Indwelling epidural catheters for pain control in gynecologic cancer patients

Seven patients with severe pain caused by an advanced, incurable gynecologic malignancy were treated with an indwelling epidural catheter connected to an implantable subcutaneous port through which morphine was infused. There were few major complications associated with insertion or maintenance of the system. The average usage was 60 days, although the system functioned continuously for 6 months in one patient. Pain distribution in these women ranged from the upper abdomen to the lower extremities. All patients, including one with liver metastases, reported good to excellent pain control with the epidural narcotics. Two subjects with upper abdominal pain occasionally required supplemental oral oxycodone, but the other five patients had adequate pain relief with the epidural system alone. The indwelling epidural system provides excellent analgesia for patients with advanced, incurable gynecologic cancer.     

Lower heat shock factor activation and binding and faster rate of HSP-70A messenger RNA turnover in heat sensitive human leukemias.

Normal bone marrow progenitors and some leukemic cells develop only a limited amount of thermotolerance. Further, once developed, thermotolerance decays at a faster rate than that normally observed in cells of nonhemopoietic origin. Thermotolerance induction and maintenance correlates with reduced levels of expression of various M(r) 70,000 heat shock proteins (HSP-70) mRNAs after heat shock. We have now compared the accumulation of HSP-70 proteins in heat-shocked human leukemic cells KG-1, HL-60, and K562 to that in Ht1080, a colon carcinoma cell line. We have found reduced accumulation of HSP-70 proteins in all leukemic cells. The rate of decay of HSP-70A mRNA, measured following heat shock by using actinomycin D treatment to inhibit further RNA synthesis, was more rapid in KG-1 and HL-60 cells compared to Ht1080 cells. The half-life of HSP-70A mRNA was 2 h in KG-1 and HL-60 cells while in Ht1080 cells it was > 7 h. HSP-70A mRNA is known to decay with a half-life of 2 h in unheated cells; this is increased to > 7 h following heat shock. We therefore postulate that leukemic cells lack the mechanism to stabilize HSP-70A mRNA after heat shock. One postulated mechanism for HSP-70 mRNA decay rate is known to be due to the nucleotide sequences at the 3'-untranslated region. We examined the 3'-untranslated region in leukemic cells. No sequence variations, however, were observed at either the genomic or the complementary DNA levels between leukemic or nonleukemic tumor cells. Heat shock factor activation and binding by gel retardation assays showed that KG-1 and HL-60 cells had a reduced heat shock factor binding to the heat shock element when compared to K562 and Ht1080 cells. Furthermore, HSF-1 mRNA was found to be expressed at relatively lower levels in HL-60 cells when compared to Ht1080 or KG-1 cells. In conclusion, reduced HSP synthesis and accumulation of leukemic cells after heat shock correlates with the reduction in heat shock factor-heat shock element binding and a faster HSP-70A mRNA decay rate that is observed in these cells.     

Effect of N-alpha-methyl histamine on ulcer healing in rats

Inflammation Research -     

Combination therapy: lonidamine, hyperthermia, and chemotherapy against the RIF-1 tumor in vivo.

Lonidamine enhances the cytotoxicity in vitro of several conventional antitumor drugs as well as that of hyperthermia (HT). We have investigated the possibility that such enhancement can also be demonstrated in vivo against the RIF-1 tumor system. Two assays were used to examine antitumor activity: tumor growth delay and clonogenicity of cells obtained from tumors from treated animals. We used drug (and HT) doses that by themselves did not achieve significant cell killing. The drugs whose interaction with lonidamine was tested were: cis-diamminedichloroplatinum (CDDP), mitomycin C (MMC), bleomycin, 5-fluorouracil, and nitrosourea. Of these only CDDP and MMC yielded positive data. Both assays gave essentially the same results, showing that antitumor activity reflected direct cell killing. CDDP and MCC activity was also enhanced by HT. When we combined all three modalities, however, the results of the trimodality therapies were no better than that of individual bimodality treatments. These last results suggest that lonidamine and HT have similar mechanisms, most likely inhibition of repair of DNA damage. Our data do suggest that lonidamine may have a role in multidrug therapies that include either CDDP or MMC as a component of the treatments.     

Alteration of pancreatic B-cells in Wistar rats treated with non-diabetogenic doses of cyclosporin A.

We have investigated the effect of non-immunosuppressive cyclosporin A (CS-A) doses on glucose tolerance, pancreatic insulin content, insulin content of isolated islets and insulin secretion in vitro in response to glucose. Within 12 weeks animals treated permanently with a dose of 2.5 mg CS-A/kg b.wt. developed glucose intolerance (but not hyperglycaemia) accompanied by a decrease of pancreatic insulin content due to a decrease of islet insulin content, whereas the relative B-cell volume density was not changed. Isolated islets obtained from rats treated for 4 weeks had a diminished sensitivity for glucose, whereas islets obtained from animals treated for greater than 4 weeks showed a diminished half-maximum and maximum secretion rate. Rats treated for 12 weeks with 1.25 mg CS-A/kg b.wt. developed an impaired glucose tolerance after 8 weeks accompanied by a diminished pancreatic insulin content. Despite continued treatment the pancreatic insulin content was able to increase and the glucose tolerance to normalize, indicating an adaptation of pancreatic B-cells to CS-A. The results support the theory that a potential toxic effect of cyclosporin A can be diagnosed by functional tests (e.g. insulin secretion in response to a stepwise increase of glucose) before the irreversible (e.g. morphological) alterations occur.     

Bone structure changes in hip joint endoprosthesis implantation over the course of many years. A quantitative study

The stability of implanted artificial joints is limited. One main factor for this is the change of the bone tissue near the implant. Therefore we studied femura with stem endoprostheses derived from autopsy. All specimens were cut in horizontal and longitudinal sections. X-rays were made of all sections. Then the specimens were embedded undecalcified and ground to 10 microns. The wellknown phenomenons at the bone cement border were found too. Direct bone cement contact is about 5%. The 4 studied femura show a higher porosity of cortical bone as controls. The loss of cortical bone is up to 40% after 55 months. There is a correlation between new load situation and the localisation of bone loss.     

MR imaging of focal splenic tumors

This study was undertaken to define the MR appearance of splenic tumors in 16 cancer patients with focal splenic lesions; 50 volunteers and liver cancer patients without splenic abnormalities served as controls. In 14 patients with focal splenic lesions, differences between splenic and lesion signal intensities permitted detection of splenic lesions on MR images, either because of cystic or necrotic areas lengthening T2 within the tumor, because of T1 shortening from tumor-associated hemorrhage, or because of T2 shortening of surrounding spleen in two cases of suspected transfusional iron overload. In one spleen, a lesion appeared isointense on both T1- and T2-weighted pulse sequences and was detected only by gross splenic deformity. In one other case, CT defined splenic metastases not visible on MR images. Measurements of signal intensity of normal spleens and tumor are so similar that spin-echo MR imaging can underestimate the size and extent of focal splenic disease or may miss lesions entirely. We conclude that MR imaging is a less sensitive technique for detecting focal lesions of the spleen than for detecting focal hepatic lesions.     

Effects of hyperthermia on the intracellular pH and membrane potential of Chinese hamster ovary cells

The effects of hyperthermia (exposure to 41-47 degrees C) on the intracellular pH and membrane potential have been studied using Chinese hamster ovary HA-1 cells. Our goal was to determine whether intracellular pH changes or changes in membrane potential correlated with cell killing. The intracellular pH (pHi) was measured using the DMO partitioning technique. A rapid acidification of the intracellular environment was observed at all the elevated temperatures studied. The pHi reached a plateau value of approximately 6.9, and started reversing towards normal values upon prolonged exposure to heat. Similar patterns were seen for delta pH (pHi-pHo). The membrane potential difference (delta psi) was measured using the fluorescence quenching of 3,3-dipropylthio-carbocyanine, and calibrated using a 86Rb+ diffusion potential. We found that delta psi falls to zero only upon prolonged exposure to temperatures above 43 degrees C. When the external pH was changed from normal values the drop in delta psi occurred more readily. Development of thermotolerance resulted in an increase in the time required to make delta psi change by half. The changes in delta psi were shown to be irreversible. When the proton electrochemical gradient (delta mu H+) was calculated using the measured values of delta psi and delta pH, the trends observed were the same as those seen for delta psi. The changes observed for pHi can be accounted for by the changes in the pK values of the components involved in the intracellular buffering. The changes in delta psi and delta mu H+ may reflect the physical breakdown of the transmembrane H+ gradients, which may be the actual mechanical process of cell death. No correlation of cell survival with the measured parameters was observed.     

Nerve biopsy findings in Niemann-Pick type II (NPC)

The severe infantile form of Niemann-Pick disease type II was diagnosed in a 4-year-old girl and confirmed by demonstrating in cultured skin fibroblasts a deficiency of low-density lipoprotein-stimulated cholesterol ester synthesis of < 5% of normal. Electrodiagnostic studies revealed changes of a predominantly demyelinating motor and sensory polyneuropathy. Light microscope and ultrastructural examination of a peroneal nerve biopsy showed unique changes. Compacted myelin sheaths were disproportionately thin with marked globular irregularities in single teased nerve fibres and evidence of chronic demyelination. The majority of axons were preserved but axonal spheroids and cytoskeletal abnormalities akin to neuroaxonal dystrophy were noted. Membrane-bound multilobulated lysosomal inclusions of floccular and electron-dense material were present in Schwann cells (SC), endoneurial fibroblasts, macrophages, pericytes and endothelial cells. SC of myelinated fibres were stuffed with whorls of concentric osmiophilic membranous profiles and electron-lucent material. The findings are diagnostic and differ from those of classical Niemann-Pick disease.