Current status of intraperitoneal therapy for ovarian cancer

Recent attention has focused on evaluating those clinical situations in which intraperitoneal drug delivery may be an appropriate treatment option for patients with ovarian cancer. When employed as a second-line strategy, approximately 20% to 30% of patients with small-volume residual disease (microscopic, largest tumor mass < or = 0.5 to 1 cm in maximum diameter) at initiation of treatment are expected to achieve a surgically documented complete response with a variety of organoplatinum-based intraperitoneal regimens. However, responses are rarely observed in such patients who have failed to demonstrate tumor sensitivity to systemically delivered organoplatinum drugs, despite the presence of small-volume residual disease. Investigators at several centers are currently exploring a possible role for regional drug delivery in the initial management of selected patients (ie, small-volume disease) with ovarian cancer. A recently reported trial of intraperitoneal taxol suggests this may be an ideal drug for regional therapy of ovarian cancer due to a major pharmacokinetic advantage associated with this route of drug delivery.     

The prospects for gene therapy in cystic fibrosis

Gene therapy provides the best prospect of a fundamental new treatment for cystic fibrosis. The lungs are the most important target, because this organ is the most severely affected by the disease and is also accessible for topical treatment. Advances in this field have been very rapid, and the prospects remain good although a number of problems need to be overcome. The two main approaches to gene transfer, namely adenoviruses and liposomes, are efficient in vitro, but early clinical trials have shown that they work less well in vivo. A number of proof of concept studies have shown that gene transfer is possible, but full functional correction of the cystic fibrosis defect has not yet been achieved. Adenoviruses have provoked an inflammatory response, and new viral vectors are being developed to overcome this. Existing lipids are relatively inefficient, but new liposomes are being developed to enhance gene transfer. Much work needs to be done to improve safety and efficacy of gene transfer before materials are ready for large scale clinical trials. However, progress is very rapid, and there is a real prospect of developing an effective gene therapy for cystic fibrosis within the next decade.     

Future prospects of emergency laboratory tests--problems of immunoserologic tests

Regarding problems in emergency and urgent immunoserologic tests, I mainly focused on infectious diseases and CPR and discussed the correspondence of dangerous needle stick injuries, and the significance of emergency CRP measurement in various body fluids using highly sensitive determination methods. The actual conditions and correspondence of infections due to dangerous needle stick injuries (accidental pricking with used needles) such as hepatitis, syphilis, acquired immunodeficiency syndrome (AIDS), adult T-cell leukemia (ATL), herpes simplex, falciparum malaria, tuberculosis, Rocky mountain spotted fever, and human colonic adenocarcinoma are discussed. With regard to emergency CRP measurement, application of highly sensitive determination methods and the significance of CRP measurement of various body fluids (healthy adult blood, cord blood, cerebrospinal fluid, urine and puncture fluid) are described. The reference values for CRP concentrations in various body fluids were established at 15 to 3,063 ng/ml for serum (male; 26 to 3.992 ng/ml, female; 11 to 1,672 ng/ml), 9 to 73 ng/ml for cord blood, 2 to 10 ng/ml for cerebrospinal fluid and less than 2 ng/ml for urine.     

APA finances: Future prospects and plans.

Proposes that the American Psychological Association (APA) will face future deficits unless plans are made to avoid them. This proposal is based on a 5-yr forecast for 1972–1976. The Council of Representatives will be asked to establish financial goals and to assign responsibility for achieving goals to boards and committees of the APA. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Gene therapy for primary and metastatic pancreatic cancer with intraperitoneal retroviral vector bearing the wild-type p53 gene

BACKGROUND: Metastatic pancreatic cancer is uniformly fatal because no effective chemotherapy is available. Mutations in the p53 tumor suppressor gene are found in up to 70% of pancreatic adenocarcinomas. We examined the efficacy of a retroviral vector containing the wild-type p53 gene on metastatic pancreatic cancer in a nude mouse model. METHODS: Bxpc3 human pancreatic cancer cells were transduced with either a retroviral p53 vector or an LXSN empty vector. Cells were examined for incorporation of tritiated thymidine to determine the effect of p53 retroviral transduction on DNA synthesis, and a TACS2 assay for apoptosis was performed. The functional activity of p53 in transduced cells was assessed by Western blot analysis with an antibody to WAF1/p21. In vivo effects of intraperitoneal injections of the p53 vector were examined in a nude mouse model of peritoneal carcinomatosis. RESULTS: Cells treated with the p53 vector exhibited a 59% to 85.5% reduction in cell number compared with the control cells (P < .05). p53-treated cells demonstrated decreased incorporation of tritiated thymidine (12.7% +/- 0.7% vs 17.5% +/- 1.4%; P = .002), increased staining for apoptosis, and increased expression of the WAF1/p21 protein. Treatment of nude mice with the retroviral p53 vector resulted in a significant inhibition of growth of the primary pancreatic tumor, as well as the peritoneal tumor deposits, compared with the LXSN control vector. CONCLUSIONS: Intraperitoneal delivery of a retroviral p53 vector may provide a novel treatment approach for peritoneal carcinomatosis from pancreatic cancer.     

Molecular targets for human papillomaviruses: prospects for antiviral therapy

A substantial medical need exists for the development of antiviral medicines for the treatment of diseases associated with infection by human papillomaviruses (HPVs). HPVs are associated with various benign and malignant lesions including benign genital condyloma, common skin warts, laryngeal papillomas and anogenital cancer. Since treatment options are limited and typically not very satisfactory, the development of safe and effective antiviral drugs for HPV could have substantial clinical impact. In the last few years, exciting advances have been made in our understanding of papillomavirus replication and the effects that the virus has on growth of the host cell. Although still somewhat rudimentary, techniques have been developed for limited virion production in vitro offering the promise of more rapid advances in the dissection and understanding of the virus life cycle. Of the 8-10 HPV gene products that are made during infection, only one encodes enzymatic activities, the E1 helicase. Successful antiviral therapies have traditionally targeted viral enzymes such as polymerases, kinases and proteases. In contrast, macromolecular interactions which mediate the functions of E6, E7 and E2 are thought to be more difficult targets for small molecule therapy.     

Tumor suppressor genes: prospects for cancer therapies

Penicillins have been shown to inhibit bacterial cell wall synthesis, and interact with penicillin binding proteins, leading to bacterial lysis. These two mechanisms, the former more than the latter are believed to be responsible for their therapeutic potential. It has further been demonstrated that only actively multiplying cells are susceptible to bactericidal effects of the antibiotic, which is in accordance with the suggested mechanism of action. Bacterial growth takes place in terms of size and number, both requiring additional cell wall. An increase in bacterial size is due to an increase in the volume of cytosol and area of the cell wall. Presently there is no proof that the former is the cause of the latter or vice versa. Penicillin by inhibiting cell wall synthesis would inhibit both growth and multiplication. Since the antibiotic is bactericidal to rapidly multiplying cells, its effect on cell wall would interfere with its bactericidal action. As per the present understanding penicillin acts principally by inhibiting cell wall synthesis. There is however a discrepancy between its observed effects and what should logically be expected, which forces us to reexamine the mechanism of action of penicillin. We believe that the present understanding of the action of penicillin is incomplete if not outright faulty. It would be expedient to radically modify the same in view of its implication, for example on drug development.     

The effect of intraperitoneal and intra-aortic chemotherapy for unresectable gastric cancer

Regional chemotherapy was given 16 unresectable gastric cancer patients. Two types of the chemotherapy, intraperitoneal (IP) and intraaortic (IA) administration, were carried out. The control group was comprised of 17 patients. The response of the chemotherapy for primary tumor was 36.4% in the IP group and 20% in the IA one. Among these patients, 2 of 11 in IP and 1 of 5 in IA were able to resect the primary tumor. The 50% survival time of IP, IA and control was 347, 227 and 78 days, respectively. One-year survival rates of IP, IA and control were 68%, 29% and 0%, respectively. IP showed a significantly longer survival rate than controls (p < 0.001). All but one patient was able to stay at home. Intraperitoneal chemotherapy showed both local and systemic effects in unresectable gastric cancer.     

The molecular basis of long QT syndrome and prospects for therapy

Long QT syndrome (LQT) is a cardiac disorder that causes sudden death from ventricular tachyarrhythmias, specifically torsade de pointes. Two types of LQT have been reported, autosomal-dominant LQT (Romano-Ward syndrome) and autosomal-recessive LQT (Jervell and Lange-Nielsen syndrome); Jervell and Lange-Nielsen syndrome is also associated with deafness. Four LQT genes have been identified for autosomal-dominant LQT: K+ channel genes KVLQT1 on chromosome 11p15.5, HERG on 7q35-36 and minK on 21q22, and the cardiac Na+ channel gene SCN5A on chromosome 3p21-24. Two genes, KVLQT1 and minK, have been identified for Jervell and Lange-Nielsen syndrome. Genetic testing and gene-specific therapies are available for some LQT patients.     

高炉系统氯元素研究进展及未来展望

 为明晰高炉中的氯元素对干法除尘高炉冶炼过程的影响,综述了高炉入炉料中氯元素的赋存状态、行为以及所带来的危害。进一步采用离子色谱法研究了国丰1号1 780 m3干法除尘高炉氯元素的来源, 焦炭和喷吹煤粉带入高炉中氯所占入炉料带入高炉中氯总量的比例分别为45.4 %和29.48 %, 而宝钢、唐钢和迁钢的3座干法除尘高炉中氯的来源主要是烧结矿,其比例分别为47.12 %、43.59%和44.89%,这主要与高炉入炉料种类、用量以及氯元素质量分数的不同有关,所以在对待高炉氯元素来源问题上应该具体高炉具体分析。通过热力学分析得出高炉入炉料中的氯化物在高炉内主要生成HCl,基于对高炉系统氯元素的研究,提出了高炉的降氯措施,并展望了高炉系统氯元素的未来研究方向。     

Progress, problems, and prospects for gene therapy in muscle

As the molecular defects that cause many muscle diseases have been identified, research has shifted to finding novel therapies. Gene therapy has been proposed both for correcting primary gene defects of muscle and as a way of using muscle for the production of proteins therapeutic in inflammatory or nonmuscle diseases. Several strategies have been developed to introduce foreign genes into diseased muscles, including myoblast transfer, direct injection of plasmids or DNA-liposome complexes, and infection with modified viruses. Related strategies, using antisense sequences or ribozymes, have been devised to modify gene expression in diseased cells. No method has yet proved itself in the clinic, although current work remains promising and some of the pitfalls that must be overcome have been identified.     

Future uses for aromatase inhibitors in breast cancer

Over recent years highly potent, well-tolerated aromatase inhibitors have been developed, which essentially obliterate peripheral aromatase activity in postmenopausal women. Their role as the optimal second-line agents (post-tamoxifen) for the treatment of advanced breast cancer has recently been established in large comparative clinical trials. Their testing as adjuvant therapy is warranted, but their eventual application in this (or the prophylactic) setting will be dependent on the currently unknown effects of profound oestrogen deprivation on the physiology of postmenopausal women as well as on its efficacy. It is also possible that these new compounds could suppress oestrogen synthesis in premenopausal women, but the consequences on ovarian folliculogenesis might prevent their widespread use in this group of patients.     

Systemic therapy for breast cancer

Currently available information suggests that the optimal duration of adjuvant therapy for breast cancer patients with no involved axillary nodes is 5 years, though controversy about this recommendation persists. In postmenopausal patients, disease-free survival appears to be improved by the addition of combination chemotherapy to tamoxifen. Recently reported studies indicate that there is no benefit to dose escalation of cyclophosphamide in adjuvant therapy and that the risk of secondary leukemia may be increased. The combination of paclitaxel and doxorubicin has been reported in single-institution studies to produce high response rates but may also be cardiotoxic. Recent reports indicate that a pharmacokinetic interaction between these two drugs may cause these clinical findings. New agents that may be of utility in the management of advanced or primary breast cancer include novel hormonal agents, notably the aromatase inhibitors, and the bisphosphonates.     

Prophylactic gene therapy for cancer

BACKGROUND: Epithelial ovarian tumors of borderline malignancy are different from benign tumors and malignant neoplasms. They exist with relatively benign clinical course, younger age and better prognosis as compared with invasive malignant carcinomas. Most of them are discovered at early stage, for example, stage Ia. This retrospective review evaluates the clinical features, treatments and prognosis of 48 patients with borderline malignancy of ovarian tumors. METHODS: Forty-eight patients with ovarian tumors of borderline malignancy, aged from 14 to 69 years (mean: 39.2 years; median: 36 years), were retrospectively studied. The histopathologic diagnosis was based on the morphologic criteria published by Tazelaar et al. in 1985. All cases, including 16 cases diagnosed before 1985, were pathologically reviewed. All information of clinical stage, surgical intervention and prognosis was achieved by reviewing hospital record or contacting patients by telephone. Two patients were lost to follow up. One patient died of sepsis resulting from another operation for another gynecological cancer. Totally forty-five patients were included for evaluation. RESULTS: Thirty-nine of the 48 patients (81.3%) were at stage Ia, 6 cases (12.5%) were at stage Ib, 2 cases (4.1%) were at stage Ic, and the remaining one patient (2.1%) was at state IIIc. Thirty-four patients (71%) were with mucinous cystadenoma of borderline malignancy, 11 cases (23%) were of serous type, and 3 patients (6%) were of mixed serous and mucinous type. Twenty-two patients underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH and BSO), but one of them remained partial ovary due to young age (27 y/o). Twelve patients were treated with unilateral oophorectomy or unilateral salpingo-oophorectomy (USO). Twelve patients underwent USO and wedge resection of contralateral ovary. One case underwent debulking surgery. One patient underwent enucleation of ovarian tumor and biopsy of contralateral ovary. Eighteen patients were treated with chemotherapy after operation. One patient developed recurrence 4 months after the primary operation. Excluding two cases lost to follow up and one case with surgical mortality for another gynecological cancer, forty-five patients were alive and were followed from 9 months to 165 months. (median: 48 months; mean: 46 months) CONCLUSIONS: Most of the patients were at the early stage of disease when first diagnosed, 81.3% were at stage Ia and only one case was at stage IIIc. Sixty-three percent of our patients underwent surgical treatment alone while the rest of them (37%) had post-operative chemotherapy with either alkeran or PAC. The use of adjuvant chemotherapy seemed unwarranted as there was no difference in survival between those with and without it. (P > 0.05) The low recurrent rate of 2% in our patients again confirmed the 9 P relative benign clinical course of this disease.     

Gene therapy for colon cancer

The enormous number of newly diagnosed cases of colorectal cancer that occur each year and the lack of agents that are highly effective for all patients underscore the need for novel approaches to combating the disease. Gene therapy as a developing treatment modality is already well established, with a number of trials ongoing and a vast range of other approaches being assessed in animal and cell culture experiments. In this brief review, we have discussed five gene therapy trials in colon carcinoma that are ongoing or in the approval process in the United States. The gene therapy approaches being employed can be divided into three major categories: (1) enzyme/prodrug systems (HSVtk/ganciclovir; CD/5-fluorocytosine); (2) tumor suppressor gene replacement therapy with wild-type p53; and (3) immune-gene therapy which is based on cytokine or tumor antigen expression to induce tumor immunity (e.g., CEA). Replication-deficient recombinant adenoviral vectors are predominantly used for colon cancer gene therapy, because they can be produced at high titer and they readily infect a number of different cell types. One trial uses polynucleotide therapy for antitumor immunization with intramuscular injection. All of these studies are phase I trials, principally designed to evaluate safety, but they will also provide data on gene delivery. Some trials may provide some insight into potential therapeutic effects. We have alluded to some of the concerns on toxicity related to the use of adenovirus, risks and side effects from transgenes, lack of tumor-specificity of transgene expression, and potential problems with efficient gene delivery to solid tumors. The clinical trials, however, will provide insight that will inform design of future studies with respect to dose, form, and frequency of administration, as well as to the value of biologic and clinical endpoints. The molecular analysis of the fundamental basis of colon cancer has moved at a remarkable pace and that progress seems set to continue. Thus, the basic foundations for gene therapy are undoubtedly in place: a clinical need; growing understanding of basic tumor biology; and ever-improving delivery systems. The field is at a very early stage in its evolution, and one concern is that the considerable hurdles that must be overcome are seen as examples of the failure of cancer gene therapy; however, we believe these challenges will be overcome. The authors also believe that colon cancer gene therapy is likely to take new directions, such as use as adjuvant to radical surgery, rather than attempts to treat end-stage disease when the liver is replaced by metastases. Other new directions might include prophylactic gene-based immunization against a panel of well-characterized tumor antigens, at least for persons shown to be at high risk of colon cancer because of genetic or other predisposition. A marriage between gene therapy approaches and conventional anticancer treatments such as radiotherapy and chemotherapy also seems likely. There is already evidence of this move with demonstration of synergism between p53 replacement and radiotherapy and chemotherapy. It is also likely that therapies will be developed that combine elements from the cancer gene therapies discussed previously, namely, suicide gene transfer, immune modulation, and modulation of defective cancer genes. Perhaps one of the main concerns is not that researchers in cancer gene therapy want to walk before they can run, but that the public and government agencies believe they can. The next 10 years will be an interesting time in the development of novel treatments against colon cancer.