Coupling the modeling of phage-bacteria interaction and cholera epidemiological model with and without optimal control.

In this work, we assess the impact of the phage-bacteria infection and optimal control on the indirectly transmitted cholera disease. The phage-bacteria interactions are described by predator-prey system using the Smith functional response, which takes into account the number of bacteria binding sites. The study is done in two steps, namely the model without control and the model with control. For the first scenario, we explicitly compute the basic reproduction number R0 which serves as stability threshold and bifurcation parameter. The proposed model exhibits a bi-stability phenomenon via the existence of backward bifurcation, which implies that the classical requirement of bringing the reproduction number under unity, while necessary, is no longer sufficient for cholera elimination from the population. We intuitively introduce a new threshold number N0 needed for the global stability of the disease free equilibrium point which is achieved when R0⩽1 and N0⩽1. It is further shown that the phage absorption is a possible cause of bi-stability, since in its absence, the condition R0⩽1 is sufficient for cholera to die out. The existence of endemic equilibrium points depends on the range of both R0 and N0. Regarding the model extended to an optimal control problem, which involves the use of virulent vibriophages to reduce or eliminate the bacteria population, we use optimal control theory techniques. We establish the conditions under which the spread of cholera can be stopped, and examine the impact of control measures on the transmission dynamic of cholera. The Pontryagin's maximum principle is used to characterize the optimal control. Numerical simulations suggest that, the release of lytic vibriophages can significantly reduce the spread of the disease. We discuss opportunities for phage therapy as treatment of some bacterial-borne diseases without side effects.

Effects of electrochemotherapy with bleomycin on normal liver tissue in a rat model.

Preliminary studies that used electric pulses in vivo to facilitate entry of chemotherapeutic agents into tumour cells resulted in a 69% complete response rate for hepatocellular carcinoma in rats. This success motivated a focused investigation to define the adverse effects of this treatment on normal liver tissue. Bleomycin doses ranging from 0.5 to 2.5 U and electric fields from 500 to 2250 V/cm were investigated. Electrical treatment was administered using an array of six needles arranged in a circular pattern. Necrosis and four other histological parameters were examined 14 and 56 days after treatment. Results indicated that treatment effects were localised to the volume of treated tissue. These parameters, at both time points, were not significantly altered for liver tissue that was treated with all drug doses and electric fields of 1250 V/cm and below. Only the combination of more intense electric pulses with bleomycin produced adverse histological events in the form of localised liver necrosis at day 14. These effects were not visible at day 56. Liver function was normal through all of the treatment except for an elevation of several enzymes 1 day post-treatment.

Electrically mediated drug delivery for treating subcutaneous and orthotopic pancreatic adenocarcinoma in a hamster model.

BACKGROUND: Current therapies for pancreatic adenocarcinoma only benefit a fraction of those diagnosed with this disease. New strategies for improving treatment are clearly needed. This study investigated the use of electrically mediated drug delivery for the treatment of pancreatic adenocarcinoma in a hamster model. MATERIALS AND METHODS: Hamster PC-1 pancreatic adenocarcinoma cells and Golden Syrian hamsters were used as a model. RESULTS: In vitro testing indicated that bleomycin was more effective than Cisplatin and Doxorubicin when delivered using pulsed electric fields. Treatment of subcutaneous tumors with bleomycin and electric fields resulted in a 100 percent complete response rate. No effect was observed when either drug or pulses were used alone. Treatment of tumors induced in the gland resulted in a 25 percent complete response rate. CONCLUSIONS: Electrochemotherapy was highly effective for subcutaneous tumors. There was also a significant antitumor effect for the more complex and clinically relevant intraoperative treatment of tumors in the pancreas.

Electrically enhanced drug delivery for the treatment of soft tissue sarcoma.

BACKGROUND: Pulsed electric fields have been shown to increase the effectiveness of antineoplastic agents by temporarily increasing the permeability of cell membranes. This type of drug delivery is called electrochemotherapy, and it has been successful in the treatment of patients with cutaneous malignancies in clinical trials. This study focused on determining the applicability of electrochemotherapy to the treatment of soft tissue sarcoma, using an animal model bearing human sarcomas. The antitumor effects of single and multiple electrochemotherapy treatments were investigated using small (250 mm3) and large (4000 mm3) tumors. METHODS: Established tumors were injected with bleomycin, then electric pulses were administered to the tumor site. Animals were followed based on periodic tumor volume determinations, which were used to categorize treatment of each tumor as a complete response, a partial response, stable disease, or progressive disease. Histologic analysis was used to confirm response data. RESULTS: Animals were randomly assigned to one of four different treatment groups. These groups received no treatment, drug only, electric pulses only, or drug combined with electric pulses. A single electrochemotherapy treatment protocol for small tumors resulted in a 100% complete response rate and a 41.7% cure rate. Multiple treatments of small and large tumors resulted in complete response rates of 83.3% and 100%, respectively. These responses were identical to the cure rates. In contrast, tumors in the groups that received no treatment, electric pulses only, and drug only progressed for both single treatment and multiple treatment scenarios, regardless of tumor size. CONCLUSIONS: In this study, a single electrochemotherapy treatment had a strong cytoreductive effect on small tumors that lasted approximately 35 days, until recurrences began. Multiple treatment of small and large tumors resulted in high complete response rates that lasted at least 100 days after treatment. This indicates the feasibility of electrochemotherapy as a modality of limb-preserving treatment for patients with sarcoma of the extremities.

Squamous-cell carcinoma of the pelvis in a giant condyloma acuminatum: use of neoadjuvant chemoradiation and surgical resection: report of a case.

A 60-year-old bisexual male was referred to our institution for management of an unresectable squamous-cell carcinoma of the pelvis arising in a giant condyloma acuminatum. He received neoadjuvant chemoradiation consisting of 5-fluorouracil and mitomycin C with concurrent external beam radiation, followed by posterior pelvic exenteration. The surgical specimen had no residual cancer. In situ hybridization was performed using a human papilloma virus omniprobe for human papilloma virus subtypes 6, 11, 16, 18, 31, 33, and 35. Two years after diagnosis the patient is doing well with no evidence of recurrent disease.

Evaluation of an intensive strategy for follow-up and surveillance of primary breast cancer.

BACKGROUND: Controversies over the frequency and intensity of the follow-up care of breast cancer patients exist. Some physicians have adopted an intensive approach to follow-up care that consists of frequent laboratory tests and routine imaging studies, including chest radiographs, bone scans, and CT scans, whereas others have established a minimalist approach consisting of only history, physical examinations, and mammograms. OBJECTIVES: Our objective was to evaluate the role of intensive follow-up on detection of breast cancer recurrence and to examine the impact of follow-up on overall survival. METHODS: During a 10-year period (1986-1996), 129 patients with recurrent disease were identified from a prospective database of 1898 breast cancer patients. The patients with recurrent disease were divided into minimalist or intensive groups according to method of detection. RESULTS: Twenty-seven of 126 (21%) patients were assigned to the intensive method of detection group (LFT, CEA, CA 15-3, chest radiograph, CT scan, and bone scan); 99 of 126 (79%) patients were assigned to the minimal detection group (history, physical examination, and mammography). Distant disease to the bone was the most common initial tumor recurrence, at 27%. History, physical examination, and mammography detected recurrent cancer in approximately the same amount of time as LFTs, tumor markers, CT scans, and chest radiographs (P = .960). When the recurrent patients were divided into intensive and minimalist groups and analyzed by time to detection of recurrence, there was no significant difference between the time to detection in those recurrences detected by intensive methods and those recurrences detected by minimalist methods (P = .95). The independent variables age, tumor size, type of surgery, number of positive nodes, time to recurrence, method of detection, and site of recurrence (regional or distant) were subject to univariate and multivariate analysis by the Cox proportional hazards model. Only two variables had an impact on survival by multivariate analysis: early timing of the recurrence (P = .0011) and the site of the recurrence (P = .02). Timing was defined as early (< or =365 days from the time of diagnosis to recurrence) or late (> or =365 days from the time of diagnosis to recurrence). Early recurrence was the first variable found to be significant on stepwise forward regression analysis. The primary site of recurrence was significant at step two. The method of detection--intensive or minimal--did not significantly affect survival (P = .18). CONCLUSIONS: There is no survival benefit to routine intensive follow-up regimens in detecting recurrent breast cancer. Expensive diagnostic tests such as bone scans, CT scans, and serial tumor markers are best used for detection of metastasis in symptomatic patients.

CD44V6 expression in human colorectal carcinoma.

CD44 is an adhesion molecule involved in cell-to-cell and cell-to-matrix interactions. This transmembrane glycoprotein exists in either standard or variant forms, originated by alternative splicing. One of the isoforms (CD44V6) has been shown, in some systems, to modify the metastatic potential of tumor cells. To investigate the role of this biomarker as possible prognostic antigen in colorectal cancer, we immunohistochemically analyzed the distribution of CD44V6 expression on formalin-fixed, paraffin-embedded tissues from resected colorectal cancers of 34 patients. The monoclonal antibody VFF7 against the amino acid sequence encoded by exon CD44V6 was applied using the avidin-biotin-peroxidase method. For each resected specimen, normal (N), adenomatous (AD), and carcinomatous (CA) colonic mucosa were tested. In 68% of the resected cases, these areas were present in the same slide, and in 76% of cases, nodal or liver metastases (MT) were available for evaluation. Adenomatous polyp biopsy specimens of 10 carcinoma-free patients were also tested. In selected cases, CD44V6 expression was also determined using the Western blot immunoprecipitation technique. CD44V6 immunoreactivity was detected in 100% of the ADs, and in 91% of CAs, but was mostly weak in only 38% of MTs (n=26). In 49% (n=35) of ADs, 11% (n=34) of CAs, and 4% of MTs (n=26), the stain was moderate to strong. CD44V6 immunoreactivity was predominantly membranous in ADs and cytoplasmic in MTs. In the CAs, both staining patterns were noted. Interestingly, the normal mucosa had a weak subnuclear localization of the stain. In the cases evaluated by Western blotting immunoprecipitation analysis, the level of CD44V6 protein expression was similar to that obtained by immunohistochemistry. No correlation was found with tumor type, stage, or patient survival. The predominant CD44V6 expression in ADs and CAs, but not in MTs, suggests that, in many cases, the expression of this adhesion molecule may be lost during the acquisition of migratory function by the tumor cells.

Cytologic evaluation of lumpectomy margins in patients with ductal carcinoma in situ: clinical outcome.

BACKGROUND: Breast conservation therapy is controversial for ductal carcinoma in situ (DCIS) due to recently reported high recurrence rates. We believe that cytologic evaluation of lumpectomy margins improves efficiency and leads to a lower recurrence rate following lumpectomy for DCIS. METHODS: A prospectively accrued database of 1255 breast cancer patients at the H. Lee Moffitt Cancer Center and Research Institute was found to have 218 patients with DCIS (17.4%). Of those 218 cases, 114 were treated with lumpectomy, axillary dissection, and radiation therapy; the remaining 104 patients were treated with mastectomy with or without reconstruction. Imprint cytology was used to evaluate all lumpectomy margins. Permanent sections and imprint cytology were reviewed by the same pathologist. RESULTS: All lumpectomy specimens (116 tumors in 114 patients) were evaluated. The median follow up was 57.5 months (range 2-110 months). One hundred and three patients with 104 tumors were selected on the basis of pure DCIS (with or without microinvasion), and treated with lumpectomy, axillary dissection and radiation therapy. Of the 104 tumors utilizing attempted breast conservation therapy, 7 (6.6%) required mastectomy. There were 6 recurrences (6.1%) with a median time for recurrence of 47.5 months (range 27-85 months); four recurrences were comedo and two were noncomedo at original diagnosis. CONCLUSIONS: The determination of lumpectomy margins in DCIS patients using imprint cytology leads to an overall recurrence rate of 6.1% with reduction in operative time, and re-excision rate. Significant recurrence rates were associated with microinvasion and multifocal tumors (28%) versus simple DCIS at 5 years. Breast conservation therapy and surgical margin determination with imprint cytology for DCIS is a cost-effective and reliable method of treatment for simple DCIS.