Tumour growth control: analysis of alternative approaches.

In this work we address the problem of tumour growth control by properly exploiting a low-dimensional model that grounds on the Chemical Reaction Network (CRN) formalism. Originally conceived to work both in deterministic and stochastic frameworks, it is shown that, except for the case of very low number of tumour cells, the deterministic approach is appropriate to characterize the system behaviour, especially for control planning purposes. Two alternative control approaches are here investigated. One trivially assumes a constant infusion of external drug administration, the other is designed according to a state-feedback control scheme, with complete or partial knowledge of the state. Pros and cons of both control laws are investigated, showing that the tumour size at the beginning of the therapy plays a role of paramount importance for fixed infusion therapies, whilst only state-feedback laws can eradicate arbitrarily large tumours.

ARDS after Pneumonectomy: How to Prevent It? Development of a Nomogram to Predict the Risk of ARDS after Pneumonectomy for Lung Cancer.

(1) Background: The cause of ARDS after pneumonectomy is still unclear, and the study of risk factors is a subject of debate. (2) Methods: We reviewed a large panel of pre-, peri- and postoperative data of 211 patients who underwent pneumonectomy during the period 2014−2021. Univariable and multivariable logistic regression was used to quantify the association between preoperative parameters and the risk of developing ARDS, in addition to odds ratios and their respective 95% confidence intervals. A backward stepwise selection approach was used to limit the number of variables in the final multivariable model to significant independent predictors of ARDS. A nomogram was constructed based on the results of the final multivariable model, making it possible to estimate the probability of developing ARDS. Statistical significance was defined by a two-tailed p-value < 0.05. (3) Results: Out of 211 patients (13.3%), 28 developed ARDS. In the univariate analysis, increasing age, Charlson Comorbidity Index and ASA scores, DLCO < 75% predicted, preoperative C-reactive protein (CRP), lung perfusion and duration of surgery were associated with ARDS; a significant increase in ARDS was also observed with decreasing VO2max level. Multivariable analysis confirmed the role of ASA score, DLCO < 75% predicted, preoperative C-reactive protein and lung perfusion. Using the nomogram, we classified patients into four classes with rates of ARDS ranking from 2.0% to 34.0%. (4) Conclusions: Classification in four classes of growing risk allows a correct preoperative stratification of these patients in order to quantify the postoperative risk of ARDS and facilitate their global management.

Characterizing Fractal Genetic Variation in the Human Genome from the Hapmap Project.

Over the last decades, the exuberant development of next-generation sequencing has revolutionized gene discovery. These technologies have boosted the mapping of single nucleotide polymorphisms (SNPs) across the human genome, providing a complex universe of heterogeneity characterizing individuals worldwide. Fractal dimension (FD) measures the degree of geometric irregularity, quantifying how "complex" a self-similar natural phenomenon is. We compared two FD algorithms, box-counting dimension (BCD) and Higuchi's fractal dimension (HFD), to characterize genome-wide patterns of SNPs extracted from the HapMap data set, which includes data from 1184 healthy subjects of eleven populations. In addition, we have used cluster and classification analysis to relate the genetic distances within chromosomes based on FD similarities to the geographical distances among the 11 global populations. We found that HFD outperformed BCD at both grand average clusterization analysis by the cophenetic correlation coefficient, in which the closest value to 1 represents the most accurate clustering solution (0.981 for the HFD and 0.956 for the BCD) and classification (79.0% accuracy, 61.7% sensitivity, and 96.4% specificity for the HFD with respect to 69.1% accuracy, 43.2% sensitivity, and 94.9% specificity for the BCD) of the 11 populations present in the HapMap data set. These results support the evidence that HFD is a reliable measure helpful in representing individual variations within all chromosomes and categorizing individuals and global populations.

A comparison among three maximal mathematical models of the glucose-insulin system.

The most well-known and widely used mathematical representations of the physiology of a diabetic individual are the Sorensen and Hovorka models as well as the UVAPadova Simulator. While the Hovorka model and the UVAPadova Simulator only describe the glucose metabolism of a subject with type 1 diabetes, the Sorensen model was formulated to simulate the behaviour of both normal and diabetic individuals. The UVAPadova model is the most known model, accepted by the FDA, with a high level of complexity. The Hovorka model is the simplest of the three models, well documented and used primarily for the development of control algorithms. The Sorensen model is the most complete, even though some modifications were required both to the model equations (adding useful compartments for modelling subcutaneous insulin delivery) and to the parameter values. In the present work several simulated experiments, such as IVGTTs and OGTTs, were used as tools to compare the three formulations in order to establish to what extent increasing complexity translates into richer and more correct physiological behaviour. All the equations and parameters used for carrying out the simulations are provided.

A mathematical model of cardiovascular dynamics for the diagnosis and prognosis of hemorrhagic shock.

A variety of mathematical models of the cardiovascular system have been suggested over several years in order to describe the time-course of a series of physiological variables (i.e. heart rate, cardiac output, arterial pressure) relevant for the compensation mechanisms to perturbations, such as severe haemorrhage. The current study provides a simple but realistic mathematical description of cardiovascular dynamics that may be useful in the assessment and prognosis of hemorrhagic shock. The present work proposes a first version of a differential-algebraic equations model, the model dynamical ODE model for haemorrhage (dODEg). The model consists of 10 differential and 14 algebraic equations, incorporating 61 model parameters. This model is capable of replicating the changes in heart rate, mean arterial pressure and cardiac output after the onset of bleeding observed in four experimental animal preparations and fits well to the experimental data. By predicting the time-course of the physiological response after haemorrhage, the dODEg model presented here may be of significant value for the quantitative assessment of conventional or novel therapeutic regimens. The model may be applied to the prediction of survivability and to the determination of the urgency of evacuation towards definitive surgical treatment in the operational setting.

Modeling continuous glucose monitoring with fractional differential equations subject to shocks.

Continuous Glucose Monitoring (CGM) produces long time-series of noisy observations of a single variable (tissue glucose concentration), whose evolution may be explained by a dynamical model. In order to represent the unknown mixture of possible control mechanisms of different orders affecting the measured variable, a fractional differential approach seems justified. In any case, variations in food intake and/or physical activity ought to be taken into account if a plausible interpretation of the dynamics is to be obtained. In the present work, the mathematical construction and the numerical implementation of a Fractional Differential Equations (FDE) initial value problem are systematically reviewed, with the intent of offering the reader a concise and mathematically rigorous description of this approach. An FDE model for CGM is formulated: the model includes compartments for stomach and intestinal glucose contents and for blood and tissue (subcutaneous) glucose concentrations, as well as the shock effects of food ingestion and of increased glucose consumption due to physical activity. The model parameters, including the (non-integer) order of differentiation, are estimated from CGM observations on six Type 1 diabetic patients. The best-fit fractional orders for the six subjects range from 1.59 to 2.13. For comparison, best fits have also been computed for all subjects using an average fractional order of 1.9 and integer orders of 1 and 2.The results indicate that in the case of CGM the fractional differential model, which should be physiologically more appropriate, in fact fits the data much better than the first-order model and also better than the 2nd-order model.

A quasi-equilibrium reduced model of pancreatic insulin secretion.

Much attention has been devoted in the last few decades to mathematical models of insulin secretion, in order to better understand the regulation of glycemia and its derangements. The glucose-insulin homeostatic mechanism is so complex and gives rise to such diverse behavior following perturbations that different models had been published, which reproduced the results of single experiments. More recently, a unifying model of pancreatic insulin secretion was proposed, which is able to account, with a single value of the (meta)parameters, for the wide array of clinically observed behavior. This model explicitly represented the pulsatile nature of the many pancreatic hormone-secreting firing units: the price to pay for its flexibility and performance is the very high dimensionality (hundreds of thousand equations) of the corresponding dynamical system. Clearly, it would be desirable to reduce this model to a much simpler form while retaining its power to reproduce heterogeneous phenomena. The present work reviews the qualitative behavior of this pancreas pulsatile model and offers some insight into its reduction in equilibrium and quasi-equilibrium conditions, also considering single-shot (non-repeated) glucose jumps from an approximately resting condition (such as would occur in standard Intra-Venous bolus dosing of glucose during diabetes diagnostic maneuvers). The resulting quasi-steady-state model can be further endowed with additional lower-order dynamics to also approximate transient behavior. Although a more accurate reduction of the original pulsatile model is left to further investigation, numerical results confirm the biomedical applicability of the formulation already obtained.

Optimal design of lock-down and reopening policies for early-stage epidemics through SIR-D models.

The diffusion of COVID-19 represents a real threat for the health and economic system of a country. Therefore the governments have to adopt fast containment measures in order to stop its spread and to prevent the related devastating consequences. In this paper, a technique is proposed to optimally design the lock-down and reopening policies so as to minimize an aggregate cost function accounting for the number of individuals that decease due to the spread of COVID-19. A constraint on the maximal number of concomitant infected patients is also taken into account in order to prevent the collapse of the health system. The optimal procedure is built on the basis of a simple SIR model that describes the outbreak of a generic disease, without attempting to accurately reproduce all the COVID-19 epidemic features. This modeling choice is motivated by the fact that the containing measurements are actuated during the very first period of the outbreak, when the characteristics of the new emergent disease are not known but timely containment actions are required. In fact, as a consequence of dealing with poor preliminary data, the simplest modeling choice is able to reduce unidentifiability problems. Further, the relative simplicity of this model allows to compute explicitly its solutions and to derive closed-form expressions for the maximum number of infected and for the steady-state value of deceased individuals. These expressions can be then used to design static optimization problems so to determine the (open-loop) optimal lock-down and reopening policies for early-stage epidemics accounting for both the health and economic costs.

Laparoscopic vaginal lateral suspension: technical aspects and initial experience.

BACKGROUND: Pelvic organ prolapse (POP) etiology is a combination of anatomical, physiological, genetic, lifestyle, and reproductive factors determine pelvic floor dysfunction. POP is very common across all ages women worldwide and has become an increasing socioeconomic problem with public health consequences, with symptoms that could lead to a significant decrease in quality of life. METHODS: This study retrospectively analyzes a small case series of our initial experience of laparoscopic vaginal suspension with mesh focusing on the technical aspects of the technique. Although sacrocolpopexy and sacrohysteropexy are the most performed surgical techniques, they are associated with serious complications. Laparoscopic vaginal suspension appears reproducible and safe to learn. RESULTS: Between November 2017 and January 2020, fifteen patients underwent laparoscopic vaginal suspension for pelvic organ prolapse repair. Despite the small number, for a minimally invasive skilled surgeon, we notice a significative reduction of the learning curve to become proficient in this procedure. CONCLUSIONS: The diagnosis and management of pelvic organ prolapse are further complicated by what is considered "successful" treatment. Laparoscopic vaginal suspension is a feasible surgical procedure for one-stage treatment of pelvic organ prolapse.

A revised Sorensen model: Simulating glycemic and insulinemic response to oral and intra-venous glucose load.

In 1978, Thomas J. Sorensen defended a thesis in chemical engineering at the University of California, Berkeley, where he proposed an extensive model of glucose-insulin control, model which was thereafter widely employed for virtual patient simulation. The original model, and even more so its subsequent implementations by other Authors, presented however a few imprecisions in reporting the correct model equations and parameter values. The goal of the present work is to revise the original Sorensen's model, to clearly summarize its defining equations, to supplement it with a missing gastrio-intestinal glucose absorption and to make an implementation of the revised model available on-line to the scientific community.

Mixture distributions in a stochastic gene expression model with delayed feedback: a WKB approximation approach.

Noise in gene expression can be substantively affected by the presence of production delay. Here we consider a mathematical model with bursty production of protein, a one-step production delay (the passage of which activates the protein), and feedback in the frequency of bursts. We specifically focus on examining the steady-state behaviour of the model in the slow-activation (i.e. large-delay) regime. Using a formal asymptotic approach, we derive an autonomous ordinary differential equation for the inactive protein that applies in the slow-activation regime. If the differential equation is monostable, the steady-state distribution of the inactive (active) protein is approximated by a single Gaussian (Poisson) mode located at the globally stable fixed point of the differential equation. If the differential equation is bistable (due to cooperative positive feedback), the steady-state distribution of the inactive (active) protein is approximated by a mixture of Gaussian (Poisson) modes located at the stable fixed points; the weights of the modes are determined from a WKB approximation to the stationary distribution. The asymptotic results are compared to numerical solutions of the chemical master equation.

Ten Years' Experience in Robotic-Assisted Thoracic Surgery for Early Stage Lung Cancer.

BACKGROUND: This study analyzed the short- and long-term outcomes of robotic-assisted thoracic surgery (RATS) for early stage non-small cell lung cancer (NSCLC). METHODS: From November 2006 to December 2016, we performed 363 RATS procedures. This study retrospectively reviewed 339 patients who underwent RATS for clinical stages I (n = 318) or II (n = 21) NSCLC. RESULTS: Twenty-nine patients underwent segmentectomy, 307 lobectomy, and 3 pneumonectomy. Conversion occurred in 22 patients (6.5%): 15 (4.4%) due to technical issues, 4 (1.2%) for oncological reasons, and 3 (0.9%) for bleeding. The median number of N1 and N2 stations resected was 2 and 3, respectively, and the median number of N1 and N2 lymph nodes resected was 9 and 6, respectively. Median operative time was 192 minutes for lobectomy, 172 minutes for segmentectomy, and 275 minutes for pneumonectomy. Median length of hospital stay was 5 days (2-191). The most common postoperative complication was prolonged air leak (12.1%). Major complications occurred in eight patients (2.4%). The 30-day and 90-day operative mortality was 0% and 0.3%, respectively. Two and 5-year cancer-specific survival rate was 96.1% and 91.5%, respectively. Five-year survival rate was 96.2% for patients who underwent segmentectomy, and 89.1% for lobectomy. All three patients who underwent pneumonectomy were alive at 5 years with no disease. CONCLUSIONS: Besides the well-known short-term outcomes showing very low morbidity and mortality rates, mediastinal lymph node dissection during RATS adequately assesses lymph node stations detecting occult lymph node metastasis and leading to excellent oncologic results. However, these results await longer follow-up studies.

Pleural catheters after thoracoscopic treatment of malignant pleural effusion: a randomized comparative study on quality of life.

BACKGROUND: Malignant pleural effusion (MPE) complicates many neoplasms and its incidence is expected to rise in parallel with the aging population and longer survival of cancer patients. Although a clear consensus exists on indwelling catheters in patients with poor performance status, no study has hitherto compared different devices in patients requiring temporary or definitive drainage following talc poudrage. METHODS: This is a prospective, two-arm, pilot study on patients with MPE undergoing talc poudrage, comparing two different catheters (PleurX® versus Pleurocath®) positioned because of the inefficacy of the procedure or the high risk of short-term failure. End points of the study were quality of life (QoL), median dyspnea and chest pain assessment by EORTC questionnaires and a 100 mm visual analog scale, total in-hospital length of stay and frequency of serious adverse events. RESULTS: No difference was observed between the two groups in in mean dyspnea and mean chest pain in any questions of the EORTC QLQ-C30 and QLQ-LC13 questionnaires. Duration of the procedure was significantly longer in the PleurX® group versus the Pleurocath® group (72±33 versus 44±13 minutes; P=0.03). No difference was observed between the two groups in total length of hospital stay (P=1.00) or complication rate (P=1.00). CONCLUSIONS: For the cohort of patients still needing indwelling pleural catheters (PC) after thoracoscopic talc poudrage, PleurX® is suggested when drain removal is unlikely due to short life expectancy or the high chance of pleurodesis failure. Conversely, Pleurocath® should be recommended in all other patients as it is faster to place and easier to remove. KEYWORDS: Malignant pleural effusion (MPE); talc poudrage; indwelling pleural catheter (indwelling PC).

Robotic-assisted thymectomy for early-stage thymoma: a propensity-score matched analysis.

The aim of this study was to analyse the feasibility and safety of robotic-assisted thymectomy (RoT) in patients with clinically early stage thymoma, investigating clinical and early oncological results. Between 1998 and 2017, we retrospectively reviewed 76 (42.2%) patients who underwent radical thymectomy for clinically early stage thymoma (Masaoka-Koga I and II), identifying all patients who underwent RoT (n = 28) or open thymectomy (OT) with eligibility criteria for robotic surgery (n = 48). Using a propensity-score matched for tumor size (3.9 ± 1.8 cm) and stage (35% stage I, 42% stage IIA, 23% stage IIB), we paired 24 patients who had RoT with 24 patients undergoing OT. RoT was left-sided in 19 (79.2%) patients. None of the patients required conversion to open surgery. OT was via sternotomy in 21 (87.5%) patients and thoracotomy in 3 (12.5%). Mean operating time was shorter in the RoT group (117 ± 40 min) than in the OT (141 ± 46 min) (p = 0.06), even if not statistically significant. Length of stay was significantly shorter in the RoT group (mean 4.0 ± 1.9 days) than in the OT (mean 5.9 ± 1.7 days) (p = 0.0009). No significant difference between the two groups regarding post-operative complications. Five patients died in the OT group after a median follow-up of 6.1 years (only one for recurrence). After a median follow-up of 1.3 years, all patients in the RoT group were alive without disease. RoT is feasible and safe for early stage thymoma with clear advantage compared to OT in term of short term outcomes. A longer follow-up is needed to better evaluate the oncological results.

Emergency drain for post pneumonectomy bronchopleural fistula: a drain placement technique based on the siphon principle.

Post pneumonectomy bronchopleural fistula (BPF) is a life-threatening complication requiring pleural cavity drainage to avoid acute mediastinal shift and contralateral aspiration pneumonia. Chest drain insertion in this situation may be technically difficult because of drastic anatomical changes such as mediastinal dislocation, diaphragm elevation and, sometimes, massive subcutaneous emphysema. In addition, the most important part of the pleural cavity to be drained is the costophrenic recess that is scarcely drained by a standard chest tube with its tip aiming high and upwards. We propose a safe, simple and effective technique based on the siphon principle to drain the lowest part of the pleural cavity.

Diagnostic biomarkers for lung cancer prevention.

Lung cancer is the leading cause of death for neoplasm. Lung cancer mortality is frequently associated with late diagnosis, therefore an early diagnosis is a key factor to significantly improve overall survival in high risk populations of asymptomatic patients. Conventional cancer screenings (low-dose computed tomography or chest x-ray) today offer early detection but are invasive and expensive. Previously these studies evaluated the solid and topographic cancer structure and morphology. Today the concept of tumor has been remodelled, being defined as a disease that has its own genetic, biological and metabolic identity; it is on this new awareness that we should base new screening methods. Recent research has shown great reliability of new tests such as exhaled breath analysis, serum biomarkers and urine analysis in early diagnosis of lung cancer. Analysis of new biomarkers associated with the high specificity of these new screening methods, which are non-invasive, safe, inexpensive and simple to perform, could allow a non-invasive approach to determine a big change in the early diagnosis of cancer and its survival rate. Furthermore, these new techniques put the patient at the core of a non-invasive diagnostic process and ensure a better quality of life during medical diagnosis. In this article, we want to analyze the possible benefits of these new and promising methods, suggesting a possible combination between them to ensure, as soon as possible, an early and effective diagnosis of lung cancer with a special focus on the patient, in a new era of personalized medicine.

New stapling devices in robotic surgery.

Minimally invasive thoracic surgery is rapidly diffusing worldwide. Robotic anatomic pulmonary resection is gaining popularity and acceptance in the thoracic community for the reported feasibility, safety, and good outcomes. The last available robotic system, da Vinci Xi System, added new technical improvements on robotic device allowing best performances in robotic lung resection. We report our initial experience in the use of EndoWrist Stapler during robotic anatomic surgery for lung cancer.

Single-Incision Versus Three-Port Laparoscopic Appendectomy: Short- and Long-Term Outcomes.

AIM: To compare the outcome of patients who had undergone single-incision laparoscopic appendectomy (SILA) with others who had undergone three-port laparoscopic appendectomy (3-PORT). MATERIALS AND METHODS: Data from all adults with uncomplicated appendicitis treated by laparoscopic appendectomy between June 2012 and December 2015 were prospectively collected. Patients with chronic pain, appendix malignancy, at least two previous laparotomies, and those undergoing concomitant surgery for different condition were excluded from analysis. Postoperative pain was assessed by a visual analog scale (VAS). Patients were reviewed postoperatively at 7 days and 1 month in the outpatient clinic. Late complications were assessed with a telephonic interview. RESULTS: A total of 91 patients were included (46 SILA; 45 3-PORT). There were 16 males and 30 females in the SILA group (mean age = 26.76 ± 10.58 years) and 18 males and 27 females in the 3-PORT group (mean age = 26.84 ± 10.79 years). The mean operative time for SILA was 48.54 ± 12.80 min, for the 3-PORT group the mean operative time was 46.33 ± 15.54 min (P = 0.46). No case required conversion. Mean postoperative hospital length of stay was 1.87 ± 0.69 days for SILA and 2.38 ± 1.11 days for 3-PORT (P = 0.01). VAS value of 3.91 ± 1.96 and mean ketorolac usage of 0.38 ± 0.65 in 3-PORT group and SILA patients reported 3.70 ± 1.58 and 0.39 ± 0.58, respectively (P = 0.91). Our mean follow-up in SILA group was 25.75 ± 10.82 months, for 3-PORT group the mean follow-up was 26.9 ± 11.8 months. Eleven patients missed long-term follow-up. No incisional hernia was found. There is a statistically significant difference in cosmetic evaluation in favor of SILA (P < 0.005). CONCLUSIONS: There was no difference in operative time, early complications, postoperative pain, analgesia requirement between SILA and 3-PORT laparoscopic appendectomy, but after SILA procedure discharge was quicker and long-term cosmetic satisfaction was superior.

Efficacy and safety of Innoseal for air leak after pulmonary resection: a case-control study.

BACKGROUND: Prolonged air leak is one of the most common complications after lung surgery and the cause of prolonged hospital stay frequently associated with major postoperative morbidity and thus responsible for even higher hospital costs. This case-control study was designed to test the sealing efficacy and safety of Enable-Innoseal TP4 in patients undergoing pulmonary resection for lung cancer. METHODS: This was a case-control trial enrolling patients with primary or single site metastatic lung cancer scheduled for elective anatomic or nonanatomic pulmonary resection presenting intraoperative grade 1 or 2 air leak at water submersion test; the study group population was then matched 1:1 according to surgical procedure, male/female ratio, preoperative FEV1, and age. RESULTS: In the study population, 21 patients (70.0%) presented intraoperative grade 1 air leak and 9 patients grade 2 (30.0%) air leak; after comparison with the control group, we observed a significant shorter time for chest drain removal in the study population (P = 0.0050), whereas no difference was registered in terms of number of days needing for discharge (P = 0.0762). CONCLUSIONS: Enable-Innoseal TP4 was effective in treating limited intraoperative air leaks after pulmonary resection and preventing prolonged postoperative air leaks in patients receiving either anatomic or nonanatomic lung resections. Further randomized double-arm studies are required to confirm the efficacy of Enable-Innoseal TP4 demonstrated by this pilot study.