Temporal profile of potassium channel dysfunction in cerebrovascular smooth muscle after experimental subarachnoid haemorrhage

The pathogenesis of cerebral vasospasm after subarachnoid haemorrhage (SAH) involves sustained contraction of arterial smooth muscle cells that is maximal 6–8 days after SAH. We reported that function of voltage-gated K⁺ (K_V) channels was significantly decreased during vasospasm 7 days after SAH in dogs. Since arterial constriction is regulated by membrane potential that in turn is determined predominately by K⁺ conductance, the compromised K⁺ channel dysfunction may cause vasospasm. Additional support for this hypothesis would be demonstration that K⁺ channel dysfunction is temporally coincident with vasospasm. To test this hypothesis, SAH was created using the double haemorrhage model in dogs and smooth muscle cells from the basilar artery, which develops vasospasm, were isolated 4 days (early vasospasm), 7 days (during vasospasm) and 21 days (after vasospasm) after SAH and studied using patch-clamp electrophysiology. We investigated the two main K⁺ channels (K_V and large-conductance voltage/Ca²⁺-activated (K_Ca) channels). Electrophysiologic function of K_Ca channels was preserved at all times after SAH. In contrast, function of K_V channels was significantly decreased at all times after SAH. The decrease in cell size and degree of K_V channel dysfunction was maximal 7 days after SAH. The results suggest that K_V channel dysfunction either only partially contributes to vasospasm after SAH or that compensatory mechanisms develop that lead to resolution of vasospasm before K_V channels recover their function.     

Ontogeny of plasma cells in the early rat yolk sac

The present study investigated the development of plasma cells in the early rat yolk sac (days 10-16 of gestation) by light microscopy, transmission electron microscopy, immunoelectron microscopy, and indirect immunofluoresce techniques. Cells delineating the morphology of plasma cells in the yolk sac were observed as early as 12 days of embryonic life. As for positive immune staining for the intra-cytoplasmic immunoglobulin (Ig) production (IgA, IgM and IgG), the intensity of the immune staining was very weak on days 10 and 11 of gestation, while it turned very dense on day 12 of gestation. At 14 days of gestation, the number of positive cells was markedly reduced. Immunoelectron microscopy visualized products of the immune reaction in cisterns of the rough endoplasmic reticulum. Conventional electron microscopic examination of 12, 13, and 16-day yolk sacs confirmed the development and differentiation of plasma cells with their well-known ultrastructural features, making this the first study to demonstrate these in the early rat yolk sac. The development of plasma cells in the early yolk sac implies the ability of the yolk sac to effect a humoral immune response at this stage of fetal life. The probable role of plasma cells in the yolk sac is also discussed.     

Radical nephrectomy with resection of vena cava thrombus using extracorporeal circulation and deep hypothermic circulatory arrest

IntroductionPatients with renal cell carcinoma (RCC) with level 3 or 4 caval thrombus have a poor prognosis, with reported five-year survival rates of 30–40%. The aim of this study was to assess the perioperative morbidity and long-term oncological outcomes for radical nephrectomy with resection of vena cava thrombus using a combined surgical approach, including extracorporeal circulation and deep hypothermic circulatory arrest.MethodsA retrospective review was performed of the institutional case log to identify all radical nephrectomies with caval thrombus performed from January 2006 to May 2020.ResultsTwenty-five patients were identified with level 2 thrombus in one (4%), level 3 thrombus in eight (32%), and level 4 in 16 (64%). The median followup was 20.6 months (range 0.2–133.3). The median age at surgery was 68.4 years (range 44.2–85.5). Twenty-one (84%) patients were symptomatic at presentation. Six (24%) patients had distant metastases at diagnosis. The median circulatory arrest time was 15 minutes (range 6–35). The 30-day grade ≥3 complication rate was 8%. The 30-day mortality rate was 8%. The one-year, two-year, three-year, and five-year recurrence-free survival (RFS) rates were 53%, 18%, 10%, and 10%, respectively. The median time to systemic treatment was 7.7 months (range 1.2–25.7). The one-year, two-year, three-year, and five-year overall survival (OS) rates were 70%, 43%, 36%, and 31%, respectively.ConclusionsRadical nephrectomy with resection of vena cava thrombus using extracorporeal circulation and deep hypothermic circulatory arrest is associated with some morbidity and mortality but remains a safe and effective strategy for advanced RCC patients who would otherwise be managed palliatively.     

Ifosfamide, methotrexate, and 5-fluorouracil: effective combination in resistant breast cancer

Ifosfamide has definite efficacy in many malignant tumours, including breast cancer. In the present study we substituted cyclophosphamide with ifosfamide in the combination CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) regimen in 25 patients with breast cancer whose disease was refractory to CMF or who had relapsed after previous response. Ifosfamide was given in an i.v. infusion at a dose of 1.2 g/m² daily for 5 days, together with mesna as a uroprotector (at 20% of the ifosfamide dose). Methotrexate was given at a dose of 40 mg/m² and 5-fluorouracil was given at 600 mg/m², both by i.v. push. Courses were repeated every 21 days. The 24 evaluable patients received 3–12 courses (average, 5 courses); results included a complete remission in 3 patients (12.5%) and a partial remission in 3 (12.5%). Among the remaining patients, improvement was seen in 4 (16.6%); stable disease, in 7; and progressive disease, in 7 (29.2%). The complete responses lasted for 11+, 13+, and 15+ months, and partial remissions, for 2, 6, and 9 months. The responses were detected in soft-tissue as well as visceral lesions, but not in bony lesions. The responders remain under follow-up. This study shows the efficacy of ifosfamide-containing chemotherapy in breast cancer. As toxicities were tolerable, higher doses of ifosfamide could safely be used in these patients. Use of this combination as first-line therapy in breast cancer could be considered for a future study.Presented at the Satellite Symposium Ifosfamide in Gynecological Tumors of the 5th European Conference on Clinical Oncology and Cancer Nursing, London, September 3–7, 1989     

Clinical significance of technetium-99m methylene diphosphonate myocardial uptake: association with carcinoma of the prostate

Benign myocardial uptake of technetium-99m labelled phosphates, not related to cardiac or metabolic disorders, has been documented except in the case of^99mTc-methylene diphosphonate (MDP). The aim of this study was to assess the frequency of myocardial uptake and its possible association with malignant tumours in general and prostatic carcinoma in particular. We reviewed bone scintigrams performed with either^99mTc-hydroxydiphosphonate (HDP) or^99mTc-MDP over a period of more than 2 years for all patients with prostatic carcinoma and a matching group of patients suffering from other malignant and non-malignant disorders. A total of 965 scintigrams of 812 patients (males=559, females=253; age range 50–91 years, average age 69.2 years) were reviewed. Increased myocardial uptake was detected in 19 scintigrams (MDP=13, HDP=6) of 18 patients (17 males, one female). Most of the male patients with increased myocardial uptake had prostatic carcinoma (13/17) and were over 80 years of age (12/17). All patients were free of any cardiac or noncardiac disorder that might account for such uptake. When scintigraphy was repeated in the same patient, the uptake of^99mTc-HDP was more diffuse and of higher grade than that of^99mTc-MDP Benign myocardial uptake of^99mTc-MDP is more common than previously thought. Although uptake of radiophosphates is attributed to asymptomatic atherosclerotic changes associated with old age, a strong association with prostatic carcinoma exists which may indicate variations in the bone: soft tissue affinity of different MDP complexes.     

Loss of Fhit expression in head and neck squamous cell carcinoma and its potential clinical implication.

PURPOSE: Abnormalities of FHIT, a candidate tumor suppressor gene, have frequently been found in multiple malignancies, including head and neck squamous cell carcinoma (HNSCC). To define its role in HNSCC treated with surgery and postoperative radiotherapy (PORT), the Fhit protein expression status was investigated in 80 patients enrolled in a prospective Phase III clinical trial addressing the dose and fractionation regimen of PORT. EXPERIMENTAL DESIGN: Immunohistochemical staining of HNSCC tissue sections for Fhit expression was performed. The Fhit expression status was correlated with the clinicopathological characteristics and clinical course. The median follow-up duration was 4.9 years. RESULTS: Loss of Fhit expression was found in 52 of the 80 study patients (65%). There was not a significant association between Fhit expression and clinical characteristics. Patients whose tumor exhibited negative Fhit expression had a significantly worse 5-year overall survival duration [hazard ratio = 0.49; 95% confidence interval, 0.23-1.03; P = 0.05 (log-rank test)] than did those whose tumor exhibited positive Fhit expression. One third of the patients with a Fhit-negative tumor had distant metastasis during the follow-up period. Paradoxically, patients classified as high risk who had a Fhit-negative tumor experienced locoregional recurrence less often (18%) than did high-risk patients who had a Fhit-positive tumor (33%). CONCLUSIONS: Loss of Fhit expression is a poor prognostic indicator in patients with HNSCC. However, tumors lacking Fhit expression may be more sensitive to PORT and therefore more susceptible to locoregional control.     

The potential palliative role and possible immune modulatory effects of low-dose total body irradiation in relapsed or chemo-resistant non-Hodgkin's lymphoma.

In a group of 35 patients with relapsed and/or chemo-resistant non-Hodgkin's lymphoma (NHL), low-dose total body irradiation (LTBI) (+involved-field radiotherapy to bulky sites) achieved a complete remission rate of 29%, 2-years progression-free survival of 32% and a median progression-free survival of 12 months. The 2-year survival was 42% and the median survival was 17 months. Immuno-staining and flow cytometry of peripheral blood in 14 patients showed that LTBI leads to a significant increase in the percentage of CD4+ cells with a consequent significant increase in the CD4+/CD8+ ratio. High lymphocytic percent and a high percentage of CD4+ cells before LTBI were significantly correlated with longer response duration and overall survival. These data may suggest that the palliative potential of LTBI should be investigated as an alternative to chemotherapy in NHL patients. The pre-treatment percentage of lymphocytes and CD4+ cells may be used as predictors for response to LTBI.     

Paclitaxel decreases the interstitial fluid pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant chemotherapy: clinical implications.

PURPOSE: It has been hypothesized that tumors with high interstitial fluid pressure (IFP) and/or hypoxia respond poorly to chemotherapy (CT) because of poor drug delivery. Preclinical studies have shown that paclitaxel reduces the IFP and improves the oxygenation (pO(2)) of tumors. Our aim is to evaluate the IFP and pO(2) before and after neoadjuvant CT using sequential paclitaxel and doxorubicin in patients with breast cancer tumors of >/= 3 cm. PATIENTS AND METHODS: Patients were randomly assigned, according to an institutional review board-approved phase II protocol, to receive neoadjuvant sequential CT consisting of either four cycles of dose-dense doxorubicin at 60 mg/m(2) every 2 weeks followed by nine cycles of weekly paclitaxel at 80 mg/m(2) (group 1) or vice versa, with paclitaxel administered before doxorubicin (group 2). Patients were re-evaluated clinically and radiologically. The IFP (wick-in-needle technique) and pO(2) (Eppendorf) were measured in tumors at baseline and after completing the administration of the first and second drug. RESULTS: IFP and pO(2) were measured in 54 patients at baseline and after the first CT. Twenty-nine and 25 patients were randomly assigned to groups 1 and 2, respectively. Paclitaxel, when administered first, decreased the mean IFP by 36% (P = .02) and improved the tumor pO(2) by almost 100% (P = .003). In contrast, doxorubicin did not have a significant effect on either parameter. This difference was independent of the tumor size or response measured by ultrasound. CONCLUSION: Paclitaxel significantly decreased the IFP and increased the pO(2), whereas doxorubicin did not cause any significant changes. Tumor physiology could potentially be used to optimize the sequence of neoadjuvant CT in breast cancer.     

ROLE OF INTERMEDIARY BIOMARKERS IN DETERMINING THE ANTICANCER EFFICACY OF MARINE COMPOUNDS

In the present study, two of the probable an umor marine compounds, manzamine A and sarcophine, were screened using benzo[a]pyrene (BP)-derived DNA adduct formation in MCF-7 cells as intermediary biomarker. Briefly, MCF-7 cells were treated with the compounds for 24 h followed by treatment with BP (0.5 μM). After 24h incubation, cellular DNA was isolated and analyzed for BP-derived DNA adducts by ³²P-postlabeling technique. Manzamine A and sarcophine increased the BP-DNA adducts by 2 to 4-folds. Further, manzamine A (50 μM) substantially down regulated the expression of p53 while sarcophine (50 μM) slightly induced the level of p21. The residual DNA repair ability was almost completely abolished by manzamine A while sarcophine was ineffective. Based on our preliminary results, these compounds may be classified as potential genotoxic.