Red fox optimized barrier-function super-twisting sliding mode control for targeted chemotherapy of brain tumors

Brain Tumor is an unwanted mass when cells grow abnormally. It puts pressure on certain areas of the brain which dangerously affects its functioning. For severe tumors like malignant, surgery is not a good option because they do not have definite boundaries and are closely attached with the other healthy tissues of the brain. So chemotherapy is preferable in this case to avoid damaging the healthy cells. The primary intention of this research is to suggest a controller for drug injection so that the tumor cells may reach the desired reference value of zero. In this paper, variable structure based nonlinear control algorithms: sliding mode control, integral sliding mode control, double integral sliding mode control and super-twisting sliding mode controllers have been proposed to reduce the tumor cells, maintain a safe number of healthy cells, keep the immune cells above a certain value and ensure suitable amount of chemotherapy drug. Lyapunov based stability theory has been used to prove stability of SMC, ISMC, DISMC and ST-SMC. MATLAB/Simulink environment has been used to analyze the performance of the proposed controllers on the basis of chattering, rate of convergence, undershoot/overshoot etc. and on the basis of these results drug through most suitable controller is advised. Among the proposed controllers, due to its better convergence, reduced chattering and less amount of drug used, ST-SMC is suggested for the chemotherapy of brain tumor.

Head Injuries. Tumors of the Cerebellar Region

Brain tumors are not rare. In the United States, nearly 11,000 new patients were seen in 1976. 1 This number can be expected to increase as systemic cancers are controlled more effectively and as longevity is prolonged. Most patients with primary or metastatic brain tumors are treated by surgery, glucocorticoid decompression, radiotherapy, or chemotherapy—alone or in various combinations. The therapeutic yield from surgery alone has reached its zenith. While radiotherapy prolongs survival, and radiosensitizers such as metronidazole may add to its efficacy, 2,3 it seems likely that further advances in the treatment of brain tumors will come from chemotherapy. To date, chemotherapy of brain tumors has been disappointing, to say the least. Most oncologists assume that to be useful for brain tumor chemotherapy a drug must be lipid soluble, be unionized at physiologic pH, and be of relatively small molecular size in order to enter the brain from the

Predicting response to chemotherapy in brain tumor patients based on MRI features

Black hairy tongue (BHT) developed in five patients (2.6%) among 192 patients undergoing chemotherapy for malignant brain tumors. Three patients with a history of diabetes mellitus developed BHT within 10days after the initiation of chemotherapy. The other two patients suffered more than 100days after induction and lymphopenia of grade 3 or worse developed for more than 20days, which was not observed in the three patients with diabetes. We found that BHT could develop after chemotherapy for malignant brain tumors. Patients with diabetes mellitus presented early after chemotherapy, while patients with longstanding severe lymphopenia presented in late phase.

The application of the most effective, introduced substances BCNU and CCNU in the chemotherapy of brain tumors is limited by their protracted and cumulative toxicity. Meanwhile, some new CNU derivatives have been developed which, contrary to the first generation, are not only water-soluble, but are also soluble in greasy solutions, and show lesser side effects on the bone marrow whilst having the same cytostatic effect. Up to now, the first clinical results in brain tumors have mainly been with ACNU. Depending on the dosage and interval the patients have to expect leuco- and thrombopenia, nausea appears in a much lesser degree (Saito et al. 1978). So far results of phase I and II studies have not shown any better effects compared to BCNU and CCNU but the side effects were small by a Large degree (Shibata 1982; Yumitori et al. 1984). In two trials ACNU was given intra-arterially with the idea of reducing the systemic toxicity while increasing the concentration of ACNU in the tumor itself at the same time (Jaschke 1985; Yamashita et al. 1983). HeCNU is an additional CNU derivative of the third generation. Experimental studies show so far in doses with the same toxicity more antineoplastic effectivity than BCNU. After repeated applications the longterm toxicity and carcinogenity is considerably smaller than with BCNU. A comparison of HeCNU using 100–120 mg/m2 with ACNU shows significantly smaller nausea and bone marrow toxicity for HeCNU (Eisenbrand 1984). The first clinical phase I-studies confirm the favorable preclinical results, although there have been no clinical studies on brain tumors so far.

We report the utility of a combined angiography and computed tomography (angio-CT) system in assessing drug distribution to the tumor during intra-arterial chemotherapy for metastatic brain tumors in a 65-year-old man. Although digital subtraction angiography did not clearly show tumor perfusion in two cerebellar tumors, angio-CT provided definite tumor perfusion in the complicated vascular territory, and anticancer agents were infused based on its findings. To our knowledge, however, this application for intra-arterial chemotherapy of brain tumors has not been previously described.

Controller design for nonlinear systems in its general form is complicated and an open problem. Finding a solution to this problem becomes more complicated when unwanted terms, such as disturbance, are taken into account. To provide a robust design for a subclass of nonlinear systems, sliding mode controllers (SMCs) are used. These controllers have a systematic design procedure and can reject bounded disturbances and at the same time guarantee stability. The guaranteed stability is achieved by separating system states into two parts and assuming that the input to state stability (ISS) condition holds for internal dynamics. This condition restricts the applicability of the SMC and limits the system performance when the controller is designed based on that. In order to remove this restriction and improve the performance, the ISS condition has been relaxed in this study. The relaxation is performed by redesigning SMCs based on suggested Lyapunov functions. The proposed idea insures global asymptotic stability of the closed loop system and is used to revise different well-known SMCs such as conventional SMC, terminal SMC, non-singular terminal SMC, integral SMC, super-twisting SMC, and super-twisting integral SMC. Comparisons between conventional and revised versions are made using simulation to demonstrate excellence of the revisited controllers.

There is general agreement that most chemotherapy agents achieve only relatively low concentrations in the normal central nervous system, that the blood-brain barrier is variably disrupted in malignant brain tumors, and that the concentration of chemotherapy drugs in the brain adjacent to tumor is intermediate between concentrations achieved in brain tumors vs normal brain. However, there is substantial controversy regarding the role of the blood-brain barrier in resistance to chemotherapy of intracerebral tumors. Many chemotherapy agents achieve concentrations in brain tumors that are comparable to those in extracerebral tumors, and drugs that cross the intact blood-brain barrier only poorly may be active against intracerebral tumors. Furthermore, the hypothesis that the brain is a pharmacological sanctuary where metastases may grow while tumor is responding in other parts of the body may be flawed: there are only 2 or 3 types of malignancies (out of all those that are sensitive to chemotherapy) in which the risk of isolated central nervous system relapse is moderately high, and even in these 2 or 3, effective central nervous system prophylaxis has minimal or no impact on overall survival. Furthermore, drugs that cross the BBB do not appear to be more effective than other drugs at reducing the risk of brain metastases, and brain metastases at the time of diagnosis do not necessarily convey a worse prognosis than metastases to various other sites. While average drug concentrations in brain adjacent to tumor are lower than those within brain tumors, very small numbers of tumor cells may be capable of inducing local leakiness in blood vessels, and there is little information on drug concentrations achieved in individual tumor cells within the brain adjacent to tumor. Furthermore, any limitation of uptake of drugs into brain tumors could be at least partially due to increased tissue pressure within tumors rather than being due to blood-brain barrier phenomena. This distinction could be important, since strategies that one might use to increase drug delivery to brain tumors might differ depending on whether the reduced delivery were due to barrier phenomena vs blood flow phenomena. The role of the blood-brain barrier in resistance of intracerebral tumors to chemotherapy remains unclear: while it may well play some role (and perhaps even a major one), self-fulfilling prophecies and unintentional bias in data selection and interpretation may have previously made it appear more important than it actually is.(ABSTRACT TRUNCATED AT 400 WORDS)

Chapter 6 - Chemotherapy for Brain Tumors

Chemotherapy for pediatric brain tumors

Veno-occlusive disease (VOD) of the liver is a life-threatening state generally occurring as a complication of bone marrow transplantation or chemotherapy for Wilms' tumor. Veno-occlusive disease after standard dose chemotherapy in malignancies other than Wilms' tumor is rare and only a few cases have been published in children. We report a 19 month-old-girl with medulloblastoma who experienced fatal VOD of liver after only one course of chemotherapy including carboplatin, vincristine and CCNU for medulloblastoma. As our knowledge, this is the first report of VOD after standard dose chemotherapy for brain tumor in childhood.

Because of their large size and high vascularity, complete removal of brain tumors in infants and young children is often difficult. In most cases the degree of resection is associated with prognosis. Neoadjuvant chemotherapy may facilitate resection by reducing the vascularity of the tumor. The authors evaluated the effectiveness of neoadjuvant chemotherapy in the management of these tumors. The authors performed a retrospective review of infants and young children who underwent tumor removal after neoadjuvant chemotherapy. Nine consecutive patients underwent resection after neoadjuvant chemotherapy during the period February 2004 to December 2012. The mean age at diagnosis was 18 months (range 2-50 months). The average largest tumor diameter was 71 mm (range 30-130 mm) at initial surgery. Five patients underwent partial resection, and 4 underwent biopsy as the initial surgery. The histopathological diagnoses were ependymoma in 2 patients, anaplastic ependymoma in 1, primitive neuroectodermal tumor (PNET) in 2, choroid plexus carcinoma in 1, atypical teratoid/rhabdoid tumor (AT/RT) in 1, glioblastoma in 1, and embryonal tumor with abundant neuropil and true rosettes in 1. After 2-4 courses of multiagent chemotherapy (mainly with vincristine, cyclophosphamide, etoposide, and cisplatin), the second-look surgery was performed. In 1 patient with a PNET, intratumoral hemorrhage was observed after 2 courses of chemotherapy. The mean interval between the initial and the second-look surgery was 3 months. The tumor volume was reduced to varying degrees in 5 patients (56%) after chemotherapy. Intraoperatively, the vascularity of the tumor was considerably reduced, and the tumor was more circumscribed in all cases. Gross-total resection was achieved in 8 patients (89%) and neartotal resection in 1 (11%). Histopathological examination demonstrated fibrotic tissue circumscribing the tumor in 6 of 9 cases (67%). The average blood loss was 20% of the estimated blood volume, and 3 patients (33%) required a blood transfusion. There was no surgical mortality. One patient had transient dysphasia postoperatively. The mean follow-up period was 28 months. At the last follow-up, 2 patients (22%) had died (1 died of tumor progression and 1 of sepsis), and 4 patients (44%) had no tumor recurrence. Neoadjuvant chemotherapy for brain tumors in infants and young children was effective in reduction of tumor vascularity and clarification of the tumor-brain interface, which significantly facilitated maximal tumor resection.

Brain tumors require multimodal therapies such as surgery, radiation treatment, and chemotherapy. There must be individual-level predictors that will influence treatment assignment patterns in the synthetic dataset to make precision medicine for neuro-oncology possible. The objective of this study is to demonstrate an interpretable machine learning (ML) approach for comparing predictors of surgery, radiation therapy, and chemotherapy in brain tumors using a synthetic dataset, with an emphasis on model comparison and SHapley Additive exPlanations (SHAP)-based explainability rather than clinical inference. The Kaggle dataset used in this study is fully synthetic and intended for methodological and educational research. Kaggle's 20,000 brain tumor patient data set was downloaded. Sixteen significant features were preprocessed and used for training nine supervised classifiers. The best performance was found using Gradient Boosting, and it was selected for SHAP analysis. SHAP beeswarm and waterfall plots were employed to interpret both global and local feature contributions. The Gradient Boosting model performed superior to all three tasks of treatment prediction—surgery, radiation therapy, and chemotherapy—when compared with five key classification metrics. SHAP analysis identified Tumor_Size, Tumor_Growth_Rate, and Age as the strongest predictors for treatments. For surgery, SHAP waterfall plots indicated that Tumor_Growth_Rate = − 1.694 had the highest negative impact (− 0.15), while Age = 0.612 and Symptom_2 = − 1.347 had positive impacts (+ 0.02 each). For radiation treatment, Location = 1.324 reduced treatment probability (− 0.05), while Tumor_Size had positive impact (+ 0.03) but Tumor_Growth_Rate = − 1.694 had a negative impact (− 0.03). Age = 0.612 was the most significant negative impact (− 0.04) in chemotherapy, with Tumor_Size = − 0.381 (− 0.03) and Family_History = − 1 following closely behind. Tumor_Growth_Rate contributed a small level of enhanced prediction (+ 0.01). These findings demonstrate the feasibility of using interpretable machine learning methods to explore treatment-related patterns in healthcare-like data and provide a foundation for future validation using real-world clinical datasets.

A combination of three chemotherapeutically active substances, i.e., adriamycin, epipodophyllotoxine, and lomustine, has been found to be active in malignant brain tumors by Pouillard et al. (1). Epipodophyllotoxine as a single agent was equally effective in a series of human brain tumors, although this substance does not cross the blood-brain barrier to a significant extent. On the other hand, good results have been described with the nitrosourea derivatives lomustine and carmustine both in human and in experimental brain tumors.