Nonlinear optimal control for the multi-variable tumor-growth dynamics.

The multivariable tumor-growth dynamic model has been widely used to describe the inhibition of tumor-cells proliferation under the simultaneous infusion of multiple chemotherapeutic drugs. In this article, a nonlinear optimal (H-infinity) control method is developed for the multi-variable tumor-growth model. First, differential flatness properties are proven for the associated state-space description. Next, the state-space description undergoes approximate linearization with the use of first-order Taylor series expansion and through the computation of the associated Jacobian matrices. The linearization process takes place at each sampling instant around a time-varying operating point which is defined by the present value of the system's state vector and by the last sampled value of the control inputs vector. For the approximately linearized model of the system a stabilizing H-infinity feedback controller is designed. To compute the controller's gains an algebraic Riccati equation has to be repetitively solved at each time-step of the control algorithm. The global stability properties of the control scheme are proven through Lyapunov analysis. Finally, the performance of the nonlinear optimal control method is compared against a flatness-based control approach.

Nonlinear optimal control for the synchronization of biological neurons under time-delays.

The article proposes a nonlinear optimal control method for synchronization of neurons that exhibit nonlinear dynamics and are subject to time-delays. The model of the Hindmarsh-Rose (HR) neurons is used as a case study. The dynamic model of the coupled HR neurons undergoes approximate linearization around a temporary operating point which is recomputed at each iteration of the control method. The linearization procedure relies on Taylor series expansion of the model and on computation of the associated Jacobian matrices. For the approximately linearized model of the coupled HR neurons an H-infinity controller is designed. For the selection of the controller's feedback gain an algebraic Riccati equation is repetitively solved at each time-step of the control algorithm. The stability properties of the control loop are proven through Lyapunov analysis. First, it is shown that the H-infinity tracking performance criterion is satisfied. Moreover, it is proven that the control loop is globally asymptotically stable.

Detection of parametric changes in the Peyrard-Bishop- Dauxois model of DNA using nonlinear Kalman filtering.

The derivative-free nonlinear Kalman filter is proposed for state estimation and fault diagnosis in distributed parameter systems of the wave-type and particularly in the Peyrard-Bishop-Dauxois model of DNA dynamics. At a first stage, a nonlinear filtering approach is introduced for estimating the dynamics of the Peyrard-Bishop-Dauxois 1D nonlinear wave equation, through the processing of a small number of measurements. It is shown that the numerical solution of the associated partial differential equation results in a set of nonlinear ordinary differential equations. With the application of a diffeomorphism that is based on differential flatness theory it is shown that an equivalent description of the system is obtained in the linear canonical (Brunovsky) form. This transformation enables to obtain local estimates about the state vector of the DNA model through the application us of the standard Kalman filter recursion. At a second stage, the local statistical approach to fault diagnosis is used to perform fault diagnosis for this distributed parameter system by processing with statistical tools the differences (residuals) between the output of the Kalman filter and the measurements obtained from the distributed parameter system. Optimal selection of the fault threshold is succeeded by using the local statistical approach to fault diagnosis. The efficiency of the proposed filtering approach in the problem of fault diagnosis for parametric change detection, in nonlinear wave-type models of DNA dynamics, is confirmed through simulation experiments.

Sarcomatoid differentiation of renal cell carcinoma: a clinical case with literature review.

A small percentage (1-10%) of renal cell carcinomas (RCC) belongs to the sarcomatoid variant. These malignancies are aggressive with worse prognosis and unfortunately the results following immuno- and/or chemotherapy administration are discouraging. A 62-year-old Caucasian male with advanced renal cell cancer and sarcomatoid component treated with sunitinib is presented. Better understanding of prognostic and molecular markers might help the selection of patients with a chance of benefiting from administration of new targeted drugs.

Low-dose capecitabine in breast cancer patients with symptomatic bone marrow infiltration: a case study.

BACKGROUND: The prognosis of patients with metastatic breast cancer and symptomatic bone marrow involvement is poor. The aim of treatment to these patients is palliation. In this study, we sought to determine the efficacy of therapy with low doses of capecitabine in this subgroup of patients. PATIENTS AND METHODS: Five consecutive breast cancer patients with overt bone marrow involvement were treated by low doses of capecitabine in our department. Four out of five patients also received bisphosphonates to palliate skeletal symptoms. The influence of this therapeutic regimen on tumor response, blood count normalization and overall survival was analysed. RESULTS: All patients except one responded in terms of their haematological profile within two months of the initiation of treatment. Duration of haematological response was 8+ months for all patients. In two of them, tumor response in other sites was evaluated as stable disease, in one as partial remission and in one as progressive disease. Two patients survived more than 22 months without bone marrow failure. CONCLUSION: These initial results are very encouraging for this subset of patients with poor prognosis and limited life expectancy. The administration of capecitabine might be an efficient alternative treatment option. Our results merit further investigation.

Urachal mucinous adenocarcinoma: a case report.

Adenocarcinomas account for 0.5-2% of all bladder cancers. Urachal carcinoma is a rare neoplasm which represents 0.01% of all cancers in adults and account for one third of bladder adenocarcinomas. A 65-year-old white man with an urachal mucinous adenocarcinoma is reported. None of the known predisposing risk factors for bladder cancer -such as tobacco use and professional exposure to chemicals -were identified in his past medical history. The patient suffered from multiple sclerosis for almost 11 years and in the last 6 years he was treated with low doses of mitoxantrone. He underwent a partial cystectomy and en block excision of the umbilical ligament and remains disease-free after one year. The development of this rare neoplasm should not be clearly dissociated from multiple sclerosis, either aetiologically sharing an unidentified common causative factor or due to its treatment with mitoxantrone.

Quality of life in metastatic breast cancer patients under chemotherapy or supportive care: a single-institution comparative study.

The aim of the present study was to evaluate quality of life (QoL) parameters in patients with metastatic breast cancer (MBC) and assess the potential differences between patients receiving chemotherapy and those undergoing supportive care interventions. In total, 210 women with MBC were enrolled in this prospective, randomized, single-institution study. The primary outcome of the trial was QoL assessment, using the self-administered European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30, version 3) and Quality of Life Questionnaire Breast 23 (QLQ-BR23) questionnaires. Quality of life was found to be statistically better (P = 0.008) in MBC patients receiving chemotherapy than those under only supportive care. Statistically significant differences in favour of chemotherapy were also found in functioning subscales, symptom single-item questions and sexual functioning. Our findings suggest that chemotherapy in MBC patients with good performance status is the more rational therapeutic approach in terms of QoL improvement.

Gemcitabine and oral vinorelbine as salvage treatment in patients with advanced anthracycline- and taxane-pretreated breast cancer.

BACKGROUND: Despite progress achieved with new chemotherapeutic and endocrine agents, advanced breast cancer (ABC) remains a disease with poor prognosis. We sought to determine the efficacy of gemcitabine (GC) and oral vinorelbine (VB) in heavily preatreated ABC. PATIENTS AND METHODS: Patients previously treated with anthracyclines and taxanes in the metastatic setting with progressive disease were eligible. Treatment consisted of VB (60 mg/m2, orally) and GC (1000 mg/m2, intravenous infusion), every two weeks of a 28- day cycle. RESULTS: Thirty-one patients with ABC were enrolled. Toxicity was acceptable, mainly haematological. Three and 8 patients achieved a complete (9.6%) and partial (25.8%) response, respectively; ten patients (32.2%) had stable disease. Median time-to-progression was 5.3 months, while in responders 8.6 months. Median overall survival was 14 months. CONCLUSION: Oral VB and GC is an active and well-tolerated combination in anthracycline/taxane-pretreated ABC, representing an interesting option in this poor prognosis group of patients.

First-line chemotherapy with fluorouracil-epirubicin-navelbine (FEN) combination in advanced breast cancer.

BACKGROUND: A phase II study was carried out to determine the safety and efficacy of the combination of vinorelbine, epirubicin and 5-fluorouracil (FEN) as first-line chemotherapy in advanced breast cancer (BC). PATIENTS AND METHODS: Thirty-four women with advanced BC, aged 32-75 years (median 59), previously untreated for recurrence, were enrolled in the study. The treatment consisted of fluorouracil 600 mg/m2 on day 1, epirubicin 75 mg/m2 on day 1 and vinorelbine 25 mg/m2 on days 1 and 8, every 3 weeks, up to a maximum of 9 cycles. RESULTS: The efficacy appeared favourable with 18 objective responses (3 complete and 15 partial) and 9 disease stabilizations, giving an overall response rate of 53% (95% CI: 36-70). The median progression-free and overall survival was 6 and 18 months, respectively (95% CI: 4.8-7.8 and 16.2-22.2, respectively). Toxicity was acceptable; the main grade 3/4 toxicity was alopecia in 94% of patients, neutropenia in 44% and less frequently gastrointestinal toxicity (9%), anaemia (6%), mucositis (6%), thrombocytopenia (3%) and diarrhoea (3%). No treatment-related death occurred, CONCLUSION: Our results suggest that FEN, as first-line chemotherapy, is an active and well-tolerated treatment for patients with advanced breast cancer.

Multiple cutaneous acral metastases in a woman with breast adenocarcinoma treated with pegylated liposomal doxorubicin: incidental or aetiological association?

This paper reports the case of a 45-year-old female with histologically documented, multiple cutaneous metastases in the palmar and plantar surface of the fingers and toes originating from a breast adenocarcinoma after treatment with a docetaxel and pegylated liposomal doxorubicin regimen. The rarity of such a metastatic pattern from breast cancer and the eventual association with the chemotherapy administered are thoroughly discussed.

Gemcitabine and docetaxel as first-line treatment for advanced urothelial carcinoma: a phase II study.

The purpose of the study was to investigate the toxicity and efficacy of the combination of gemcitabine and docetaxel in untreated advanced urothelial carcinoma. Patients with previously untreated, locally advanced/recurrent or metastatic urothelial carcinoma stage-IV disease were eligible. Patients with Performance status: PS ECOG >3 or age >75 years or creatinine clearance <50 ml min(-1) were excluded. Study treatment consisted of docetaxel 75 mg m(-2) (day 8) and gemcitabine 1000 mg m(-2) (days 1+8), every 21 days for a total of six to nine cycles. A total of 31 patients with urothelial bladder cancer, 25 men and six women, aged 42-74 (median 64) years were enrolled. The majority of patients had a good PS (51.6%; PS 0). In all, 15 (48.3%) patients had locally advanced or recurrent disease only and 16 (54.8%) presented with distant metastatic spread, with multiple site involvement in 22.5%. Toxicity was primarily haematologic, and the most frequent grade 3-4 toxicities were anaemia 11 (6.7%) thrombocytopenia eight (4.9%), and neutropenia 45 (27.6%), with 10 (6.1%) episodes of febrile neutropenia. No toxic deaths occurred. A number of patients had some cardiovascular morbidity (38.7%). Nonhaematological toxicities except alopecia (29 patients) were mild. Overall response rate was 51.6%, including four complete responses (12.9%) and 12 partial responses (38.7%), while a further five patients had disease stabilisation (s.d. 16.1%). The median time to progression was 8 months (95% CI 5.1-9.2 months) and the median overall survival was 15 months (95% CI 11.2-18.5 months), with 1-year survival rate of 60%. In conclusion, this schedule of gemcitabine and docetaxel is very active and well tolerated as a first-line treatment for advanced/relapsing or metastatic urothelial carcinoma. Although its relative efficacy and tolerance as compared to classic MVAC should be assessed in a phase III setting, the favourable toxicity profile of this regimen may offer an interesting alternative, particularly in patients with compromised renal function or cardiovascular disease.

Simultaneous endometrioid ovarian and uterine carcinoma diagnosed after an in vitro fertilization procedure--case report and review of the literature.

BACKGROUND: The presence of simultaneous carcinomas involving both the ovary and uterus is relatively uncommon, while the possible link between fertility drugs and carcinogenesis still remains controversial. CASE: The case of a 40-year-old patient with simultaneous aggressive endometrioid carcinoma of the ovary and uterus a few months after the sixth attempt of in vitro fertilization is presented. The patient had de novo lung disease at surgery and diffuse metastatic spread to adjacent bone, subcutaneous tissue and the central nervous system (CNS) soon after a spectacular response to the primary paclitaxel/carboplatinum chemotherapy and while on maintenance and second-line chemotherapy, respectively. CONCLUSION: The fulminating course of our patient might in part be attributed to the existence of advanced disease at presentation. Definite conclusions about the possible association with the previously performed assisted reproduction cannot be drawn but close clinical surveillance of such patients before, during and after infertility treatment is strongly warranted.

Non-allergic nature of docetaxel-induced acute hypersensitivity reactions.

Based on observations of a discrepancy between 'hypersensitivity' reactions to docetaxel (DT) and the clinical features of allergic reactions, we explored the hypothesis that DT-induced acute hypersensitivity reactions (AHRs) have a non-allergic origin. Forty cancer patients receiving DT and 16 patients receiving other potentially allergenic chemotherapeutic agents were included in the study. All DT patients received standard pre- and post-medication. Before, during and after administration of the drugs, clinical symptoms and signs were recorded, and serial blood sampling was performed for the first 2 cycles for all patients or in all subsequent cycles in case of AHRs. Plasma histamine and serum tryptase, two established drug allergy markers, were measured. Seventy-five chemotherapy sessions were evaluable. Nine patients on DT, two on paclitaxel (PT) and one on pegylated doxorubicin experienced an AHR during the first course of chemotherapy. In all cases, heart rate remained stable or increased, while arterial pressure was unchanged or raised; no hypotension or bradycardia was noted. All episodes resolved with discontinuation of drug and did not reappear during a re-challenge with the same agent 30 min later. Tryptase levels were normal in all pre- and post-exposure samples (post-exposure: 11.32+/-35.63 microg/l, normal values <13.5 microg/l). In all but one AHR-free PT, pre- and post-exposure histamine concentrations remained normal (post-exposure: 2.86+/-11.88 nM, normal values <10 nM). No eosinophilia or basophilia was observed. We conclude that 'hypersensitivity' reactions to DT seem not to be histamine or tryptase mediated; thus, their allergenic nature should be questioned. The underlying mechanism may be related to other biological processes such as the release of vasoactive molecules or non-histamine/tryptase-mediated allergy. If the former is demonstrated by further study, the safety of DT administration will be confirmed, and the pre- and post-medication practice might be revisited.

In vivo synergism between docetaxel and gemcitabine in patients with metastatic breast cancer: general concepts and future perspectives.

The docetaxel and gemcitabine combination is an active regimen as salvage therapy in taxane-resistant or taxane-refractory patients with metastatic breast cancer (MBC). We recently conducted a phase II study administering this combination to patients with MBC after docetaxel failure, with remarkably high response rates that could be attributed to an in vivo synergism between the two drugs. Women with MBC who were refractory or resistant to docetaxel monotherapy as first- or second-line treatment were recruited. Patients with progressive or stable disease after receiving a minimum of four cycles of docetaxel received gemcitabine 900 mg/m(2) on days 1 and 8 plus docetaxel 100 mg/m(2)on day 8, every 3 weeks. Forty-six percent of patients responded (three complete responses, 20 partial responses), while 28% had stable disease and 26% had progressive disease. Median duration of response was 6.07 +/- 2.43 months. Neutropenia was the only grade 4 toxicity, and reported in seven patients. Other grade 3 toxicities included neutropenia (12 patients), thrombocytopenia (seven patients), and anemia (one patient), while nonhematologic toxicities were easily manageable. These data outline the importance of a rational combination of existing, active chemotherapeutic agents for MBC, and broadens our perspectives for more effective combination regimens in various solid tumors in the future.

Phase II study of pegylated liposomal doxorubicin (Caelyx) and docetaxel as first-line treatment in metastatic breast cancer.

BACKGROUND: The aim of this study was to determine the activity and safety of pegylated liposomal doxorubicin (PLD; Caelyx) and docetaxel combination as first-line treatment in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-four patients with a median age of 63 years were treated with PLD 30 mg/m(2) (day 1) and docetaxel 75 mg/m(2) (day 2) every 3 weeks for six cycles. Recombinant human Granulocyte Colony-Stimulating Factor (rhG-CSF) could be used in patients with grade > or =3 neutropenia after the first cycle. RESULTS: Forty-two of 44 patients were assessable for response. The response rate (RR) was 64.3% (95% confidence interval 49.8% to 78.8%). Six patients (14.3%) achieved complete response (complete disappearance of all measurable and assessable disease lasting at least 4 weeks, no new lesions, no disease-related symptoms), partial response was observed in 21 patients (50%) > or =50% decrease of measureable disease lasting at least 4 weeks, no progression of assessable disease, no new lesions, no disease-related symptoms), eight patients had stable disease and seven patients progressive disease. Median disease-free and overall survival were not reached, but were in excess of 17 months (range 6-17 months). Twenty of the patients had received previous adjuvant chemotherapy (10 with epirubicin-containing regimen with a median cumulative dose of 400 mg/m(2)). Grade > or =3 neutropenia occurred in 18.4% and neutropenic fever in 9% of patients. Palmar-plantar erythrodysesthesia was observed in four patients. Dose reduction was necessary in seven patients. Two patients discontinued treatment: one due to prolonged grade 3-4 neutropenia and one due to neurotoxicity. No treatment-related deaths occurred. CONCLUSIONS: The combination of PLD and docetaxel achieved high RRs with acceptable toxicity as first-line treatment in MBC.

Evidence for in vivo synergism between docetaxel and gemcitabine in patients with metastatic breast cancer.

BACKGROUND: The docetaxel and gemcitabine combination is active as salvage therapy in taxane-resistant/refractory patients with metastatic breast cancer (MBC). We conducted a phase II study to determine if this activity is due to an in vivo synergistic effect. PATIENTS AND METHODS: Women with measurable MBC, who were refractory or resistant to docetaxel monotherapy as first- or second-line treatment, were enrolled. Patients with progressive disease (PD) or stable disease (SD) after receiving at least four cycles of docetaxel received gemcitabine 900 mg/m(2) on days 1 and 8 plus docetaxel 100 mg/m(2 )on day 8, every 3 weeks. Granulocyte colony-stimulating factor could be used prophylactically in patients who experienced grade 3/4 neutropenia after the first cycle. RESULTS: Between January 1999 and March 2002, 173 courses of docetaxel and gemcitabine were administered to 50 patients. The median number of metastatic sites was two (range one to three). Forty-six percent of patients responded (three complete responses, 20 partial responses), whereas 28% had SD and 26% had PD. The median duration of response was 6.1 +/- 2.4 months. The median time to disease progression was 7.5 months (range 1-25) and the overall median survival was 15 months (range 3-57). Neutropenia was the only National Cancer Institute Common Toxicity Criteria grade 4 toxicity (in seven patients). Hematological grade 3 toxicities included neutropenia in 12 patients, thrombocytopenia in seven and anemia in one, while non-hematological toxicities were mild and manageable. CONCLUSIONS: The high overall response rate of the docetaxel plus gemcitabine combination after docetaxel failure in patients with MBC can be attributed to an in vivo synergism between the two drugs. These data warrant confirmation in a randomized study.

Fuzzy reinforcement learning control for compliance tasks of robotic manipulators.

A fuzzy reinforcement learning (FRL) scheme which is based on the principles of sliding-mode control and fuzzy logic is proposed. The FRL uses only immediate reward. Sufficient conditions for the convergence of the FRL to the optimal task performance are studied. The validity of the method is tested through simulation examples of a robot which deburrs a metal surface.