Bioactive suture: a novel immunotherapy for head and neck cancer.

PURPOSE: We have proposed to characterize the mechanism through which bioactive surgical sutures generate a T(H)1 immune response and to define the immune-stimulating half-life of the sutures. EXPERIMENTAL DESIGN: Bioactive sutures of interferon gamma (IFNgamma), interleukin 2 (IL-2), anti-CD3/CD28, anti-CD3/CD28 + IL-2, or anti-CD3/CD28 + IFNgamma sutures were used to stimulate lymphocytes from normal donors and from head and neck cancer patients in vitro over a 24-day period. Cell supernatants were analyzed by ELISA, and T cells were phenotyped to characterize the immune response generated. Intracellular cytokine staining was performed to measure the expansion of flu-specific T cells. Electromobility shift assay and supershift assay were used to measure the intranuclear DNA binding activity of nuclear factor kappaB and its p65 subunit in T cells activated by sutures in the presence and absence of a proteasome inhibitor, MG-132. RESULTS: Anti-CD3/CD28, anti-CD3/CD28 + IL-2, or anti-CD3/CD28 + IFNgamma generated a prolonged T(H)1 immune response for 18 days in vitro. Anti-CD3/CD28 expanded flu-specific T cells. Activated T cells demonstrated enhanced CD40 ligand (CD40L) expression within 72 hours of stimulation, which stimulated other cells to secrete IL-12. Stimulated T cells demonstrated increased intranuclear expression of nuclear factor-kappaB, which was blocked by MG-132, and also reduced CD40L and IL-12 expression. CONCLUSIONS: This is the first report to demonstrate that bioactive surgical sutures can generate a prolonged T(H)1 immune response and expand flu-specific T cells. Bioactive sutures, which are primarily a T-cell stimulant, also stimulated other cells to secrete IL-12 and prolonged the immune response. Sutures may provide a novel in situ stimulating strategy for enhancing the immune system of cancer patients.     

Bladder pheochromocytoma encountered on sonography

Pheochromocytomas of the bladder are rare neoplasms, constituting <0.06% of all vesical tumours. Common presenting features of this tumour include episodes of sweating, hypertension, haematuria and postmicturition syncope. We describe a case of bladder pheochromocytoma in a 66‐year‐old man whose only symptom of macroscopic haematuria was initially assessed with ultrasonography. Clinical presentation highlights the need for a high index of suspicion during sonographic evaluation of bladder neoplasms because such tumours might present without symptoms of adrenergic excess.     

The outcome of liver transplantation in patients with hepatocellular carcinoma in the United States between 1988 and 2001: 5-year survival has improved significantly with time.

PURPOSE: We hypothesized that the outcome of liver transplantation in patients with hepatocellular carcinoma (HCC) has improved over the past decade because of the application of published criteria for patient selection. In this study, we compared the outcome of liver transplantation in patients with and without HCC at different time periods using the United Network for Organ Sharing data. PATIENTS AND METHODS: We excluded children, patients with multiple organ transplantation or retransplantation, and those with incomplete survival data. The study period was arbitrarily divided into three time intervals: 1987 to 1991, 1992 to 1996, and 1997 to 2001. RESULTS: During the study period, 985 patients with HCC (HCC group), and 33,339 without HCC underwent liver transplantation (control group). Kaplan-Meier patient and graft survivals were significantly lower for the HCC group compared with the control group. Cox regression analysis (after adjusting for other confounding variables) confirmed a lower patient survival in the HCC group (1-year survival, 77.0% v 86.7%; hazard ratio [HR], 1.7; 95% CI, 1.5 to 2.0; P <.0001) compared with the control group (5-year survival, 48.2% v 74.7%; HR, 2.2; 95% CI, 1.9 to 2.4; P <.0001); HCC was an independent predictor of survival. Kaplan-Meier analysis showed a significant improvement in 5-year patient survival with time in patients with HCC (1987 to 1991, 25.3%; 1992 to 1996, 46.6%; 1997 to 2001, 61.1%; P <.0001). During the same period, there was only minimal improvement in survival among the control group. CONCLUSION: Five-year survival of patients transplanted for HCC is excellent, with a steady improvement in survival over the past decade. It is possible that the published criteria for patient selection may have contributed to the better outcome.     

Actual half-life of alpha-fetoprotein as a prognostic tool in pediatric malignant tumors

In a retrospective study, the prognostic value of monitoring the decay of alpha-fetoprotein (AFP) was assessed. Serum AFP was determined serially in 18 children with malignant germ-cell or hepatic tumors: 7 endodermal sinus tumor, 3 embryonal carcinoma, 5 malignant teratoma, 2 hepatoblastomas, and 1 hepatocellular carcinoma. The actual half-life (AHL) of AFP was computed after surgical resection of the tumor. In group 1, which had complete resection and no recurrence during follow-up (n = 13), the AHL of AFP was 4.0 ± 0.9 days. In group 2, which had incomplete resection or recurrence during follow-up (n = 5), the AHL of AFP was 24.8 ± 20 days, significantly longer than that of group 1 (P = 0.0026). The increased AHL of AFP indicated residual active tumor after surgical resection. The AHL of AFP may be more sensitive than serial monitoring of AFP in detecting preclinical recurrence after surgical resection of AFP-secreting tumors. Treatment strategies can be based on AFP clearance, and prospective clinical trials are warranted.     

Hydrogen peroxide inhibits gap junctional intercellular communication in glutathione sufficient but not glutathione deficient cells

Cell to cell communication via gap junctions is essential in the maintenance of the homeostatic balance of multicellular organisms. Aberrant intercellular gap junctional communication (GJIC) has been implicated in tumor promotion, neuropathy and teratogenesis. Oxidative stress has also been implicated in similar pathologies such as cancer. We report a potential link between oxidative stress and GJIC. Hydrogen peroxide, a known tumor promoter, inhibited GJIC in WB-F344 rat liver epithelial cells with an I50 value of 200 microM. Inhibition of GJIC by H2O2 was reversible as indicated by the complete recovery of GJIC with the removal of H2O2 via a change of fresh media. Free radical scavengers, such as t-butyl alcohol, propylgallate, and Trolox, did not prevent the inhibition of GJIC by H2O2, which indicated that the effects of H2O2 on GJIC was probably not a consequence of aqueous free radical damage. The depletion of intracellular GSH reversed the inhibitory effect of H2O2 on GJIC. The treatment of glutathione- sufficient cells with H2O2 resulted in the hyperphosphorylation of connexin43, which is the basic subunit of the hexameric gap junction protein, as determined by Western blot analysis. TPA, a well-known tumor promoter, also inhibits GJIC via hyperphosphorylation of GJIC, which is a result of protein kinase-C activation. However, H2O2 also induced hyperphosphorylation in GSH-deficient cells that had normal rates of GJIC. Therefore, the mechanism of GJIC inhibition must be different from the TPA-pathway and involves GSH.      

Quality of life (QOL) assessment of MIP (mitomycin, ifosfamide and cisplatin) chemotherapy in advanced non-small cell lung cancers (NSCLC)

BACKGROUND: Quality of life (QOL) assessment has emerged to measure and quantify the balance between treatment benefit and toxicity, and has a value in predicting response and overall survival in cancer patients. METHODS: From July 1995 to February 1997, 38 symptomatic patients with advanced non-small cell lung cancer (NSCLC) were treated with MIP chemotherapy (mitomycin 6 mg/m2, ifosfamide 3000 mg/m2 and cisplatin 50 mg/m2 on day 1 every 3 weeks). Patients were assessed for QOL including physical well-being, general symptoms and lung cancer-specific symptoms, as well as objective response. RESULTS: The overall response rate was 38.9% (14/36, all were partial response) and the median duration of response was 3.5 months [95% confidence interval (CI) 2.0-4.0]. The median duration of overall survival was 7 months (95% CI 5.9-8.5). The overall improvement of QOL was 58.3% with 21 patients feeling better on treatment. The toxicity of chemotherapy was mild, mainly nausea/vomiting and minimal alopecia. Using multiple clinical predictors of survival (age, histology, stage, performance status), only change of QOL emerged significantly (P = 0.0007). CONCLUSIONS: MIP had an endurable response and low toxicity profile, and provided good QOL. Integral QOL data in our study provided the strong prediction of survival in advanced NSCLC. Further experienced QOL study will provide greatly enhanced outcome data in clinical trials.      

Mechanism of the beneficial effects of pentoxifylline during sepsis: maintenance of adrenomedullin responsiveness and downregulation of proinflammatory cytokines

BACKGROUND: Although it is known that pentoxifylline (PTX) produces various beneficial effects during sepsis, it remains unknown whether this agent has any salutary effects on the depressed vascular responsiveness to adrenomedullin (ADM), a novel potent vasodilatory peptide, under such conditions. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). One hour after CLP, PTX (50 mg/kg body wt) or vehicle (normal saline) was infused intravenously over 90 min. Twenty hours after CLP (i.e., the late, hypodynamic stage of sepsis), the thoracic aorta and small intestine were isolated and preconstricted by norepinephrine. Rat ADM (10(-7) M) was applied, and the percentage of ADM-induced relaxation in the aortic rings and resistance vessels in the small intestine was determined. In addition, plasma ADM was determined by radioimmunoassay and tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 levels were measured by enzyme-linked immunosorbent assay. RESULTS: The percentage of ADM-induced vascular relaxation in the aortic rings and resistance vessels of the isolated gut was significantly reduced 20 h after CLP. Administration of PTX early after the onset of sepsis, however, prevented the decrease in vascular ADM responsiveness at the macro- and microcirculatory levels. Plasma ADM levels increased after CLP, irrespective of PTX infusion, indicating that the effect of PTX was not mediated by altering ADM release. The upregulated TNF-alpha, IL-1beta, and IL-6 during late sepsis were, however, attenuated by PTX administration, suggesting that maintenance of ADM responsiveness by this agent appears to be due to downregulation of these cytokines. CONCLUSIONS: Since early administration of PTX maintains vascular ADM responsiveness even during the late stage of sepsis, this agent appears to be a useful adjunct in preventing the deterioration in hemodynamics and cardiovascular function during the progression of polymicrobial sepsis.     

Impacts of Informal Caregiver Availability on Long-term Care Expenditures in OECD Countries

Objective. To quantify the effects of informal caregiver availability and public funding on formal long-term care (LTC) expenditures in developed countries.
Data Source/Study Setting. Secondary data were acquired for 15 Organization for Economic Cooperation and Development (OECD) countries from 1970 to 2000.
Study Design. Secondary data analysis, applying fixed- and random-effects models to time-series cross-sectional data. Outcome variables are inpatient or home heath LTC expenditures. Key explanatory variables are measures of the availability of informal caregivers, generosity in public funding for formal LTC, and the proportion of the elderly population in the total population.
Data Collection/Extraction Method. Aggregated macro data were obtained from OECD Health Data, United Nations Demographic Yearbooks, and U.S. Census Bureau International Data Base.
Principal Findings. Most of the 15 OECD countries experienced growth in LTC expenditures over the study period. The availability of a spouse caregiver, measured by male-to-female ratio among the elderly, is associated with a $28,840 (1995 U.S. dollars) annual reduction in formal LTC expenditure per additional elderly male. Availability of an adult child caregiver, measured by female labor force participation and full-time/part-time status shift, is associated with a reduction of $310 to $3,830 in LTC expenditures. These impacts on LTC expenditure vary across countries and across time within a country.
Conclusions. The availability of an informal caregiver, particularly a spouse caregiver, is among the most important factors explaining variation in LTC expenditure growth. Long-term care policies should take into account behavioral responses: decreased public funding in LTC may lead working women to leave the labor force to provide more informal care.