Management of locally advanced cervical cancer

PURPOSE OF REVIEW: Cervical cancer is a significant global public health problem. In underdeveloped countries where screening programs are not widely available and in underserved populations in developed countries, women commonly present with locally advanced disease that is not curable by any extent of radical hysterectomy. This review will critically evaluate the evidence supporting the available treatment modalities for locally advanced cancer of the uterine cervix. RECENT FINDINGS: Concurrent cisplatin-based chemotherapy and radiation have demonstrated significant survival improvement for patients with locally advanced cervical cancer. Advances in imaging and radiotherapy technologies, the inclusion of newer agents to the chemoradiation regimens, the use of new hypoxic cell radiosensitizers and monoclonal antibodies that inhibit cell growth, with consequent increase in malignant cell kill fractions, are some of the new therapeutic options that may be used to improve the survival of these patients. SUMMARY: Continued improvement in understanding the natural history of cervical cancer, the limitations of the current staging system, and these newer therapeutic options will increase the efficacy of chemoradiation and improved the survival of these patients.     

Dehydroepiandrosterone inhibits the progression phase of mammary carcinogenesis by inducing cellular senescence via a p16-dependent but p53-independent mechanism

Introduction

Dehydroepiandrosterone (DHEA), an adrenal 17-ketosteroid, is a precursor of testosterone and 17β-estradiol. Studies have shown that DHEA inhibits carcinogenesis in mammary gland and prostate as well as other organs, a process that is not hormone dependent. Little is known about the molecular mechanisms of DHEA-mediated inhibition of the neoplastic process. Here we examine whether DHEA and its analog DHEA 8354 can suppress the progression of hyperplastic and premalignant (carcinoma in situ) lesions in mammary gland toward malignant tumors and the cellular mechanisms involved.

Methods

Rats were treated with N-nitroso-N-methylurea and allowed to develop mammary hyperplastic and premalignant lesions with a maximum frequency 6 weeks after carcinogen administration. The animals were then given DHEA or DHEA 8354 in the diet at 125 or 1,000 mg/kg diet for 6 weeks. The effect of these agents on induction of apoptosis, senescence, cell proliferation, tumor burden and various effectors of cellular signaling were determined.

Results

Both agents induced a dose-dependent decrease in tumor multiplicity and in tumor burden. In addition they induced a senescent phenotype in tumor cells, inhibited cell proliferation and increased the number of apoptotic cells. The DHEA-induced cellular effects were associated with increased expression of p16 and p21, but not p53 expression, implicating a p53-independent mechanism in their action.

Conclusion

We provide evidence that DHEA and DHEA 8354 can suppress mammary carcinogenesis by altering various cellular functions, inducing cellular senescence, in tumor cells with the potential involvement of p16 and p21 in mediating these effects.     

Interseasonal variability in biomarkers of exposure in fish inhabiting a southwestern Australian estuary

The Swan-Canning Estuary, in southwestern Australia, undergoes distinct seasonal changes, with freshwater discharge predominant in the winter (wet) season and low flow with high salinity predominant in the dry summer season. To investigate seasonal variability in biomarkers of exposure in fish, black bream (Acanthopagrus butcheri) were collected from seven sites in the Swan-Canning Estuary in winter 2000 and in summer 2001. No interseasonal or intersite differences in serum sorbitol dehydrogenase concentration were found, indicating the measured mixed-function oxygenase (MFO) enzymes were not influenced by liver damage. The ethoxyresorufin-O-deethlyase (EROD) activity of the postspawning females was higher in summer than in winter but was significantly lower than that in males in both seasons, suggesting estradiol suppression in females. Sexual differences in ethoxycoumarin-O-deethylase (ECOD) activity were not evident in either season. Both EROD and ECOD activities and polycyclic aromatic hydrocarbons (PAH) biliary metabolites had significantly different patterns of induction between seasons. The ratio of naphthalene-type to benzo(a)pyrene-type biliary metabolites was significantly higher in summer, indicating the sources of petroleum hydrocarbons were petrogenic compared to in winter, when the source was a mixture of pyrogenic and petrogenic PAHs. There was no upstream or downstream gradient of response in any biomarker in either season, demonstrating that there were multiple sources of contaminant input into the estuary. Although winter biomarker levels were triggered by the discharge runoff from major roads and drains, summer biomarker levels appear to have been related to recreational boating use on the estuary.     

Methodologic considerations for improving and facilitating human milk research

Over the past several decades, interest in using human milk as a biomonitoring matrix has increased. However, it is not always an easy matter for a new mother to provide a milk sample. In this article, guidance on facilitating collection of human milk is provided. This includes addressing the mother's ease in expressing a milk sample, and engaging with many audiences to reduce the likelihood of negatively impacting the already low breastfeeding rates in the United States. In addition, this article covers concepts regarding long-term storage and integrity of human milk samples to maximize the utility of those samples, and proposed methods for improving public access to the full spectrum of human milk biomonitoring data, with context to understand the information presented. The environmental chemicals and chemical classes for which robust analytical methods exist are enumerated, and a process for prioritizing the development of analytical methods for additional environmental chemicals is described.     

The pharmacokinetics of etanercept in patients with end-stage renal disease on haemodialysis

Inflammation is strongly associated with malnutrition and cardiovascular risk in patients with chronic renal failure on haemodialysis (HD). The acute-phase inflammatory response, defined by the increased synthesis of positive acute-phase proteins, is stimulated by the production of such cytokines as interleukin 6 (IL-6), interleukin 1 (IL-1) and tumour necrosis factor-alpha TNF-alpha The availability of cytokine antagonists allows testing of the hypothesis that suppression of inflammation reverses the malnutrition-inflammation syndrome in HD patients. Etanercept is a soluble TNF-alpha receptor fusion protein used to suppress inflammation in rheumatoid and psoriatic arthritis. Its metabolism in HD patients is unknown. In a study designed to test the safety and pharmacokinetics of etanercept in HD patients, etanercept was administered to six HD patients with albumin levels above 4.2 g dL(-1) and C-reactive protein levels <5 mg L(-1) (five men, one woman, age range 34-59 years). Etanercept (25 mg) was administered subcutaneously twice weekly immediately after dialysis for 13-16 weeks. Etanercept concentrations were measured pre- and post-dialysis by ELISA. Concentrations were compared graphically to assess whether, firstly, dialysis affects etanercept apparent clearance and, secondly, etanercept kinetics were similar between HD patients and the more extensively studied psoriasis population with normal renal function (PS). The second stage examined model-based parameter predictions of the terminal elimination rate constant (k) for HD patients. Steady-state etanercept levels were comparable between HD and PS patients. Treatment with HD had no effect on etanercept levels. When etanercept was discontinued, the terminal rate constant for HD patients was not significantly different from that observed in PS patients. No adverse effects were noted during the 3-month treatment phase and subsequent 6-month follow-up. Albumin and C-reactive protein levels did not change in these non-inflamed patients during the study period. The pharmacokinetics of etanercept in patients with chronic renal failure on HD are similar to patients with normal renal function. It is, therefore, feasible to administer etanercept to HD patients without adjusting the dose.     

Interannual variability in fish biomarkers in a contaminated temperate urban estuary

During the past decade the Swan-Canning estuary, Western Australia, has shown signs of stress which has been attributed to high nutrient inputs. There is little information on the effect of nonnutrient contaminants on biota inhabiting the estuary. A suite of biomarkers was measured on black bream (Acanthopagrus butcheri) to determine whether annual variations in fish biomarkers exist in the wet (winter) and dry (summer) seasons. Serum sorbitol dehydrogenase showed no significant differences between years, indicating that measured mixed-function oxygenase (MFO) enzyme activities were not affected by annual variations in hepatic tissue damage. Ethoxyresorufin-O-deethylase activity was lower in female black bream than in male fish while ethoxycoumarin-O-deethylase activity was not influenced by gender. Biomarker levels measured at various sites confirm that major roads and drains are significant contributors of MFO-inducing chemicals into the Swan-Canning estuary. No consistent upstream or downstream gradient in biomarker response was identified. The ratio of naphthalene-type to benzo(a)pyrene-type biliary metabolites was linked to runoff from urban areas into the estuary. There was high annual variability in all biomarkers in both seasons, suggesting that biannual monitoring is required to evaluate the effect of contaminants on the biota in the estuary.     

Pain Impacts Sexual Functioning among Interstitial Cystitis Patients

Ethnographic methods were used to gather illness narratives on 11 men and 38 women diagnosed with interstitial cystitis (IC). Content analysis using the Spradley ethnographic method reveals that patients directly link IC pain to diminished sexual functioning. We conclude: (1) Patients with IC are deeply concerned about diminished sexual function. Physicians and rehabilitation specialists should actively investigate and treat this problem. (2) Management of IC pain is inadequate and leads to disability and changes in sexual practices. (3) Linking treatments for sexual dysfunction with appropriate pain management strategies could substantially improve the quality of life for patients with IC. Structural factors in medical delivery along with health insurance policies reduce patient access to a comprehensive and interdisciplinary set of needed health interventions that could make a difference in the treatment of persistent pelvic pain and sexual dysfunction. Recognition of these structural issues is the key to improved health service delivery.     

Simultaneous ipsilateral ruptures of the anterior cruciate ligament and patellar tendon: a case report

The simultaneous diagnosis of ipsilateral patellar tendon rupture and anterior cruciate ligament tear is rare. Surgical repair is complicated by different rehabilitation regimens as well as anterior cruciate ligament graft choices. We present a case where at the same operative setting, the patellar tendon was repaired, and the anterior cruciate ligament reconstructed with autologous hamstring graft.