Rectal injuries following radiation therapy for cervical cancer

Injuries of the rectal wall were examined up to 327 days in patients with uterus cancers after radiation therapy with 60Co gamma-rays. Various types of morphological changes were observed at the end of the therapy and the changes could be seen even 327 days after therapy with doses of 3,240-6,040 rad. The percentage of goblet cells in the rectal wall fluctuated for about 50 days after therapy and then became stable, but was slightly less than pre-irradiation level. The changes in the percentage seemed to represent radiation damages to the epithelial cells in the wall. The late effects in the blood vessels were probably more important than damages to the epithelial cells in the wall.     

Human papillomavirus infection and risk determinants for squamous intraepithelial lesion and cervical cancer in Japan

Smooth muscle cell (SMC) proliferation is inhibited both in vivo and in vitro by heparin. However, the precise mechanisms of action are still not understood. The analogy between two sulfated polysaccharides, heparin and fucan, has led us to compare in detail their effects on SMC growth. We have prepared and characterized a 19 kDa fucan fraction from brown seaweed, Ascophyllum nodosum. Fucan affects the growth of SMCs in a time- and dose-dependent, reversible and non-toxic fashion. As determined by cell counting, [3H]thymidine incorporation, and microcytofluorimetry analysis, heparin was less active than fucan in inhibiting SMC growth. Fucan and heparin act by preferential blocking of G0/G1, thus decreasing the G0/S transition. Binding experiments with [125I]fucan indicated saturable, unlabeled-fucan displaceable binding sites with an apparent Kd of 30 nM. Moreover, displacement experiments performed with various polysaccharides revealed that antiproliferative compounds interacted with these membrane sites, but non-antiproliferative polysaccharides (dextran, chondroitin sulfate) did not, providing evidence of a correlation between binding to SMCs and their antiproliferative activity. When cells were exposed at 37 degrees C to a fluorescent 5-([4,6-dichlorotriazin-2-yl]-amino)fluorescein (DTAF)-fucan, internalization occurred and punctate vesicles were observed which accumulated rapidly in the perinuclear region as previously reported for heparin. Nuclear preparations (membranes + contents) of cultured SMCs previously incubated with radiolabeled heparin or fucan indicated the presence of radioactivity, suggesting an antiproliferative action of both polysaccharides at the nuclear level. Collectively, these observations indicated that fucan and heparin share some similar mechanisms of action, such as SMC growth inhibition, binding, and internalization. In the accompanying paper (Logeart et al., Eur. J. Cell Biol. 74, 1997, this issue), we describe the effect of fucans of different molecular weights and conclude that there is no direct link between polysaccharide degradation and the antiproliferative effect on SMCs.     

Human papillomavirus as an etiological factor in cervical cancer: significance for health care practice

The migration of substances from rubber packaging materials into drug products can be significant with certain packaging materials in contact with organic solvent systems. Recommendations for testing drug products for leachables are continually evolving to address new developments. Testing packaging materials using simulated solvents is not always an acceptable protocol for the pharmaceutical industry. We describe a rational strategy for evaluation of the drug product for packaging extractables. A profile of the extractables from rubber packaging materials was made with a range of organic solvents and stress conditions to provide information on substances to target in the drug product. The drug product was evaluated to determine if the matrix would cause interferences that might inhibit detection of the found extractables. Analytical methods were selected based on these findings. The procedures were validated according to FDA guidelines. A stability program using time and storage conditions as variables provided information for acceptance criteria. This same strategy can be used on other types of pharmaceuticals and packaging materials.     

Human papillomavirus genotype as a major determinant of the course of cervical cancer

PURPOSE: To determine whether the prognosis of invasive cancers of the uterine cervix is related to the type of human papillomavirus (HPV) associated with the tumor. PATIENTS AND METHODS: Two hundred ninety-seven patients with invasive cervical cancer were prospectively registered from 1986 to 1994. HPV typing was performed on DNA extracted from frozen tumor specimens by means of Southern blot hybridization (SBH) and polymerase chain reaction (PCR) techniques. The median follow-up was 38 months. RESULTS: HPV sequences were detected in 246 patients (83%): 150 patients had HPV16, 31 patients had HPV18, and 14 patients had one of the intermediate-oncogenic-risk HPV types (HPV31, 33, 35, 52, 58). In 51 patients, HPV type remained undetermined, and in 51 patients, no viral sequences were found. No significant associations were observed between virologic data and tumor stage or node status. The 5-year disease-free survival (DFS) rate was 100% for patients with intermediate-risk HPV-associated tumors, 58% for patients with HPV16-positive tumors, and 38% for patients with HPV18-positive tumors (P = .02). In multivariate analysis, patients with HPV18-associated tumors had a relative risk (RR) of death 2.4 times greater (95% confidence interval [CI], 1.29-4.59) than that for patients with HPV16, and 4.4 times greater (95% CI, 3.48-5.32) than that for patients with a tumor associated with a viral type different from HPV16/18. CONCLUSION: The prognosis for invasive cancers of the uterine cervix is dependent on the oncogenic potential of the associated HPV type. HPV typing may provide a prognostic indicator for individual patients and is of potential use in defining specific therapies against HPV-harboring tumor cells.     

Human papillomaviruses and cervical cancer

In the United States, the Phase I Feasibility Study under IDE G970065 was approved by the Food and Drug Administration on 04/11/97. The approved protocol called for implantation of the bifurcated Talent spring stent-graft system on patients who are high-risk candidates for conventional surgery because of cardio-respiratory, medical, general, or local anatomical reasons which would likely complicate the technical execution of the operation or be accompanied by a high expected mortality rate. Patient enrollment was complete with 16 cases as of September 26, 1997. This was a multicenter experience involving five different sites. This is an ongoing study and patients, of course, will continue to be followed longitudinally. Phase II will likely be approved by the FDA for initiation in January or February of 1998. Standard-risk AAA patients will be entered into the study at this time; comparison with concurrent controls will be used for comparison with conventional surgery.     

Human papillomavirus in normal cervical smears from Cape Town

OBJECTIVE: To determine the prevalence of human papillomavirus (HPV) types in South African women with normal cervical cytology and to determine whether our results are comparable to what has been found elsewhere in the world. DESIGN: Cervical smears were collected from 262 women. SETTING: The Cape Town metropolitan area. PARTICIPANTS: A total of 262 women, aged 19-85 years. Eighty-five women attended the family planning clinic of the Gynaecology Department at Groote Schuur Hospital and 177 women consulted private gynaecological practices. MAIN OUTCOME MEASURES: The prevalence and types of HPV in 192 women with normal cervical cytology. RESULTS: The incidence of HPV DNA in cervical smears from Cape Town women with normal cytology was found to be 13% (25/192) using Southern blot hybridisation. The types of HPV found in normal cervical tissue from Cape Town did not differ significantly from those found elsewhere in the world. Nine per cent (17/192) were positive for "high-risk' HPV types which are associated with premalignant and malignant cervical lesions. In the age group 20-39 years, 15 of 92 (16%) were positive for HPV DNA, while in the age group above 39 years, 3 of 53 (6%) women were positive for HPV DNA. CONCLUSIONS: In this study, 25 of 192 (13%) women with normal cytology were positive for HPV.     

Vesicouterine fistula twenty years following brachytherapy for cervical cancer

Assessment of maternal pelvic dimensions is usually considered necessary where vaginal delivery is contemplated in a breech presentation or if reduced pelvic dimensions are suspected in a current or previous pregnancy. Pelvimetry techniques include computed tomography (CT), conventional radiography, digital fluorography and magnetic resonance imaging (MRI). The first three techniques result in a radiation dose to mother and fetus which, depending on how the technique is performed, can vary by up to 40-fold. Of the techniques using X-rays, CT pelvimetry with a lateral scanogram generally gives the lowest radiation dose and conventional radiography using an air gap technique with a single lateral view is a relatively low-dose alternative where CT is not available. A questionnaire was sent to 227 hospitals during 1993 and 1996 to assess whether there was a move towards lower dose techniques of pelvimetry. The results show a trend away from conventional pelvimetry (48.4% in 1993 to 28% in 1996) with a small proportion of centres using MRI (4%) in 1996. Of the centres still using conventional pelvimetry, relatively few were using a low-dose air-gap technique (2.1% in 1993 to 10.9% in 1996). An increasing majority of centres were using one-view CT (69.3% in 1993 and 80.4% in 1996) but a significant proportion were still performing more than one view. This study shows that there was a move towards lower dose techniques of pelvimetry but that there were still many hospitals that had not implemented a policy of reducing radiation exposure in these patients.     

Human papillomavirus investigation of patients with cervical intraepithelial neoplasia 3, some of whom progressed to invasive cancer

Unstable expansion of the CTG repeats in the 3' untranslated region encoding a member of the protein kinase family in the q13.3 band on chromosome 19 is a mutation specific for myotonic dystrophy. To examine the correlation between clinical expression and CTG trinucleotide repeat length, we carried out Southern blot analysis in a family with myotonic dystrophy. In this pedigree, the expanded CTG repeats were transmitted maternally. The mother had three female children. The mother had about 200 CTG repeats, and the number of repeats for each child was about 800, 1500 and 1600 in birth order. The mother and the patient with 800 repeats were unaware of muscle weakness or myotonia. Symptoms were present from age 3 years in the patient with 1500 repeats and from birth in the one with 1600 repeats. Although the mother menstruated regularly, the patients with 800 and 1500 repeats both menstruated irregularly, and the one with 1600 repeats has never menstruated. The age of onset and severity of the disease were correlated with the size of the expanded repeats. Endocrinological studies revealed that the basal levels of the gonadotropins, PRL and E2 were within normal range, and a pituitary response to LHRH was observed. These data suggest that the amenorrhea and menstrual irregularities were caused by a suprahypophyseal dysfunction. When expanded CTG repeats are transmitted maternally, abnormal products resulting from the metabolic disturbance in the affected mother may harm the fetus in utero. A heterozygous fetus, who has more CTG repeats, may be unable to metabolize the pathologic products sufficiently and therefore may become more severely affected. This may explain the exclusive maternal transmission of congenital myotonic dystrophy.     

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.     

Association of the antibodies against human papillomavirus 16 E4 and E7 proteins with cervical cancer positive for human papillomavirus DNA

Occurrence of the antibodies against human papillomavirus (HPV) 16 proteins E4 and E7 is specifically but independently associated with cervical cancer. To correlate HPV DNA and antibody data, we examined the biopsy specimens and sera, by polymerase chain reaction (PCR) and by ELISA, respectively, from 51 patients with cervical cancer (including 3 recurrent cases) and 22 with cervical intra-epithelial neoplasia. Consensus primers for the L1 region were used for PCR and bacterially expressed, purified fusion protein HPV-16 E4 and non-fusion protein HPV-16 E7 were used for ELISA. HPV-16 DNA and other HPV types were detected in 17 and 25, respectively, out of 51 cases of cervical cancer. Ten out of the 17 HPV-16-DNA-positives were positive either for anti-E4 or for anti-E7: positivities for anti-E4, for anti-E7, and for both were 6/17, 5/17 and 1/17 respectively. Three anti-E7-positives consisted of those for HPV-33, -52 and -58 DNA, suggesting that limited cross-reaction occurred between the HPV types. Among the HPV-16-DNA-positive cases of cancer, lymph-node or distant metastasis was recorded more frequently in the seropositives than in the seronegatives. Our results show that the HPV-16 anti-E4 or anti-E7 occurs in some, but not in all, of the HPV-16-DNA-positive cases, and support the hypothesis that the presence of the HPV-16 antibodies can be used as a marker for possible metastasis.     

Current status of endocrine therapy for metastatic breast cancer

Hormonal manipulation is currently the mainstay of palliative care for metastatic breast cancer because it is well tolerated and produces significant responses in approximately one-third of unselected patients. Tamoxifen, a nonsteroidal antiestrogen, is currently considered first-line therapy. Second-line agents include progestins and aromatase inhibitors. New agents, such as the "pure" antiestrogens and the gonadotropin-releasing hormone (GnRH) agonists, are being tested. Other approaches for affecting the hormonal milieu are also under investigation, including combinations of hormonal agents, hormonal agents plus biologics, and hormonal agents plus antiproliferative agents. This review will address the basis for endocrine therapy and possible mechanisms of hormonal resistance, currently available agents and newer ones on the horizon, and areas of future interest.     

Human papillomaviruses, tumour suppressor genes and cervical cancer

There is now a considerable body of evidence that links HPV infection with anogenital squamous carcinoma, particularly for specific 'high risk' HPV types (HPV16 and 18) and invasive carcinoma of the cervix. Recent advances in the molecular study of these viruses have elucidated some potential mechanisms by which they may contribute to the development of these diseases. In this review we concentrate on the interactions of 2 of the HPV encoded proteins, E6 and E7, with cellular tumour suppressor gene products. We provide a model of how these interactions may be important in tumourigenesis and draw together current knowledge of this exciting and rapidly evolving field.     

乳腺癌抗血管生成治疗:现状与前景

Tumor angiogenesis plays an important role in the growth, invasion and metastasis of breast cancer, therefore recently a very active area of breast cancer research involves the addition of antiangiogenic therapy. Numerous clinical studies for several antiangiogenic agents have recently been conducted in breast cancer patients and have shown clinically significant improvement in outcomes. This review gives a brief background to breast cancer angiogenesis, also focusing on current progress in the field of antiangiogenic therapy for breast cancer and issues regarding future therapeutic development.     

The roles of the human major histocompatibility complex and human papillomavirus infection in cervical intraepithelial neoplasia and cervical cancer

Germ theory and pure culture methods have provided invaluable information concerning the role of bacteria in diseases resulting from a single organism which bypasses a host's defenses. However, they do not provide sufficient information concerning the synergisms which allow the members of biofilm communities to proliferate more effectively as communities rather than as individuals. The mechanisms of these synergies are potential targets for antimicrobial agents as well as potential mechanisms of resistance to antimicrobial agents. Understanding community-level phenomena in oral biology requires the culture, identification, and classification of functional plaque communities as well as new methods of identifying and quantifying communal relationships. Cultured biofilm communities also provide ideal models of bacterial self-organization in which information related to adaptive strategies arises not only through the recombination of genes within genomes, but also through the recombination of organisms within communities.     

Current status of monoclonal antibodies for imaging and therapy of prostate cancer

It is clear that there is significant need for improved staging and therapy of prostate cancer. The attributes and strengths of MoAbs seem particularly well-suited to the setting of prostate cancer. Recent progress in the application of MoAbs to in vivo imaging and therapy is encouraging. Clearly, further such efforts in prostate cancer are warranted.     

Whipple's disease - current status of diagnostics and therapy

Whipple's disease is a multisystemic infectious disease whose pathogen, a gram-unstable actinomycete, has been characterized in the meantime by molecular-biological techniques (polymerase chain reaction). This infectious disease which was firstly described in 1907 by G.H. Whipple as intestinal lipodystrophy appears rarely and sporadically and can affect nearly every organ, in the course of which the small intestine is also concerned in the majority of patients. The symptoms and signs are polymorphous and depend on organic involvement and stage. This leads to significant difficulties concerning differential diagnosis and to a delay in diagnosis. Misjudging the syndromes provokes invalidism and death whereas correct therapy leads to a cure in most of the cases.     

Mucosal de novo cancer of the rectum following radiation therapy for uterine cancer

A 54-year-old woman who underwent a hysterectomy and radiation therapy for carcinoma of the uterine cervix developed mucosal de novo cancer of the rectum 12 years later. The rectal lesion was elevated, measuring 0.8 x 0.7 x 0.3 cm, and its surface was relatively smooth. Microscopically, this tumor consisted of a well-differentiated tubular adenocarcinoma which had invaded the depth of the mucosa. Late radiation injuries were observed around the tumor. We diagnosed this lesion as a radiation-induced mucosal de novo adenocarcinoma of the rectum on the basis of the criteria of Black and Ackerman (Clin Radiol 16:278, 1965). This case underscores the need for careful long-term follow-up studies of the large intestines of patients who underwent therapeutic irradiation for uterine cancer.     

Human papillomavirus distribution in cervical tissues of different morphology as determined by hybrid capture assay and PCR

OBJECTIVE: To evaluate the functional response, morbidity and histostructural changes in rats enterectomized and without cecum using two types of syngenic enteral transplants. MATERIAL AND METHODS: Controlled randomized surgical-therapeutic trial. Four groups of male Lewis rats 8-10 weeks old underwent the following procedures: 1. Lethal enteral resection (n = 10). 2. Lethal enteral resection + total yeyuno-ileal transplant (n = 28). 3. Lethal enteral resection + distal segmentary of 40% and cecum transplant (n = 32). 4. Control group (n = 10). RESULTS: 11% of the transplanted animals died due to technical failures; both transplanted groups had a similar proportion of late complications, mostly enteral obstruction. A persistent diarrhea was observed in 20% of the yeyuno-ileal transplanted group, but no significant differences were found between the two groups concerning survival, weight gain, protein and triglycerides serum levels, and a maltose absorption test; villus and crypt hypertrophy was observed in both grafts. The enteral graft integration was followed by structural changes similar to those found in intestinal remnants on deficit conditions after enteral resection. CONCLUSION: The bowel distal segmentary transplant with ileocecal valve and cecum may be a good option in cases of irreversible enteral failure, as the functional response and morbidity are similar to those found with the standard total transplant.     

Human papillomavirus infection and esophageal cancer: a nationwide seroepidemiologic case-control study in Sweden

BACKGROUND: Despite being immunogenic, gastric cancers overcome antitumour immune responses by mechanisms that have yet to be fully elucidated. Fas ligand (FasL) is a molecule that induces Fas receptor mediated apoptosis of activated immunocytes, thereby mediating normal immune downregulatory roles including immune response termination, tolerance acquisition, and immune privilege. Colon cancer cell lines have previously been shown to express FasL and kill lymphoid cells by Fas mediated apoptosis in vitro. Many diverse tumours have since been found to express FasL suggesting that a "Fas counterattack" against antitumour immune effector cells may contribute to tumour immune escape. AIM: To ascertain if human gastric tumours express FasL in vivo, as a potential mediator of immune escape in stomach cancer. SPECIMENS: Thirty paraffin wax embedded human gastric adenocarcinomas. METHODS: FasL protein was detected in gastric tumours using immunohistochemistry; FasL mRNA was detected in the tumours using in situ hybridisation. Cell death was detected in situ in tumour infiltrating lymphocytes using terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL). RESULTS: Prevalent expression of FasL was detected in all 30 resected gastric adenocarcinomas examined. In the tumours, FasL protein and mRNA were co-localised to neoplastic gastric epithelial cells, confirming expression by the tumour cells. FasL expression was independent of tumour stage, suggesting that it may be expressed throughout gastric cancer progression. TUNEL staining disclosed a high level of cell death among lymphocytes infiltrating FasL positive areas of tumour. CONCLUSIONS: Human gastric adenocarcinomas express the immune downregulatory molecule, FasL. The results suggest that FasL is a prevalent mediator of immune privilege in stomach cancer.     

The current status of adjuvant hormonal therapy combined with radiation therapy for localised prostate cancer

The limbic system comprises the hippocampal formation, fornix, mamillary bodies, thalamus, and other integrated structures. It is involved in complex functions including memory and emotion and in diseases such as temporal lobe epilepsy. Volume measurements of the amygdala and hippocampus have been used reliably to study patients with temporal lobe epilepsy but have not extended to other limbic structures. We performed volume measurements of hippocampus, amygdala, fornix and mamillary bodies in healthy individuals. Measurements of the amygdala, hippocampus, fornix and mamillary bodies revealed significant differences in volume between right and left sides (P < 0.001). The intraclass coefficient of variation for measurements was high for all structures except the mamillary bodies. Qualitative image assessment of the same structures revealed no asymmetries between the hemispheres. This technique can be applied to the study of disorders affecting the limbic system.