Cetuximab potentiates oxaliplatin cytotoxic effect through a defect in NER and DNA replication initiation.

Preclinical studies have demonstrated that the chemotherapeutic action of oxaliplatin, a third generation platinum derivative, is improved when combined with cetuximab, a monoclonal antibody inhibitor of epidermal growth factor receptors. To explore the mechanism of this synergistic benefit, we used HCT-8 and HCT-116, two human colon cancer cell lines, respectively, responsive and non-responsive to the oxaliplatin/cetuximab combination. We examined the effect of drug exposure on glutathione-S-transferase-mediated oxaliplatin detoxification, DNA-platinum adducts formation, cell cycle distribution, apoptosis, and the expression of multiple targets involved in DNA replication, recombination, and repair. The major changes we found in HCT-8 were a stimulation of oxaliplatin-DNA adduct formation associated with reduced expression of the key enzyme (excision repair cross complementation group1: ERCC1) in the key repair process of oxaliplatin-DNA platinum adduct, the nucleotide excision repair (NER), both at the mRNA and protein levels. We also observed a reduced expression of factors involved in DNA replication initiation, which correlates with an enrichment of cells in the G1 phase of the cell cycle as well as an acceleration of apoptosis. None of these changes occurred in the non-responsive HCT-116 cell that we used as a negative control. These findings support the fact that cetuximab potentiates the oxaliplatin-mediated cytotoxic effect as the result of inhibition of NER and also DNA replication initiation.

Term delivery following conservative treatment for villoglandular papillary adenocarcinoma of the uterine cervix: report of a case and analysis of the literature.

BACKGROUND: Villoglandularpapillary adenocarcinoma (VPA) of the cervix is often indolent, and surgical treatment has a favorable outlook. Risk factors include depth of invasion, lymphovascular invasion, and the presence of other histologic types of cancer. CASE: An amputation of the cervical portio was required to satisfactorily resect a 2.5-cm ectocervical lesion in a 28-year-old nulligravida. A diagnosis of pure VPA with a depth of invasion less than 2 mm was established. During a subsequent pregnancy, second trimester ultrasound showed extreme effacement of her cervix and an abdominal cerclage was placed. The pregnancy continued until delivery of a healthy infant at 36 weeks. CONCLUSIONS: In cases of tumor invasion less than 3 mm, and in the absence of lymphovascular space involvement, extrauterine spread of pure VPA has not been described. When conservative treatment is planned, amputation of the cervical portio may be better suited than conization to the achievement of an adequate margin of resection. Cervical cerclage may be needed to offset the extensive cervical surgery.

Treatment of Helicobacter pylori.

Helicobacter pylori causes several gastroduodenal diseases. Various antibiotic regimens are available that eradicate H. pylori in 80 to 90% of patients, but no regimen cures all patients. Dual therapy is now obsolete. Triple therapy with two antibiotics and either a proton pump inhibitor or bismuth is the regimens of choice. Metronidazole and clarithromycin are the two key antibiotics. Antibiotic resistance against these two drugs is becoming more problematic and should be taken into consideration when choosing a regimen. Antibiotic resistance is usually induced after failure. Quadruple therapy has been used as a salvage regimen in failed cases but it is also the most complicated regimen. Several new agents are being studied including a single capsule that contains bismuth, metronidazole, and tetracycline.

In vitro fertilization following conservative management of stage 3 serous borderline tumor of the ovary.

Among patients with advanced stage serous borderline tumors of the ovary, those with micropapillary architecture or invasive implants have the greatest risk of malignant transformation. In the absence of these patterns, consideration can be given to preservation of reproductive function. A 28-year-old, nulliparous patient presented with symptoms mimicking advanced ovarian cancer. Histology showed a serous borderline tumor with a hierarchical branching pattern. Surgery was able to remove all visible disease but still preserve the uterus and a portion of one ovary. She subsequently underwent in vitro fertilization and delivered a full-term infant.

Efficacy of a 1-week regimen of ranitidine bismuth citrate in combination with metronidazole and clarithromycin for Helicobacter pylori eradication.

BACKGROUND: In order to improve the efficacy and simplicity of the FDA-approved regimen of ranitidine bismuth citrate (RBC) and clarithromycin dual therapy, we added an inexpensive antibiotic (metronidazole), changed the dosage scheme to twice daily dosing, and decreased the duration of therapy to 1 week. METHODS: This was an open label study in which subjects with previously untreated Helicobacter pylori infection documented by serology or endoscopy and confirmed by the 13C-urea breath test received a 1-week course of RBC 400 mg b.d., metronidazole 500 mg b.d. and clarithromycin 500 mg b.d. A repeat breath test was performed 4-6 weeks after completing therapy. RESULTS: Forty-seven out of 50 subjects completed the protocol. Intention-to-treat and per protocol cure rates were 86% and 91%, respectively. The regimen was well tolerated. Study drugs were stopped in two patients due to side-effects. The most common side-effect was self-limited diarrhoea. CONCLUSION: Twice daily RBC-based triple therapy with metronidazole and clarithromycin for 1 week is well tolerated and effective in eradicating H. pylori infection.

Pharmacological therapy of Helicobacter pylori infection.

Helicobacter pylori has been associated with several diseases including peptic ulcer disease and gastric cancer. Eradication of H pylori not only results in ulcer healing, but reduces recurrences essentially curing peptic ulcer disease. Eradicating H pylori can be difficult. There are several reasons for antimicrobial failure, and the resistance rates for several antibiotics are increasing. The most common drugs used to treat this infection include amoxicillin, clarithromycin, tetracycline, bismuth, and omeprazole and lansoprazole. Dual therapy using a proton pump inhibitor and a single antibiotic gives a suboptimal eradication rate. Triple therapy using at least two antibiotics and either bismuth or a proton pump inhibitor gives satisfactory eradication rates of 90%. However, these regimens are complicated and have significant side effects and compliance problems. The ideal regimen has yet to be developed. In the future, we will prevent infection with immunization. Several vaccines are being developed.

Vector potential of houseflies (Musca domestica) for Helicobacter pylori.

The mode of transmission of Helicobacter pylori is unknown. Since viable bacteria have been shown to be excreted in feces from infected individuals and houseflies habitually develop and feed on excrement, we hypothesized that flies ingest and harbor H. pylori and, in turn, contaminate the human environment. This study examined the possible vector potential of houseflies (Musca domestica) for H. pylori. Caged houseflies were exposed to freshly grown H. pylori on agar plates. After a 6-h feeding period, the plates were removed and were replaced with sterile petri dishes containing a droplet of sterile brucella broth. At regular intervals, small numbers of houseflies were removed for microbiological and histological analysis, and the petri dishes were replaced with fresh sterile plates with fresh drops of brucella broth. The flies' bodies, the flies' dissected alimentary tracts, and excreta on the petri dishes were cultured for H. pylori, whose identity was confirmed by the urease, catalase, and oxidase reactions and Gram staining. In contrast to control flies, viable H. pylori could be isolated from external surfaces for up to 12 h and from gut and excreta for as long as 30 h after the initial feeding period. After 30 h other gram-negative bacteria overgrew the cultures of samples from all locations tested, rendering the selective culture of H. pylori colonies impossible. Histological analysis revealed Helicobacter-like organisms in the gut lumen and attached to intestinal epithelial cells. We conclude that houseflies can harbor viable H. pylori on their bodies and in their intestinal tracts. They are also able to disseminate viable H. pylori in excreta, and they may therefore present a significant reservoir and be a vector in the transmission of H. pylori.

Management of Helicobacter pylori infection in ulcer disease.

Eradication of the bacterium not only heals the ulcer but essentially cures the underlying peptic ulcer disease. Although there is still no simple, all-purpose regimen, a decade of experience has identified safe, well- tolerated drug combinations that yield eradication rates exceeding 90% without generating a high frequency of bacterial resistance.

Rabbit and ferret parietal cell inhibition by Helicobacter species.

We tested sonicates of Helicobacter pylori, H. mustelae, and H. felis for inhibition of acid secretion in rabbit and ferret isolated gastric glands. Three H. pylori strains, two of three H. mustelae strains, and two H. felis strains significantly inhibited acid secretion in rabbit cells by 95.2-93.3%, 55.9% and 96.4%, and 83.4-96%, respectively. All Helicobacter strains examined inhibited acid secretion by ferret cells by 65.3-76.8%, 89.1-97.6%, and 85.8-92.8%. H. pylori inhibited acid secretion after stimulation with histamine and isobutylmethylxanthine or with 8-bromo-cyclic adenosine monophosphate (P < 0.05 for all tests). These findings demonstrate that acid inhibition is a property common to the three Helicobacter species tested. It occurs independently of the mammalian origin of the parietal cell, and it does not involve blockade of histamine-2 receptors.

The political correctness of a physician hospital organization may precipitate its demise in a community hospital.

Health maintenance organizations are placing an increased pressure on physicians and hospitals to assume the risk of providing health care services under capitated agreements. They believe that if the providers' profits are based upon their cost-efficient provision of medical services, they will control their use of medical resources and reduce health care spending. Managing the risks of a capitated contract necessitates the integration of the hospital's and the physician's incentives. However, is the most appropriate legal structure that will enable physicians and hospitals to form risk-sharing contracts with managed care entities and manage these contracts profitably a physician-hospital organization? It is estimated that over 50 percent of the physician-hospital organizations that are created each year fail within the first two years of their operation because of political and financial reasons. A multispecialty group composed of select physicians, who are willing to integrate their practices and who have a low length of stay in the hospital, may be in a better position to manage the risks imposed by capitated contracts.

Changes in cell cycle-associated gene expression in a model of impaired liver regeneration.

Following partial hepatectomy (PH) there is compensatory regeneration of the remnant liver which eventually restores hepatic mass and function. The response to PH was studied in normal BALB/c and athymic nude mice, a model of impaired liver regeneration. Following PH, nude mice demonstrated diminished peak hepatic [3H]thymidine uptake and delayed liver mass restoration through 60 h post-PH. However, between 72-120 h there was no significant difference in mass restoration between the groups. The expression of genes associated with different stages of the cell cycle was evaluated in both models. In nude mice, there was an increase in peak expression of c-jun transcripts, while c-myc transcript expression was moderately attenuated. Thymidine kinase (TK) and cyclin-dependent kinase 1 (CDK1) mRNA expression was also diminished in athymic nude mice. The results suggest that while the defect in the regenerative response of the nude mouse after PH affects events in several phases of the cell cycle, mass restoration of the liver is only delayed and not attenuated.

Cyclin and cyclin-dependent kinase 1 mRNA expression in models of regenerating liver and human liver diseases.

There is compelling evidence that the eukaryotic cell cycle is controlled by a family of proteins called cyclins, which complex with cyclin-dependent kinases (CDK) to modulate key events during cell division. We have examined the regulation of these genes in models of experimental liver regeneration and their expression in human liver diseases. Seventy percent partial hepatectomy (PH) was performed on rats and normal BALB/c and athymic nude mice to determine patterns of cyclin and CDK1 mRNA expression. It has been previously shown by [3H]thymidine incorporation that athymic nude mice manifest impaired regeneration after PH. Our results demonstrate a sequential pattern of cyclin and CDK1 transcript expression in each of the models. Cyclin D1 was the most abundant mRNA steady-state transcript in the regenerating livers. CDK1 and cyclins associated with later stages of the cell cycle showed delayed and diminished expression in nude mice compared with normals. Nuclear run-off assays performed at key time points post-PH revealed little change in transcription rates, suggesting that steady-state mRNA expression of the cyclin genes is regulated primarily by posttranscriptional events. Human liver tissue from various acute and chronic hepatic diseases showed increased expression of cyclins A and D1. We conclude that the regenerating liver post-PH offers an excellent in vivo model for studying cyclin and CDK gene expression. Impaired regeneration in the nude mouse is associated with altered cyclin and CDK1 mRNA transcript expression. Furthermore, cyclins may eventually provide clinically relevant molecular markers of regenerative activity in human liver diseases.

Placental site trophoblastic tumor: a report of radiologic, surgical, and pathologic methods of evaluating the extent of disease.

A dramatic vaginal hemorrhage occurred 1 year after a normal vaginal delivery. A curettage showed placental site trophoblastic tumor. Magnetic resonance imaging and color flow Doppler documented a marked increase in uterine vascularity, as well as an abnormal endomyometrial appearance. Surgery included total abdominal hysterectomy and pelvic lymph node dissection. This confirmed the extensive uterine tumor and also showed an extremely small focus of tumor cells in one lymph node. Immunohistochemical staining for human placental lactogen and for cytokeratin confirmed the histologic finding. After surgery, we gave adjuvant chemotherapy with the EMACO regimen. The radiologic, surgical, and pathologic procedures utilized in this case provided a more complete understanding of the extent of her disease. These techniques may be helpful in making therapeutic decisions for other women with this rare disorder.

Primary biliary carcinoma with metastasis to the ovary.

The ovary is a relatively frequent site of metastasis from malignant neoplasia arising elsewhere in the body, the majority of these originating from the GI tract. The best known tumor of this type is signet-ring cell adenocarcinoma (Krukenberg tumor) of gastric origin. The gall bladder and bile ducts are rare sources of these metastases. Asymptomatic carcinoma of the cystic duct metastasizing to the ovary is extremely rare. We are reporting such a case in which the patient presented with no GI or hepatic symptoms. The cystic duct carcinoma was an incidental finding from routine and careful examination of the abdominal viscera.

Pollution prevention as a market-enhancing strategy: a storehouse of economical and environmental opportunities.

EPA's (Environmental Protection Agency) Green Lights Program for energy-efficient lighting illustrates the economic benefits and the market-transforming value of a pollution prevention philosophy. Using technologies available today, and assuming current prices, this program is expected to reduce air pollution 5%, while saving the nation's businesses up to 20 billion in electric bills every year. However, these pollution prevention and savings estimates may be low. As Green Lights transforms the market for lighting services by creating a higher demand for better technologies at lower costs, the program will likely achieve even larger pollution reductions and electricity savings.

Integrating biologic and psychologic treatment: the need for a unitary model.

Psychiatric illness tends to be conceptualized as either a biologic or psychologic process, a dichotomy that is inevitably reflected in treatment. A unitary model encourages the psychotherapist to incorporate biologic modalities as a meaningful interaction within the therapy. The biologic therapist, in turn, can be more effective when aware that even severe mental illness is also a psychologic process. Causality cannot be inferred from severity of illness nor should it be used to rationalize a two-track approach to treatment. Biologic treatment should never be considered a treatment of last resort.

Long-term fluoxetine treatment of a large number of obsessive-compulsive patients.

A group of 75 outpatients suffering from obsessive-compulsive disorder began treatment with the bicyclic antidepressant fluoxetine in an open clinical setting. Their progress was evaluated using the Hamilton Depression Scale, the Hamilton Anxiety Scale, and a global scale of severity of obsessive-compulsive symptoms. The group showed significant improvement on all measures. This improvement continued and was progressive over a 5-month period. Weight loss was present but not significant by the end of the 5-month period.

Immature teratoma of the ovary.

Twenty-five cases of patients with pure immature teratoma of the ovary, accrued from the Connecticut Tumor Registry from 1969 to 1984, were reviewed. Two patients had grade 1 tumors, twelve had grade 2 tumors, and eleven had grade 3 tumors. The majority of patients (23) were stage I at the time of initial surgery. Twenty-one of the twenty-three patients were treated with some form of unilateral adnexal surgery with or without adjuvant combination chemotherapy (VAC). Two of the twenty-three patients were treated with total abdominal hysterectomy/bilateral salpingo-oophorectomy (TAH/BSO) with the addition of either VAC chemotherapy or radiation therapy. Recurrence occurred in two patients, both of whom had grade 3 tumors and were subsequently treated with surgical resection plus VAC chemotherapy. One patient, who recurred after initial therapy with unilateral salpingo-oophorectomy (USO) plus VAC chemotherapy, was successfully treated with surgical resection and further chemotherapy. Two patients were stage III at the time of initial surgery, one of whom was treated with USO plus adjuvant combination chemotherapy and radio-therapy. The other patient was treated with TAH/BSO plus VAC chemotherapy. In our series, no patient died from immature teratoma (one patient died from advanced breast carcinoma). It is reasonable to withhold chemotherapy from patients with stage I, grade 1 and 2, immature teratoma which may be treated initially with conservative surgery. The risk of recurrence in patients with grade 3 tumors warrants the addition of further chemotherapy.