Role Of Chemotherapeutic Agents Research Articles

Drug delivery in transarterial chemoembolization of hepatocellular carcinoma: Ex vivo evaluation using transparent tissue imaging

In this study, we elucidated for the first time the role of anti-cancer drugs in transarterial chemoembolization (TACE) via direct visualization of the spatial distribution of drugs with respect to blood vessels in intact transparent hepatocellular carcinoma (HCC) tissues. To date, precise estimation of drug penetration into tumors using thin 3D tissue sections has been challenging. This study utilized the tissue optical clearing technique to resolve the lack of tissue clarity, thereby enabling deep tissue imaging for the quantitative assessment of drug delivery following TACE. We compared the drug delivery effect, time-dependent embolic effect, and immunogenic response following conventional TACE (cTACE), drug-eluting embolic TACE (DEE-TACE), and transarterial embolization (TAE) in a rat model of HCC. After each treatment, three-dimensional drug delivery was quantitatively evaluated via the transparent liver tumor imaging, and time-dependent tumor necrosis was analyzed by serial tumor harvesting and histological staining. The results showed that chemotherapeutic agents travel only short distances after cTACE (∼80µm) and DEE-TACE (∼110µm), whereas necrosis occurs extensively within 24 h of treatment (85.3–97.2% of tumor cells). In addition, the percentages of CD4 and IL-17+ CD4 T cells increased significantly following treatment; however, drug-loading did not appear to affect the immune response following TACE. In conclusion, transarterially delivered chemotherapeutic agents appeared to exert a limited role, owing to the rapid and overwhelming effect of embolization. Statement of significanceTACE has been widely used for the treatment of HCC, especially for unresectable intermediate and advanced HCCs. Drug use in TACE is expected to provide patients with synergistic therapeutic benefits with the effect of embolic agents; however, the role of chemotherapeutic agents in TACE remains controversial. This study quantitatively verified that chemotherapeutic agents travel only short distances after TACE, while necrosis occurs extensively within 24h, and drug loading does not significantly affect immune responses following TACE. Three-dimensional imaging of intact transparent HCC can contribute to a better understanding of drug delivery mechanisms associated with TACE and also reveal that drug use in TACE may need to be reconsidered and limited to situations when embolization is expected to be insufficient.

Optimized Gemcitabine Therapy in Combination with E7 Peptide Immunization Elicits Tumor Cure by Preventing Ag-Specific CTL Inhibition in Animals with Large Established Tumors.

The role of chemotherapeutic agents in tumor immunotherapy is still controversial. In this study, we test using a TC-1 tumor model whether gemcitabine plus E7 peptide vaccine regimens (E7 peptides+CpG-ODN+anti-4-1BB Abs) may result in tumor cure in mice with large established tumors, with a focus on their effects on Ag-specific cytotoxic T lymphocyte (CTL) and myeloid-derived suppressor cell levels. Gemcitabine inhibited tumor growth by its direct cytotoxicity to tumor cells in vivo. E7 peptide vaccine regimens enhanced Ag-specific CTL lytic and antitumor therapeutic activity. Initial combination therapy using gemcitabine and E7 peptide vaccine regimens resulted in tumor regression with tumor relapse in animals with large established tumors, which appeared to result from the suppression of Ag-specific CTL activity by gemcitabine treatment. However, optimization of gemcitabine therapy by reducing its dose and frequency led to complete tumor regression without any recurring tumors in all tested mice even after discontinuation of therapy, possibly due to Ag-specific CTL responses. Thus, this study shows that the optimal dose and therapy frequency of gemcitabine are critical for achieving tumor cure in tumor-bearing animals undergoing E7 peptide vaccine regimen therapy, mainly by preventing CTL suppression. These findings may have implications for designing peptide-based therapeutic vaccines in cancer patients undergoing chemotherapy.

Role of chemotherapeutic agents in the management of cystic echinococcosis.

Hydatid disease is caused by infection with the metacestode stage of Echinococcus tapeworms of the family Taeniidae. The primary carriers are dogs and wolves, and humans are accidental hosts that do not contribute to the normal life cycle of this organism. The liver is the most commonly involved organ in the body by cystic echinococcosis (CE) secondary to infection with Echinococcus granulosus . Management options for CE should depend on the World Health Organization (WHO) diagnostic classification. Small (<5 cm) WHO stage CE1 and CE3a cysts may be primarily treated with benzimidazoles; the first-choice drug is albendazole. In some situations the combination of albendazole and praziquantel may be preferred. Chemotherapy with a benzimidazole or albendazole plus praziquantel is also used as adjunctive treatment to surgery and percutaneous treatment. Drug treatments have been the indispensable therapeutic modalities for cystic echinococcosis.

Intraoperative hyperthermic chemotherapy perfusion for malignant pleural mesothelioma: An in vitro evaluation

Hyperthermic chemotherapy perfusion has been used in the treatment of both pleural and peritoneal mesothelioma without an extensive basic science foundation. Clinical data are limited with no prospective randomized trials to support the use of this potentially toxic therapy. We sought to generate basic scientific support for this clinical practice and to define the optimal conditions for use in future clinical trials. Growth of a variety of in vitro established cell lines, including a hyperthermia-sensitive Chinese hamster ovary (CHO)-K1 cell line, a normal lung fibroblast line (MRC-5), a lung cancer line (A549), and 3 human mesothelioma cell lines (NCI-H28, NCI-H2052, and MSTO-211H), was assessed using a novel tetrazolium compound (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt [MTS]) and an electron coupling reagent (phenazine methosulfate), which measures the absorbance at 490 nm of a formazan product reduced from MTS by living cells (MTS metabolic assay), or a standard dilution clonogenic assay, which enumerates colony-forming units of more than 50 cells. Each cell line was plated into flasks and then exposed to varying combinations of chemotherapy agents and hyperthermia (37°C-45°C). The cells then were harvested and assessed in either assay. The role of chemotherapeutic agents currently most commonly used in clinical practice, including cisplatin, gemcitabine, and pemetrexed, was assessed with and without simultaneous heat exposure. Conditions initially were explored using hyperthermia alone in CHO-K1, A549, and NCI-H28 cell lines using temperatures of 37°C, 42°C, and 45°C for 20, 40, and 60 minutes, respectively. This showed a reproducible dose-response curve in CHO-K1 cells with increasing temperature producing lower survival to only 1.5% of the control at 45°C for 60 minutes (P < .01). The A549 cells also showed a response but only at the highest temperature, and the NCI-H28 cells showed a more modest reduction to 65% at 45°C for 60 minutes (P < .01). When the 2 assays were directly compared, the MTS assay failed to detect differences between groups and therefore was discontinued from the remainder of these experiments. Next, hyperthermia was limited to the physiologic limit of 42°C, and the addition of chemotherapy was assessed. Doses were chosen on the basis of prior pharmacokinetic data from studies showing a maximum tissue/blood level of 200 ng/mL for cisplatin pleural instillation and were thought to more accurately reflect actual tumor levels. Cisplatin alone modestly reduced the clonogenic potential to 26%, 16.4%, and 13.6% at 42°C, respectively, for 60 minutes (P < .01); however, this was only a further reduction of 29.6%, 33.8%, and 34.2%, respectively, from the cisplatin alone control. Therefore, most of the reduction was attributable to chemotherapy and not hyperthermia. With combinations of cisplatin/gemcitabine and cisplatin/pemetrexed, the effect was larger, with reduction to 9.6%, 0%, and 0%, respectively (P < .01) (incremental reduction of 16.5%, 0%, and 0%, respectively, due to hyperthermia). Cisplatin/pemetrexed produced essentially identical results. Intrapleural chemotherapy seems to be most effective when using 2 drug combinations. All mesothelioma cell lines showed no particular sensitivity to heat. The use of hyperthermia alone or with chemotherapy produces at best only a modest effect and does not necessarily support its current clinical use.

Systematic Review of CNS Metastasis in Patients with Breast Cancer (P07.113)

Objective: To review the existing literature on the issue of brain metastasis in relationship to the breast cancer and the factors are relevant to the higher incidence of brain metastasis and patients survival. Background Brain metastases are the most common intracranial tumors in adults, accounting for more than one-half of brain tumors. Breast cancer is the 2 nd most common cause of brain metastases. Progressive neurologic disability often results and the prognosis is generally poor. Design/Methods: We did a systematic research using the pubmed and Yale library search engine including all relevant articles in the past 20 years (refined MRI and modern treatment became available). A total of 38 papers fulfilled the above criteria and furnished the optimum information. Results: Many factors correlated with higher incidence of brain metastasis like younger age, ethnicity, and size of the primary tumor ( 2cm: 70-80%). Multiple brain lesions is common than solitary brain lesions. Incidence rate of BCBM increased from 15% to 80% over the span of 5 years. Brain was the first site of metastasis in 13%- 45% (mean 30%).The most common site of metastasis was cerebral grey and white matter and cerebellum. The most common symptoms were headache (15-58%), motor weakness (13-38%) and seizures (5-23%). Triple negative BC was associated with the worst prognosis while the HER2+/HR+, HER2+/HR-, HER2-/HR+ showed inconsistent results. Whole brain radiation therapy, neurosurgery, stereotactic radio surgery and medical therapy have a role in the management with promising role of chemotherapeutic agents in the recent literature. The median survival for patients with metastatic breast cancer is 18 to 24 months, although the range extends from only a few months to many years. Conclusions: Brain metastasis remains a major complication of breast cancer and indicates an unfavorable prognosis. Biomarkers play a key role in the treatment and survival outcome. Disclosure: Dr. Azadi has nothing to disclose. Dr. Mittal has nothing to disclose. Dr. Tavassoli has nothing to disclose. Dr. Jabbari has nothing to disclose.

Minocycline containing local drug delivery system in the management of chronic periodontitis: A randomized controlled trial

Background:The role of chemotherapeutic agents in periodontal therapy as adjuncts to mechanical debridement maybe justified by the inherent limitations of mechanical therapy. The aim of this study was to evaluate the long term efficacy of a locally delivered 2% minocycline gel as an adjunct to scaling and root planing in managing chronic periodontitis.Materials and Methods:This was a randomized controlled trial using a split-mouth study design. Twenty two pairs of sites with similar probing depths were randomly allocated to test and control groups. All sites received thorough scaling and root planing followed by minocycline gel application in the test sites. Probing depths, relative attachment levels, plaque index, and microbiological parameters were evaluated for both the groups over a 9-month period.Results:Overall parameters improved from baseline in both the test and control groups. For most parameters, the differences between test and control groups were not significant at different time intervals. The probing depth values in the test group at six (3.64±0.83 mm) and nine months (3.81±0.79 mm) were significantly less than control group(4.24±0.95 mm at six and 4.63±0.94 mm at nine months), these differences being significant at P<0.05 and <0.01, respectively. At the end of nine months, the number of non-motile bacilli in test group (21.65±3.74) were significantly less than control group (25.5±3.01), the difference being significant at P<0.02.Conclusion:The overall view of results in our investigation did not show any significant advantage of using 2% minocycline gel over scaling and root planning as an effective local drug delivery system and calls for further clinical trials to objectively evaluate its adjunctive in treatment of periodontitis.

Management of colorectal cancer in elderly patients: focus on the cost of chemotherapy.

The treatment of colorectal cancer has evolved dramatically over the last 15 years. Advances in surgery, radiotherapy and chemotherapy have enabled oncologists to cure more patients and offer improved quality of life to patients not amenable to cure. Specific knowledge of colorectal cancer care of the elderly, while lagging behind the treatment of younger patients, is beginning to emerge. Informed by recent trials, the approach towards elderly patients is shifting towards more aggressive treatment and multimodal therapy. Surgeons are operating on the elderly with greater frequency, less operative mortality and greater success; 5-year survival following potentially curative surgery has risen from 50% to 67%.Research of adjunctive therapy for colorectal cancer is enrolling more elderly patients, and with this has come an understanding of the role of chemotherapeutic agents in the treatment of the elderly, used individually and within multi-drug regimens. This research offers insight into how the elderly respond to chemotherapy, informing clinicians on anticipated benefits and toxicities of treatment. Fluorouracil-based regimens, which have long been the standard adjuvant chemotherapy, have been shown to offer benefits to the elderly compared with those not receiving adjuvant chemotherapy (71% versus 64% 5-year survival), and to cause similar toxicities as seen in younger patients. The role of novel chemotherapeutic agents in the treatment of elderly patients with colorectal cancer is also emerging, with studies finding that irinotecan, in combination with a fluorouracil-based regimen, can offer a further survival benefit of over 2 months compared with fluorouracil alone. While newer agents such as capecitabine, oxaliplatin, raltitrexed and tegafur/uracil (UFT) have been focused upon by clinical researchers, data on their use in the elderly remain unconvincing. Not only are we approaching a clearer understanding of the effectiveness of cancer care among the elderly, but research is also beginning to identify the cost effectiveness of both standard and emerging chemotherapeutic agents. Cost effectiveness of fluorouracil-based regimens, depending on delivery strategy, use of modulating agents and stage of cancer vary from US dollars 2000 per quality-adjusted life-year (QALY) to US dollars 20200 per QALY (1992 values). Irinotecan therapy has not been fully investigated from the perspective of cost effectiveness; the figure of US dollars 10000 per QALY (1998 values) for irinotecan monotherapy over fluorouracil regimens is likely an underestimate, while cost analysis of irinotecan and fluorouracil combination therapy has not yet been reported. Our understanding of cost effectiveness of other novel agents has lagged behind; further research on these agents is needed. Nonetheless, as the effects of these novel agents upon both outcomes and costs continue to be defined, both curative and palliative treatment of colorectal cancer in the elderly patient will become more sophisticated and effective.

Experimental Infection of Humans with Filariae

This report summarizes the findings of the 17 published studies involving humans who have been experimentally infected with filarial parasites. Over the past 60 years, 45 individuals have been deliberately infected with Wuchereria bancrofti, Brugia malayi, Brugia pahangi, Loa loa, Mansonella perstans, Mansonella ozzardi, and/or Onchocerca volvulus. The findings from these experimental infections of humans have helped define microfilarial survival and periodicity within human hosts, the prepatent period for the causative agents of lymphatic filariasis, etiologic agents for particular clinical syndromes, immunologic and hematologic consequences of filarial infection, and the role of chemotherapeutic agents in the prevention and treatment of filarial infections.

Impact of early detection of breast cancer on adjuvant chemotherapy.

It has only been since the late 1940s that chemotherapy emerged as part of the therapeutic armamentarium for treating patients with disseminated breast cancer. Recently, however, the role of chemotherapeutic agents in prolonging life and disease-free interval in patients with breast cancer has come to be questioned.

Hypothesis test for causal explanations in human pathology: evaluation of pulmonary edema in 181 autopsied patients with leukemia

Symbolic logic, as used in the formal theory of scientific explanation proposed by Hempel and Oppenheim, has been suggested as the basis for automated medical diagnosis. In human autopsy pathology the determination of cause-and-effect relationships is a major area subject to logical analysis. We propose a modification of the Hempel-Oppenheim schema in which the logical relationships must only be satisfied “much” of the time, as determined by binomial significance tests. The analysis employs “certainty levels” logic with a more limited consistency requirement than classical logic. The analysis is applied to a series of 181 autopsied patients with leukemia in an attempt to determine a possible role of chemotherapeutic agents in the etiology of pulmonary edema. Among 51 patients who had received cytosine arabinoside (Ara-C) within 30 days of death, there was significantly more unexplained moderate or massive pulmonary edema than among patients with no or remote therapy ( p<0.001). The results suggest that a symbolic logical analysis combined with a binomial significance test can elucidate cause-and-effect relationships observed at autopsy, especially when there are multiple possible explanations for the same effect.

Acute cardiac toxicity of antineoplastic agents as the first manifestation of pheochromocytoma

A 47-year-old male with histiocytic lymphoma and no previous history of heart disease developed significant fluctuations of blood pressure, electrocardiographic evidence of myocardial ischemia, and life-threatening arrhythmia after the first dose of BACOP (bleomycin, adriamycin, cyclophosphamide, Oncovin, and prednisone) chemotherapy. The presence of pheochromocytoma was suspected, and it was demonstrated by elevated urinary metanephrines, catecholamines, and vanillylmandelic acid, and finally confirmed on autopsy. The possible role of chemotherapeutic agents in stimulating excessive catecholamine release, thus causing transient cardiac injury, is suggested.