Microvascular closure in malignant histiocytosis.

Two patients with malignant histiocytosis were found to have capillary occlusion by aggregates of neoplastic histiocytes, in skeletal muscle in one, and in renal glomeruli in the other. One patient had clinical evidence of similar occlusions in the arterioles and capillaries of the ocular fundi. Occlusion of small vessels by tumour cells may explain the confusion of both patients.     

Evaluation of multi-target and single-target liposomal drugs for the treatment of gastric cancer

We studied the effects of multi- and single-target liposomal drugs on human gastric cancer cell AGS both in vitro and in vivo. The cytotoxic effect of dihydrotanshinone I was significantly enhanced by treatment with octreotide-polyethylene glycol(PEG)-liposome, Arg-Gly-Asp(RGD)-PEG-liposome, and RGD/octreotide-PEG-liposome encapsulated with 0.5 mug/ml of dihydrotanshinone I to AGS cell for 24 h, compared to control. Furthermore, the AGS cell survival rate for multi-target versus single target liposomal drugs was significantly suppressed. Microscopic examination revealed that significant cell death occurred in the multi- and single-target liposomal encapsulated drug groups. Significant suppression of tumor growth in AGS cell xenograft nude mice given octreotide-PEG-liposome, RGD/octreotide-PEG-liposome encapsulated drug, versus those given a free drug was noted after 13 d of experimentation with the multi-targeted liposome: up to 60.75% and 41.2% reduction of tumor volume as compared to dimethylsulfoxide (DMSO) control and the free drug groups respectively. The treated animals showed no gross signs of toxicity. The results have potential clinical application.     

Evaluation of liposomal forms of rifampicin and prodigiozan in the treatment of experimental chronic tonsillitis

Therapeutic effect of liposomal dosages of rifampicin and prodigiozan was studied on rabbits with simulated chronic tonsillitis in comparison to that of commercial ones of the drugs. The treatment schemes included daily intra-tonsillar++ injections of the dosage forms for 5 days. A high efficacy of their liposomal dosage forms in treatment of experimental chronic tonsillitis was confirmed microbiologically and immunologically. Approval of the liposomal dosage forms used in the therapy of patients with chronic tonsillitis requires clinical trials.     

Maturation of Howell-Jolly bodies observed in a case of malignant histiocytosis

The maturation of Howell-Jolly bodies was microscopically observed on the May-Grünwald-Giemsa-stained film of bone marrow obtained from a patient with malignant histiocytosis. The bodies separated from the nucleus at the polychromatophilic normoblast stage and condensed faster than the main nucleus before denucleation in the normoblast stage.     

The cytology of malignant histiocytosis (sinusoidal hematolymphoid malignancy)

Malignant histiocytosis (MH: sinusoidal hematolymphoid malignancy) is a rare lymphoreticular disorder characterized by an aggressive clinical course in younger patients with weight loss, hepatosplenomegaly, generalized lymphadenopathy and pancytopenia. Five cases of MH were identified over a five-year period (1982 to 1987) at Indiana University Medical Center. The patients' ages were 12, 16, 20, 30 and 57 years; all presented with classic clinical symptoms. Four cases were diagnosed by fine needle aspiration biopsy; one case was diagnosed by the examination of ascitic fluid. All patients had confirmatory surgical biopsies. The salient cytologic features of MH included (1) a lack of background lymphoglandular bodies, (2) a population of variably sized dyscohesive cells, (3) a component of large bizarre cells with abundant eccentric, deep-blue cytoplasm on Wright-Giemsa-stained preparations, (4) prominent cytoplasmic vacuolization and (5) inconspicuous erythrophagocytosis occurring in the most benign-appearing histiocytic cells. Ancillary studies on cytologic and histologic material (immunostaining for alpha-1-antichymotrypsin and alpha-1-antitrypsin and staining for nonspecific esterases) confirmed the histiocytic nature of the malignant cells. Recognition of the distinctive morphology of MH and the performance of ancillary studies on cytologic preparations should facilitate the rapid diagnosis and early treatment of this aggressive disease.     

Drug treatment of primary hyperparathyroidism: use of clodronate disodium.

Clodronate disodium (dichloromethylene diphosphonate), a specific inhibitor of bone resorption, was given by mouth (1.0-3.2 g daily) to nine patients with primary hyperparathyroidism for two to 32 weeks so that its clinical and metabolic effects could be evaluated. Bone resorption decreased in all patients as judged by a fall in the fasting urinary calcium to creatinine and hydroxyproline to creatinine ratios. Serum calcium concentration was increased in all patients before treatment and fell in response to treatment to values near the upper end of the normal range. Hypercalcaemia and hypercalciuria recurred when treatment was stopped. In three patients treated for longer than 19 weeks clodronate failed to sustain the reduction in serum calcium concentration but the concentration remained below pretreatment values. These results suggest that clodronate may be of use in the medical management of primary hyperparathyroidism, particularly in patients in whom suppression of bone disease is desirable before surgery or in whom surgery is contraindicated.     

Evaluation of tetraether lipid-based liposomal carriers for encapsulation and retention of nucleoside-based drugs

Although liposomal nanoparticles are one of the most versatile class of drug delivery systems, stable liposomal formulation of small neutral drug molecules still constitutes a challenge due to the low drug retention of current lipid membrane technologies. In this study, we evaluate the encapsulation and retention of seven nucleoside analog-based drugs in liposomes made of archaea-inspired tetraether lipids, which are known to enhance packing and membrane robustness compared to conventional bilayer-forming lipids. Liposomes comprised of the pure tetraether lipid generally showed improved retention of drugs (up to 4-fold) compared with liposomes made from a commercially available diacyl lipid. Interestingly, we did not find a significant correlation between the liposomal leakage rates of the molecules with typical parameters used to assess lipophilicity of drugs (such logD or topological polar surface area), suggesting that specific structural elements of the drug molecules can have a dominant effect on leakage from liposomes over general lipophilic character.     

Pegylated liposomal doxorubicin in the treatment of AIDS-related Kaposi's sarcoma

Kaposi's sarcoma is a vascular tumor of skin and viscera first described in 1872. Prior to the 1980s, this disease was rarely seen in the Western world, but was quite prevalent in Sub-Saharan African countries. Since the onset of the HIV pandemic in the 1980s, the incidence of Kaposi's sarcoma has increased markedly in Africa and continues to be a significant problem in association with AIDS in Western countries. Many therapies have been demonstrated to be effective in the treatment of HIV-related Kaposi's sarcoma, including alitretinoin gel, interferon alpha, and various forms of cytotoxic chemotherapy. Antiretroviral therapy combined with cytotoxic agents has yielded significantly greater efficacy than chemotherapy alone. However, as reviewed in this report, pegylated liposomal doxorubicin has been established as the treatment of choice for patients with AIDS-associated Kaposi's sarcoma in Western countries. Compelling preclinical and clinical evidence, reviewed herein, has demonstrated that the nanoparticle (pegylated liposome) delivery system of this formulation leads to greater tumor localization of doxorubicin and consequent improved efficacy, as well as reduced toxicity.     

Physical biochemistry of a liposomal amphotericin B mixture used for patient treatment

There seems little doubt now that intravenous liposomal amphotericin B can be a useful treatment modality for the management of immunocompromised patients with suspected or proven disseminated fungal infections. Interestingly, the very significant reduction in toxicity reported when amphotericin B is part of a bilayer membrane is closely tied to the physical characteristics of the liposomes involved, although these are poorly understood at the molecular level. We record here an examination by spectroscopy and freeze-etch electron microscopy of unsonicated amphotericin B multilamellar vesicles prepared along the lines that we and others have followed for samples used in clinical trials and preclinical in vivo or in vitro studies. Our study has focussed on liposomes of 7:3 dimyristoylphosphatidylcholine/dimyristoylphosphatidylglycerol (DMPC/DMPG) bearing 0-25 mol% amphotericin B, since this lipid mixture has been the choice for the first clinical trials. Phase transition behaviour of these liposomes was examined by electron paramagnetic resonance (EPR) spectroscopy of a nitroxide spin label partitioning into the bilayers. The same experiments were then performed on similarly prepared liposomes of the disaturated species, dipalmitoylphosphatidylcholine (DPPC), and the diunsaturated species, dielaidoylphosphatidylcholine (DEPC). Partial phase diagrams were constructed for each of the lipid/drug mixtures. Melting curves and derived phase diagrams showed evidence that amphotericin B is relatively immiscible with the solid phase of bilayer membranes. The phase diagram for DEPC/amphotericin B was very similar to that of DPPC/amphotericin B, and both exhibited less extensive temperature ranges of phase separation than did the 7:3 DMPC/DMPG mixture with amphotericin B. Between 25 and 37 degrees C the measured fluidity of the 7:3 DMPC/DMPG liposomes was similar to that of the (unsaturated fatty acid) DEPC liposomes, and considerably higher than that seen for (saturated fatty acid) DPPC liposomes. Preparations of 7:3 DMPC/DMPG, DPPC, and DEPC containing 0-25 mol% amphotericin B were examined by freeze-etch electron microscopy at 35 and 22 degrees C (to cover the temperature range of the mammalian body core and periphery). The same liposome features were present in all three liposome types studied. The appearance of individual liposomes at x 100,000 magnification reflected their molecular characteristics, which were found to be significantly heterogeneous within each batch. The lipid/drug structures were bilayer in nature, although liposomes showing considerable disruption were common, particularly at the highest drug concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)     

Sunitinib treatment for refractory malignant pheochromocytoma

We report the clinical response and adverse events of a female patient treated for recurrent malignant pheochromocytoma using the tyrosine kinase inhibitor sunitinib. A 41-year-old woman underwent adrenectomy and nephrectomy forpotentially malignant adrenal pheochromocytoma. Fifty-four months after surgery, abdominal computed tomography (CT) and Iodine-131 metaiodobenzylguanidine((131)I-MIBG) scintigraphy revealed multiple tumors in the liver. Two chemotherapy protocols were administered in succession (first line: cyclophosphamide/vinblastine/dacarbazine; second line: cisplatin/docetaxel/ifomide). Despite these treatments, however, the tumors continued to progress. Treatment with sunitinib was initiated, but the patient quickly developed critical hypertension caused by tumor lysis syndrome. The sunitinib dose was reduced, and a partial response, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST), was observed after 6 treatment cycles. Moreover, no severe adverse events occurred during this lower-dose sunitinib treatment. Unfortunately, sunitinib treatment became unaffordable for the patient, who eventually resorted to palliative care and died 37 months later. This case study is consistent with previous reports indicating that appropriate doses of sunitinib can induce a partial antitumor response in patients with refractory pheochromocytoma.     

Synergy in cancer treatment between liposomal chemotherapeutics and thermal ablation

Minimally invasive image-guided tumor ablation using short duration heating via needle-like applicators using energies such as radiofrequency or microwave has seen increasing clinical use to treat focal liver, renal, breast, bone, and lung tumors. Potential benefits of this thermal therapy include reduced morbidity and mortality compared to standard surgical resection and ability to treat non-surgical patients. However, improvements to this technique are required as achieving complete ablation in many cases can be challenging particularly at margins of tumors>3 cm in diameter and adjacent to blood vessels. Thus, one very promising strategy has been to combine thermal tumor ablation with adjuvant nanoparticle-based chemotherapy agents to improve efficiency. Here, we will primarily review principles of thermal ablation to provide a framework for understanding the mechanisms of combination therapy, and review the studies on combination therapy, including presenting preliminary data on the role of such variables as nanoparticle size and thermal dose on improving combination therapy outcome. We will discuss how thermal ablation can also be used to improve overall intratumoral drug accumulation and nanoparticle content release. Finally, in this article we will further describe the appealing off-shoot approach of utilizing thermal ablation techniques not as the primary treatment, but rather, as a means to improve efficiency of intratumoral nanoparticle drug delivery.     

Evaluation of creatinine phosphokinase in screening patients for malignant hyperpyrexia.

Evidence is presented that serum creatinine phosphokinase (CPK) activity is of no direct value in screening patients for susceptibility to malignant hyperpyrexia and does not correlate with halothane-induced muscle contracture or the presence of myopathy. Widely differing CPK values were found at different times in the same people. In most "malignant hyperpyrexia" families the susceptible patients had either normal or inconsistently raised CPK values.     

Cytology of primary cutaneous Langerhans cell histiocytosis with a malignant phenotype. A case report

BACKGROUND: Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cells, but the nature of LCH, whether reactive, benign, or malignant and neoplastic, is controversial. We encountered a case of LCH showing a malignant phenotype initially localized in the skin of an elderly woman. Since there is no other report on the cytologic appearance of primary cutaneous LCH or on LCH with a malignant phenotype, we compared the cytologic features of this case with those of benign cases at other sites reported in the literature. CASE: A 74-year-old woman presented with a gradually enlarging and partially ulcerated skin lesion expanding both sides of her right hand. On histologic and ultrastructural analyses of surgically resected tissue, we diagnosed the lesion as Langerhans cell histiocytosis originating in the skin. Although the patient had no recurrence or metastases for six months after surgical resection of the primary skin lesion and radiation therapy, the tumor extended multisystemically, and the patient died of multiple organ failure 14 months after the initial diagnosis. CONCLUSION: Imprint and scrape cytology of multiple skin lesions six months after surgery was useful in immediately diagnosing the recurrent LCH. The tumor cells had indented, twisted or grooved nuclei, and some had intranuclear inclusions. Immunocytochemically the cells were positive for CD1a and S-100 protein. Numerous eosinophils were seen in the background.     

Safe and successful endoarterial infusion of liposomal amphotericin B in treatment of mucormycosis

Mucormycosis is a rare invasive mycotic infection treated by antifungini or amphotericin B. We describe the case of a patient with septic fever and a necrotic lesion, with phlegmon of medial left thigh. Surgery was performed to drain the abscess content and to remove the necrotic tissue; mucormycosis was diagnosized by histological and culture tests and treated by intravenous amphotericin B. Since the lesion worsened, liposomal amphotericin B was directly infused into the left common iliac artery, with progressive improvement, and treatment was continued until complete recovery. Therefore, the endoarterial infusion of liposomal amphotericin B was a safe and successful treatment of advanced lesions of mucormycosis. In such lesions, intravenous general antibiotic administration probably is not sufficient to reach the whole infected area.     

The role of adjuvant clodronate therapy for prevention of bone metastasis in breast cancer

Bisphosphonates are effective against increased bone resorption because they inhibit osteoclast activity. The use of these drugs is well established for the treatment of metastatic breast and other cancers; they reduce skeletal complications, hypercalcemia, bone pain, and metastatic progression and they can improve the overall survival and quality of life. Preclinical observations and early clinical data indicate that early bisphosphonate treatment reduces the incidence and the extent of newly developed metastases in breast cancer. There is considerable interest in determining whether bisphosphonate treatment is to prevent the incidence of bone metastases and associated complications. To date three randomized, controlled clinical trials have examined the effect of long-term use of clodronate (1600 mg/d po.) on the incidence of bone metastases, other metastases, the survival of patients, and the side effects of the study drug as well. All the trials have observed significant reduction of the occurrence of bone metastases, although this reduction was significant only during the medication period. One of the trials mentioned have shown an unexpected reduction in non-osseous metastases, and two of them have revealed significant improvements in the death rates. These promising results need further evaluation by large clinical trials with longer treatment periods to establish the clinical role of adjuvant bisphosphonate treatment of primary breast cancer.     

Macrophage cell lines transformed by the malignant histiocytosis sarcoma virus: increase of CSF receptors suggests a model for transformation

The malignant histiocytosis sarcoma virus (MHSV) contains Ha-v-ras-related oncogenic sequences and rapidly transforms myeloid cells in vivo and in vitro. Myeloid cell lines can be derived which do not require growth factor for continued proliferation. We initiated this work to define the process of transformation leading to autonomy of cell growth in transformed myeloid cells. Five established cell lines were examined. All express macrophage-specific cell-surface antigens and exhibit several other properties typical for mature macrophages. Growth properties, growth factor release, and growth factor receptor presentation were examined: Release of growth factors is not a consistent feature. All cell lines show cell-density-independent colony formation and do not release self-stimulating factors, thus excluding autocrine stimulation as a model leading to transformation. All cell lines express unusually high levels of granulocyte-macrophage (GM)- and multi-CSF receptors and, except for one, M-CSF receptors. The high increase in GM-CSF and other growth factor receptors may be causally related to the transformed state of the cells. MHSV can be used as a tool to easily derive cell lines of the macrophage pathway as a model to study myeloid transformation, differentiation, and macrophage function.     

Training stem cells for treatment of malignant brain tumors

The treatment of malignant brain tumors remains a challenge. Stem cell technology has been applied in the treatment of brain tumors largely because of the ability of some stem cells to infiltrate into regions within the brain where tumor cells migrate as shown in preclinical studies. However, not all of these efforts can translate in the effective treatment that improves the quality of life for pa-tients. Here, we perform a literature review to identify the problems in the field. Given the lack of efficacy of most stem cell-based agents used in the treatment of malignant brain tumors, we found that stem cell distribution(i.e., only a fraction of stem cells applied capable of targeting tumors) are among the limiting factors. We provide guidelines for potential improvements in stem cell distribution. Specifically, we use an engineered tissue graft platform that replicates the in vivo microenvironment, and provide our data to validate that this culture platform is viable for producing stem cells that have better stem cell distribution than with the Petri dish culture system.