Creation and application of virtual patient cohorts of heart models.

Patient-specific cardiac models are now being used to guide therapies. The increased use of patient-specific cardiac simulations in clinical care will give rise to the development of virtual cohorts of cardiac models. These cohorts will allow cardiac simulations to capture and quantify inter-patient variability. However, the development of virtual cohorts of cardiac models will require the transformation of cardiac modelling from small numbers of bespoke models to robust and rapid workflows that can create large numbers of models. In this review, we describe the state of the art in virtual cohorts of cardiac models, the process of creating virtual cohorts of cardiac models, and how to generate the individual cohort member models, followed by a discussion of the potential and future applications of virtual cohorts of cardiac models. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.

Lymphatic microsurgical preventing healing approach (LYMPHA) for primary surgical prevention of breast cancer-related lymphedema: over 4 years follow-up.

Breast cancer-related lymphedema (LE) represents an important morbidity that jeopardizes breast cancer patients' quality of life. Different attempts to prevent LE brought about improvements in the incidence of the pathology but LE still represents a frequent occurrence in breast cancer survivors. Over 4 years ago, Lymphatic Microsurgical Preventing Healing Approach (LYMPHA) was proposed and long-term results are reported in this study. From July 2008 to December 2012, 74 patients underwent axillary nodal dissection for breast cancer treatment together with LYMPHA procedure. Volumetry was performed preoperatively in all patients and after 1, 3, 6, 12 months, and once a year. Lymphoscintigraphy was performed in 45 patients preoperatively and in 30 also postoperatively after at least over 1 year. Seventy one patients had no sign of LE, and volumetry was coincident to preoperative condition. In three patients, LE occurred after 8-12 months postoperatively. Lymphoscintigraphy showed the patency of lymphatic-venous anastomoses at 1-4 years after operation. LYMPHA technique represents a successful surgical procedure for primary prevention of arm LE in breast cancer patients.

Role of the Cadaver Lab in Lymphatic Microsurgery Education: Validation of a New Training Model.

BACKGROUND: Microsurgical transplantation of vascularized lymph nodes (VLNT) or lymphatic vessels (VLVT) alongside derivative lymphaticovenous procedures are promising approaches for treatment of lymphedema. However, clinically relevant training models for mastering these techniques are still lacking. Here we describe a new training model in human cadaver and validate its use as training tool for microsurgical lymphatic reconstruction. METHODS: 10 surgeons with previous exposure to microsurgery were trained in a controlled environment. Lymphatic vessel mapping and dissection in 4 relevant body regions, harvesting of five different VLNTs and one VLVT were performed in 5 fresh-frozen cadavers. The number of lymphatic vessels and lymph nodes for each VLNT were recorded. Finally, the efficacy of this model as training tool was validated using the Dundee Ready Education Environment Measure (DREEM). RESULTS: The average cumulative DREEM score over each category was 30,75 (max = 40) while individual scoring for each relevant category revealed highly positive ratings from the perspective of teaching (39,3), training 40,5 (max = 48) and self perception of the training 30,5 (max = 32) from all participants. The groin revealed the highest number of lymphatic vessels (3.2 ± 0.29) as all other regions on the upper extremity, while the gastroepiploic VLNT had the highest number of lymph nodes (4.2 ± 0.37). CONCLUSIONS: This human cadaver model represents a new, reproducible "all-in-one" tool for effective training in lymphatic microsurgery. Its unique diligence in accurately reproducing human lymphatic anatomy, should make this model worth considering for each microsurgeon willing to approach lymphatic reconstruction.

Hydrogen breath test--diet and basal H2 excretion: a technical note.

BACKGROUND: Hydrogen breath tests are widely used in clinical practice. For a correct evaluation of data, low basal H2 excretion is required, thus, 12-hour fasting is usually prescribed. An additional reduction in the intake of complex carbohydrates in the preceding 24 h is suggested in some centers. The issue, however, has never been directly investigated. AIM: The aim of the present study was to analyze the effect of the pretest diet on the basal H2 excretion and the number of subjects excluded from the test due to high basal H2 excretion. METHODS: Two cohorts of 500 consecutive patients undergoing a lactose tolerance test in the years 1997-1998 (when 12-hour fasting was required) and in 2007-2008 (when a low-carbohydrate diet in the preceding 24 h was also prescribed) were retrospectively reviewed. RESULTS: The mean basal H2 excretion was significantly lower (p < 0.0001) in the low-carbohydrate diet group (2.46 +/- 6.8 vs. 4.73 +/- 3.3 ppm). In 1997-1998, 46/500 patients (9.2%) were excluded from the test due to basal H2 values as compared to 7/500 (1.4%) in the period 2007-2008. DISCUSSION: To the best of our knowledge, ours is the first study to provide objective data on the advantage offered by reducing the intake of complex carbohydrates before H2 breath tests.

Randomized trial of chemotherapy versus chemotherapy plus radiotherapy for stage I-II Hodgkin's disease.

A total of 277 patients with untreated Hodgkin's disease, clinical stages I-II, were randomized to cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP) alone for 6 monthly cycles or to CVPP plus radiation therapy (RT), 3,000 rad, to involved areas (CVPP plus RT). One or more of the following factors were considered as unfavorable prognosis: age greater than 45 years, more than two lymph node areas involved, or bulky disease. In the favorable group, disease-free survival (77% vs. 70%) or overall survival (92% vs. 91%) at 84 months for CVPP versus RT plus CVPP was similar. Patients with unfavorable prognosis treated with RT plus CVPP had longer disease-free survival (75% vs. 34%) (P = .001) and overall survival (84% vs. 66%) than patients treated with CVPP alone.

Prognostic factors in multiple myeloma: definition of risk groups in 410 previously untreated patients: a Grupo Argentino de Tratamiento de la Leucemia Aguda study.

Four hundred ten previously untreated multiple myeloma patients entered onto two consecutive Grupo Argentino de Tratamiento de la Leucemia Aguda (GATLA) protocols were analyzed to identify significant prognostic factors influencing survival. The univariate analysis selected the following variables: performance status, renal function, percentage of bone marrow plasma cells at diagnosis, hemoglobin, and age. A multivariate analysis showed that performance status, renal function, percentage of bone marrow plasma cells, hemoglobin, and age were the best predictive variables for survival. A score was assigned to each patient according to these variables, which led to their classification in three groups: good, intermediate, and poor risk, with a probability of survival of 26% and 10% at 96 months, and 5% at 56 months, and median survival of 60, 37, and 14 months, respectively (P = .0000). In our patient population, this model proved to be superior to the Durie-Salmon staging system in defining prognostic risk groups, and separating patients with significantly different risks within each Durie-Salmon stage.

An update of two randomized trials in previously untreated multiple myeloma comparing melphalan and prednisone versus three- and five-drug combinations: an Argentine Group for the Treatment of Acute Leukemia Study.

An update of two consecutive randomized studies in previously untreated multiple myeloma was performed. The first study (10-M-73) began in 1973; 150 patients were treated with melphalan and prednisone (MP) or semustine, cyclophosphamide, and prednisone (MeCP). In a second randomized study (3-M-77), begun in 1977, 260 patients were treated with MP or melphalan, prednisone, cyclophosphamide, semustine, and vincristine (MPCCV). A total of 27 of the 67 patients (40%) treated with MP and 33 of the 83 patients (40%) treated with MeCP showed a good response in protocol 10-M-73; 48 of 145 patients (33%) treated with MP and 51 of the 115 patients (44%) treated with MPCCV in protocol 3-M-77 obtained a good response (P is not significant). Median survival in protocol 10-M-73 was 30 months for MeCP and 38 months for MP. At 84 months, 19% and 9% remain alive, respectively. Median survival for protocol 3-M-77 was 44 months for those treated with MPCCV and 42 months for MP. At 60 months, 9% and 11% remain alive; this difference was not significant. Also, there was no survival difference for favorable or unfavorable prognostic groups among the four treatment arms of both protocols. It can be concluded, with a long-term follow-up of both protocols, that the combination of MP is as effective as the three- and five-drugs combinations, and in view of its simplicity and cost-saving advantages, it should be favored for initial therapy of multiple myeloma patients.

Randomized trial of CVPP for three versus six cycles in favorable-prognosis and CVPP versus AOPE plus radiotherapy in intermediate-prognosis untreated Hodgkin's disease.

PURPOSE: To evaluate in a randomized trial the impact of three versus six cycles of cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP) chemotherapy in favorable-prognosis and CVPP versus doxorubicin, vincristine, prednisone, and etoposide (AOPE) plus involved-field radiotherapy (RT) in intermediate-prognosis previously untreated Hodgkin's disease. PATIENTS AND METHODS: Of 256 patients evaluated, 80 with a favorable prognosis according to a prognostic index designed by the Grupo Argentina de Tratamiento de Leucemia Aguda (GATLA) were randomized to three versus six cycles of CVPP without RT and 176 with intermediate risk to CVPP versus AOPE, both for six cycles with RT between the third and fourth cycles of 30 Gy to the involved areas at diagnosis. CVPP consisted of intravenous (I.V.) cyclophosphamide and vinblastine on days 1 and 8, and oral procarbazine and prednisone on days 1 to 14, every 28 days. AOPE consisted of I.V. doxorubicin and vincristine on day 1, oral prednisone on days 1 to 5, and I.V. etoposide on days 1 and 3, every 28 days. RESULTS: Complete remission was obtained in 39 of 41 (95%) patients treated with three cycles of CVPP and 36 of 39 (92%) treated with six cycles in the favorable-risk group (difference not significant [NS]). In the intermediate-risk group, 89 of 92 (97%) treated with CVPP plus RT versus 75 of 84 (89%) treated with AOPE plus RT achieved a complete remission (P = .05). At 60 months, the event-free survival (EFS) and overall survival rates in the favorable-risk group were 80% and 91% for CVPP x 3 and 84% and 97% for CVPP x 6, respectively (P = NS). In the intermediate-risk group, 60-month EFS rate for CVPP plus RT was 85%, compared with 66% for AOPE plus RT (P = .009). The overall survival rate was 95% versus 87% respectively (P = .157). CONCLUSION: Three cycles of CVPP without RT are equally effective as six cycles in the favorable-risk group. However, in the intermediate-group, CVPP plus RT is superior to AOPE plus RT, with significantly fewer events before and after induction (P = .009), without a difference in overall survival.

Monitoring of sensory evoked potentials during surgery of skull base tumours.

Despite advances in instrumentation and the use of microsurgical techniques, neurosurgical procedures involving extensive areas of skull base or other critical areas of brain still carry significant risk for neurological injury. The use of intraoperative recording of sensory evoked potentials (SEP) has been advocated to monitor neurologic function during these major neurosurgical procedures to reduce the risk of injury to neural structures. This report summarizes our experience with intraoperative monitoring of SEP in over 200 patients, and details our findings in a group of 12 patients with skull base and posterior fossa tumours. Somatosensory evoked potentials (SSEP) were monitored in all patients, and brain stem auditory evoked potentials (BAEP) in five. While minor changes in BAEP and SSEP parameters were noted in most patients, significant changes occurred in five. Irreversible loss of BAEP in one patient was associated with complete hearing loss postoperatively. Marked, persistent alteration of both BAEP and SSEP was associated with postoperative brainstem dysfunction. No patient with stable BAEP and SSEP at the end of the procedure suffered additional neurological deficit. We conclude that intraoperative SEP monitoring may be valuable in minimizing neural injury during major neurosurgical procedures.

[Sepsis due to Vibrio cholerae no 01]. / Sepsis por Vibrio cholerae no 01.

Two fatal sepsis cases in two male patients (58 and 14 years old) due to Vibrio cholerae non 01 are described. Their original diseases were hepatic cirrhosis and acute lymphoblastic leukemia in its third complete remission. In this last case, gastroenteritis due to V. cholerae non 01 was also diagnosed. These sepsis presented a rapid evolution and positive hemoculture after 24 and 48 hours of incubation. Both strains isolated presented similar biochemical characteristics and did not agglutinate in the presence of the specific serum against V. cholerae. Both strains were susceptible to most of the antibiotics available. Sepsis due to V. cholerae non 01 is usually associated to other original diseases and to immunodepression. Management of these sepsis is difficult and mortality rates are very high.

[Eight years of experience in a single institution in hematopoietic stem cell autologous transplantation in malignant hematological diseases and in solid tumors]. / Ocho años de experiencia en una sola institucion en trasplante autólogo de células progenitoras hematopoyéticas en enfermedades hematológicas malignas y en tumores solidos.

Between August 1991 and December 1998, 400 patients (lymphomas: 197; acute leukemia: 86; multiple myeloma: 70 and solid tumors: 47) were admitted for autologous transplantation. All patients were mobilized with chemotherapy plus G-CSF. The hematological recovery was similar in all disease groups. Patients with acute leukemias and multiple myeloma had a slower platelet recovery. Treatment-related death was 4.5%. The status of the disease at diagnosis was the most significant prognostic factor. With a median follow-up of 23 months the probability of event-free survival at 60 months was 46% for low grade lymphoma, 44% for intermediate and high grade lymphoma, 58% for Hodgkin's disease, 45% for acute myeloblastic leukemia, 38% for solid tumors and 15% for multiple myeloma. The probability of survival at 60 months was 67% for low grade lymphoma, 47% for intermediate and high grade lymphoma, 75% for Hodgkin's disease, 52% for acute myeloblastic leukemia, 54% for solid tumors and 25% for multiple myeloma. It can be concluded that autologous progenitor cell transplantation induces a complete and faster hematological recovery in all groups of patients without any late graft failure. Results are similar to those published in the literature. The treatment-related death was low and acceptable.

Collagen (NeuraGen®) nerve conduits and stem cells for peripheral nerve gap repair.

Collagen nerve guides are used clinically for peripheral nerve defects, but their use is generally limited to lesions up to 3 cm. In this study we combined collagen conduits with cells as an alternative strategy to support nerve regeneration over longer gaps. In vitro cell adherence to collagen conduits (NeuraGen(®) nerve guides) was assessed by scanning electron microscopy. For in vivo experiments, conduits were seeded with either Schwann cells (SC), SC-like differentiated bone marrow-derived mesenchymal stem cells (dMSC), SC-like differentiated adipose-derived stem cells (dASC) or left empty (control group), conduits were used to bridge a 1cm gap in the rat sciatic nerve and after 2-weeks immunohistochemical analysis was performed to assess axonal regeneration and SC infiltration. The regenerative cells showed good adherence to the collagen walls. Primary SC showed significant improvement in distal stump sprouting. No significant differences in proximal regeneration distances were noticed among experimental groups. dMSC and dASC-loaded conduits showed a diffuse sprouting pattern, while SC-loaded showed an enhanced cone pattern and a typical sprouting along the conduits walls, suggesting an increased affinity for the collagen type I fibrillar structure. NeuraGen(®) guides showed high affinity of regenerative cells and could be used as efficient vehicle for cell delivery. However, surface modifications (e.g. with extracellular matrix molecule peptides) of NeuraGen(®) guides could be used in future tissue-engineering applications to better exploit the cell potential.

Evolution of chylous fistula management after neck dissection.

PURPOSE OF REVIEW: The present review is focused on the management of lymphatic, chylous, and thoracic duct lesions following head and neck surgery, with particular attention to these complications after neck dissection. Postoperative scenarios may include chylous fistula, chylothorax, chylomediastinum, chylopericardium, lymphocele, persistent lymphorrhea, and secondary lymphedema. RECENT FINDINGS: There is a paucity of literature on the treatment of lymphatic, chylous, and thoracic duct injuries following head and neck surgery; however, this review suggests that the most appropriate treatment should include both conservative and surgical approaches. Nonsurgical options consist of low-fat diet with medium-chain triglycerides, total parenteral nutrition, careful monitoring of fluid and electrolytes, drainage of the leakage, somatostatin analogs such as octreotide, and negative-pressure wound therapy. On the other hand, surgical management includes therapeutic percutaneous lymphography-guided thoracic duct cannulation and embolization, thoracic duct ligation, excision and imbrication of leaking lymphatics, chylous fistula surgical/microsurgical repair, fistula closure by locoregional flaps, video-assisted thoracoscopic surgery, thoracotomy, pleurodesis and decortication, pericardial 'window', and pleura-venous/pleura-peritoneal shunts. In addition, single or, preferably, multiple lymphovenous anastomoses may be taken into account. SUMMARY: The various possible clinical presentations of such challenging lymphatic, chylous, and thoracic duct injuries require an appropriate multidisciplinary approach by experienced teams. Primary prevention of these complications can be achieved through adequate surgical planning to minimize lesions, including structured and thorough patient assessment, and centralization of resources and teams.

Core elements of physiotherapy in cerebral palsy children: proposal for a trial checklist.

BACKGROUND: Currently international literature describes physiotherapy in cerebral palsy (CP) children only in generic terms (traditional / standard / background / routine). AIM: The aim of this study is to create a checklist capable of describing the different modalities employed in physiotherapeutic treatment by means of a non-bias, common, universal, standardised language. DESIGN: A preliminary checklist was outlined by a group of physiotherapists specialised in child rehabilitation. SETTING: For its experimentation, several physiotherapists from various paediatric units from all over Italy with different methodological approaches and backgrounds, were involved. METHODS: Using the interpretative model, proposed by Ferrari et al., and through collective analysis and discussion of clinical videos, the core elements were progressively selected and codified. A reliability study was then carried out by eight expert physiotherapists using an inter-rate agreement model. RESULTS: The checklist analyses therapeutic proposals of CP rehabilitation through the description of settings, exercises and facilitations and consists of items and variables which codify all possible physiotherapeutic interventions. It is accompanied by written explanations, demonstrative videos, caregiver interviews and descriptions of applied environmental adaptations. All checklist items obtained a high level of agreement (according to Cohen's kappa coefficient), revealing that the checklist is clearly and easily interpretable. CONCLUSION: The checklist should facilitate interaction and communication between specialists and families, and lead to comparable research studies and scientific advances. CLINICAL REHABILITATION IMPACT: The main value is to be able to correlate therapeutic results with core elements of adopted physiotherapy.

Identification and phenotypic characterization of a subpopulation of T84 human colon cancer cells, after selection on activated endothelial cells.

The extravasation of metastatic cells is regulated by molecular events involving the initial adhesion of tumor cells to the endothelium and subsequently the migration of the cells in the host connective tissue. The differences in metastatic ability could be attributed to properties intrinsic of the various primary tumor types. Thus, the clonal selection of neoplastic cells during cancer progression results in cells better equipped for survival and formation of colonies in secondary sites. A cell line (T84SF) exhibiting an altered phenotypic appearance was selected from a colon cancer cell line (T84) by repetitive plating on TNFalpha-activated human endothelial cells and subsequent selection for adherent cells. Cell growth, motility, chemoinvasive abilities, tyrosine phosphorylation signaling, and the metastasis formation in nude mice of the two cell lines was compared. T84SF cells displayed in vitro an higher proliferation rate and a more invasive behavior compared to the parental cells while formed in vivo a greater number of metastatic colonies in nude mice. As concerns the signaling underlying the phenotypes of the selected cells, we examined the general tyrosine phosphorylation levels in both cell lines. Our results indicate that T84SF have an increased basal tyrosine phosphorylation of several proteins among which src kinase was identified. Treatment of cells with a specific inhibitor of src activity caused a greater in vitro inhibition of proliferation and invasive properties of T84 parental cells with respect to T84SF cells and diminished metastasis formation in vivo. Altogether, these data provide evidences that this new cell line may be valuable for identifying molecular mechanisms involved in the metastatic progression of colon cancer.

Improved results of an intensified therapy in adult acute lymphocytic leukemia.

Two consecutive studies for adult patients with acute lymphoblastic leukemia without previous treatment were analyzed and compared. Protocol ALL-79 included 137 patients treated with a 'standard therapy' consisting of prednisone, vincristine and daunomycin as induction, CNS prophylaxis with IT chemotherapy and maintenance with 6-mercaptopurine, methotrexate and pulses with vincristine and prednisone. Protocol ALL-82 included 145 patients treated with an 'intensive therapy' consisting of 8 weeks of induction with vincristine, prednisone, daunomycin and L-asparaginase, followed by 6-mercaptopurine, cyclophosphamide and cytosine arabinoside. At 3 months after induction, a 6-week consolidation therapy was given, with vincristine, adriamycin, dexamethasone and L-asparaginase, followed by cyclophosphamide, cytosine arabinoside and 6-mercaptopurine. Rates of complete remission were 80% and 78% for protocols ALL-79 and ALL-82 respectively. The probability of remaining in complete remission at 80 months was 20% and 34%, respectively (p = 0.0014). Median survival for protocol ALL-79 was 14 months, and 34 months for protocol ALL-82; at 80 months the probability of survival is 22% and 35% for the two protocols (P = 0.0024). In protocol ALL-82, the probability of remaining in CR for favorable prognosis patients (age = less than 35 years and WBC = less than 50.000) is 56% at 80 months, and only 8% at 50 months for the unfavorable group (age greater than 35 and/or WBC greater than 50.000) (P = 0.0012). The probability of survival was statistically superior in patients with favorable prognoses, with 54% of them still alive at 60 months compared to only 13% of patients with unfavorable prognoses (P = 0.0085).(ABSTRACT TRUNCATED AT 250 WORDS)