of consolidation, n = 56; and before OCTADAD, n = 57). MRD results were classified as negative, intermediate (<5∗10−4), and high (≥5∗10−4).
The 6-year event-free and overall survival was 73.9% (standard error SE = 3.6) and 87.2% (SE = 2.7). Relapses occurred early, within 36 months from diagnosis in 28 of 31 (90%) infants. Treatment-related mortality was 3.6%. Age <6 months was a favourable prognostic factor with a 6-year disease-free survival (DFS) of 91% (SE = 9.0) compared with 71.7% (SE = 4.2) in infants >6 months of age (P = 0.04). Patients with high EOI MRD ≥5 × 10−4 had a worse outcome (6-year DFS 61.4% SE = 12.4, n = 16), compared with patients with undetectable EOI MRD (6-year DFS 87.9% SE = 6.6, n = 28) or intermediate EOI MRD <5 × 10−4 (6-year DFS 76.4% SE = 11.3, n = 24; P = 0.02).
We conclude that young age at diagnosis and low EOI MRD seem favourable prognostic factors in infants with KMT2A-germline ALL and should be considered for risk stratification in future clinical trials.
•Prognostic factors for infants with KMT2A-germline acute lymphoblastic leukaemia (ALL) are not well known.•Characteristics of 167 uniformly treated infants with KMt2A-germline ALL were analyzed.•Young age at diagnosis (<6 months) was associated with better outcome.•End of induction minimal residual disease (MRD), rather than end of consolidation MRD, was a prognostic factor for outcome.•Combined MRD and genetic-based stratification of KMT2A-g infants should be considered.
Detection of minimal residual disease (MRD) is the most sensitive method to evaluate treatment response and one of the strongest predictors of outcome in childhood acute lymphoblastic leukemia (ALL). ...The 10-year update on the I-BFM-SG MRD study 91 demonstrates stable results (event-free survival), that is, standard risk group (MRD-SR) 93%, intermediate risk group (MRD-IR) 74%, and high risk group (MRD-HR) 16%. In multicenter trial AIEOP-BFM ALL 2000, patients were stratified by MRD detection using quantitative PCR after induction (TP1) and consolidation treatment (TP2). From 1 July 2000 to 31 October 2004, PCR target identification was performed in 3341 patients: 2365 (71%) patients had two or more sensitive targets (< or =10(-4)), 671 (20%) patients revealed only one sensitive target, 217 (6%) patients had targets with lower sensitivity, and 88 (3%) patients had no targets. MRD-based risk group assignment was feasible in 2594 (78%) patients: 40% were classified as MRD-SR (two sensitive targets, MRD negativity at both time points), 8% as MRD-HR (MRD > or =10(-3) at TP2), and 52% as MRD-IR. The remaining 823 patients were stratified according to clinical risk features: HR (n=108) and IR (n=715). In conclusion, MRD-PCR-based stratification using stringent criteria is feasible in almost 80% of patients in an international multicenter trial.
Purpose
Giant inguinoscrotal hernia are a real challenge for every kind of surgeon. The technique that we adopt is suggested as a good option to deal with this cases. We report our experience in five ...cases of giant inguinoscrotal hernia with loss of domain from 2005 to 2012.
Method
Five patients with hernia that descended below the knees in the standing position, with an anteroposterior diameter not inferior to 30 cm and a laterolateral diameter of about 50 cm. Penis was not visible. We did the same procedure for all the five patients: single pararectus incision extended to groin region until proximal half of scrotum, isolation of the entire large sac out of the scrotal cavity, paying attention to not opening it, progressive reduction of the viscera without opening the sac with the hug technique, as shown in the video, placement of a heavyweight polypropylene meshes in the preperitoneal space, scrotal skin reductive plastic. In three of our five cases we obtained restoration of herniated viscera without resection of them. Orchiectomy was performed in all cases.
Results
No general neither wound complications were recorded. Long term follow up ranges from 8 years to 18 months: we did not record recurrence or chronic groin pain and scrotal size is normal in each patient.
Conclusion
The technique proposed permits to treat with success giant inguinaoscrotal hernia, avoiding the use of further specific procedure such as the preoperative progressive pneumoperitoneum. All our patients were satisfied with the surgeries and their quality of daily life had definitely improved.
Background
Indocyanine green fluorescence vision is an upcoming technology in surgery. It can be used in three ways: angiographic and biliary tree visualization and lymphatic spreading studies. The ...present paper shows the most outstanding results from an health technology assessment study design, conducted on fluorescence-guided compared with standard vision surgery.
Methods
A health technology assessment approach was implemented to investigate the economic, social, ethical, and organizational implications related to the adoption of the innovative fluorescence-guided view, with a focus on minimally invasive approach. With the support of a multidisciplinary team, qualitative and quantitative data were collected, by means of literature evidence, validated questionnaires and self-reported interviews, considering the dimensions resulting from the EUnetHTA Core Model.
Results
From a systematic search of literature, we retrieved the following studies: 6 on hepatic, 1 on pancreatic, 4 on biliary, 2 on bariatric, 4 on endocrine, 2 on thoracic, 11 on colorectal, 7 on urology, 11 on gynecology, 2 on gastric surgery. Fluorescence guide has shown advantages on the length of hospitalization particularly in colorectal surgery, with a reduction of the rate of leakages and re-do anastomoses, in spite of a slight increase in operating time, and is confirmed to be a safe, efficacious, and sustainable vision technology. Clinical applications are still presenting a low evidence in the literature.
Conclusion
The present paper, under the patronage of Italian Society of Endoscopic Surgery, based on an HTA approach, sustains the use of fluorescence-guided vision in minimally invasive surgery, in the fields of general, gynecologic, urologic, and thoracic surgery, as an efficient and economically sustainable technology.
PDF
