Measurement of response to treatment in colorectal liver metastases

Assessment of tumour response to chemotherapy is important when assessing efficacy of treatment and comparing differing therapeutic regimens. Percentage hepatic replacement (PHR) is commonly used to assess response to treatment of colorectal hepatic metastases. PHR is dependent not only on tumour volume, but also on hepatic parenchymal volume. The effect of tumour growth on hepatic parenchymal volume is unclear but is of importance owing to its effect on PHR. We assessed tumour and hepatic parenchymal weights in an animal tumour model using dissection, and tumour and hepatic parenchymal volumes in patients with colorectal hepatic metastases using CT scanning, in order to establish how hepatic parenchyma varied with change in metastasis size. There was no significant correlation between tumour and liver parenchyma in either the animal model (r = -0.03, P > 0.05) or the patient study (r = 0.3, P < 0.05). This suggests that hepatic parenchymal volume was preserved in the presence of increasing tumour volume. In a further study of computerised tomographic (CT) scans before and after treatment in patients whose tumours either responded to chemotherapy or continued to grow, change in PHR (median proportion of PHR change = 0.40) significantly (P = 0.04) underestimated the change in tumour volume (median proportion of tumour volume change = 0.56), particularly at higher (> 400 ml) volumes. There was good correlation between change in tumour volume and WHO criteria in assigning patients to tumour growth, stable disease or tumour response categories. This study suggests that, in clinical trials comparing colorectal liver metastasis treatments, metastasis volume and not PHR should be used to assess extent of disease and the effect of treatment.     

The natural history and treatment of adrenal myelolipoma

PURPOSE: We determined the natural history and clarified the treatment of adrenal myelolipoma. MATERIALS AND METHODS: A retrospective review of medical records and radiographic imaging studies of 20 patients diagnosed with adrenal myelolipoma was performed. RESULTS: Of 20 patients 4 presented with abdominal pain and 1 had Cushing's syndrome. The remaining tumors were discovered incidentally. Four patients underwent surgery because of abdominal pain in 2, adrenal hyperfunction (Cushing's syndrome) in 1 and a tumor 10.5 cm. in largest dimension in 1. Of 15 patients (16 adrenal myelolipomas) followed without surgical intervention for an average of 3.2 years (range 0.3 to 10.8) 13 remained asymptomatic and 2 experienced persistent, vague abdominal discomfort. One patient was lost to followup. A total of 13 tumors from 12 patients was serially imaged, with tumor size increasing in 6, decreasing in 2 and remaining unchanged in 5. CONCLUSIONS: These data suggest that the majority of adrenal myelolipomas can be treated conservatively. While tumors can become enlarged, they also exhibit variable growth, and size and growth rate do not necessarily correlate with symptoms. Computerized tomography can be used for diagnosis.     

The natural history and pathophysiology of treatment resistant schizophrenia

Defining treatment resistance among schizophrenia patients is problematic since most patients experience persistent morbidity over the course of their illness and full remissions are infrequent. In addition, the level of response to antipsychotic medication is not an immutable feature of the patient's illness that is present at its onset; rather, it can change over the course of the illness (usually unidirectionally with patients becoming less responsive to treatment) and is determined by various modifying factors. Although treatment resistance may be an enduring feature of a patient, present at illness onset and throughout, more commonly it develops over the course of patients' illnesses. Evidence from both retrospective and prospective studies suggests that a longer duration of untreated psychosis in the early stage of schizophrenia is associated with a longer time to remission and a lower level of recovery, a greater likelihood of relapse and a worse overall outcome. The pattern of deterioration observed is analogous to a well replicated neurobiologic phenomenon, termed behavioral sensitization. In sensitized animals a pathologic behavioral process emerges whereby the response to a pharmacologic or stress challenge is progressively increased in proportion to the number of pretreatments. Thus, endogenous neurochemical sensitization resulting from the inability to regulate presynaptic dopamine release in the limbic striatum may be a useful way to conceptualize the continuum of response-refractoriness that is clearly evident in schizophrenia patients. Most importantly, early detection, intervention and optimal maintenance treatment may improve the long term course of schizophrenia.     

Conflict and somatization: psychoanalytic treatment of the psychophysiologic response in the digestive tract

Somatization of intrapsychic conflicts, as manifested in the mouth, the stomach, the small intestine, the large bowel, and the anus, is described in this long-term study of the psychoanalytic treatment of three patients with peptic ulcer, regional ileitis, and ulcerative colitis respectively. The theoretical and practical aspects of treatment are considered, and the efficacy of and indications for psychoanalysis as the treatment of choice are discussed.     

Liver metastases from breast cancer 14 years after radical mastectomy; successful treatment with hepatic arterial infusion chemotherapy and systemic endocrine therapy--a case report

The patient was a 73-year-old woman who was admitted to our hospital for epigastric discomfort and body weight loss. She had undergone radical right mastectomy in March 1982. Ultrasonography and computed tomography revealed multiple tumors in the liver. Three of the tumor markers (CA-125, CA 19-9, and CA 15-3) were positive. US-guided fine needle aspiration biopsy of the liver tumor showed small atypical cells with solid cell nests. Immunohistochemical tests revealed estrogen receptor was positive. We diagnosed the patient as recurrent breast cancer metastatic to liver, 14 years postoperatively. The liver tumors were successfully controlled with the combination of intra-arterial infusion chemotherapy (5-fluorouracil, epirubicin, and mitomycin C) along with systemic endocrine therapy (medroxyprogesterone acetate and fadrozole hydrochloride hydrate).     

The natural history of the immune response to exogenous factor VIII in severe haemophilia A

The development of inhibitory antibodies to factor VIII (fVIII) in severe haemophilia A patients is a serious therapeutic complication. Using a highly sensitive immunoprecipitation (IP) assay which measures all anti-fVIII antibodies, we have tested severe haemophilic plasmas from two clinical studies. Inhibitor titres in the range of 0.4 to 1 Bethesda units/ml (BU/ml) could not be verified by IP as being due to an immune response to fVIII in 35% of plasmas tested. Low fVIII recoveries were likewise correlated with the presence of antibodies in 29% of plasmas tested. However, 16% of plasmas without inhibitor titres had immune responses as measured by IP. The rapidity of antibody appearance did not allow their effective detection by IP before development of inhibitor titres. These results suggest that the IP assay can provide a valuable confirmation of anti-fVIII antibody production when the Bethesda assay is low or negative and where clinical observations suggest their presence, but they cannot be used reliably to detect early immune responses.     

The atherosclerotic Yucatan animal model to study the arterial response after balloon angioplasty: the natural history of remodeling

OBJECTIVE: Remodeling in de novo atherosclerosis and in restenosis after balloon angioplasty constitutes a change in total arterial circumference which, together with plaque growth or neointimal formation, determines the lumen of the artery. To better understand the fundamental biology of neointimal formation, remodeling and their interaction, animal studies are needed. In this study, we described in detail the methodology used and the natural history of neointimal formation and remodeling after balloon angioplasty in atherosclerotic Yucatan micropigs. METHODS AND RESULTS: Atherosclerosis was induced in 60 peripheral arteries of sixteen Yucatan micropigs by a combination of denudation and atherogenic diet. Balloon angioplasty was performed in 38 arteries, with serial intravascular ultrasound (IVUS) and quantitative angiography before and after intervention and at 2, 4, 7, 14 or 42 days follow-up. Remodeling, expressed as late media-bounded area (MBA) loss, increased progressively over time. At 42 days, late MBA loss after balloon angioplasty was significantly different compared to late MBA loss in control arteries, 2.2 +/- 1.0 versus -0.3 +/- 1.1 mm2 and p = 0.02. Late lumen loss increased over time and was highest at 42 days after balloon angioplasty (2.8 +/- 0.7 mm2). The contribution of neointimal formation to late lumen loss decreased over time and the contribution of late MBA loss to late lumen increased over time and was highest at 42 days (78%). Medial necrosis was 48% at two days after balloon angioplasty and the repopulation of the media was almost completed at seven days. CONCLUSION: Remodeling following balloon angioplasty has an early onset and progresses with neointimal formation to cause restenosis over the standard 42-day time course for Yucatan micropigs. This correlates to six months renarrowing in humans. In this model, atherosclerosis and the natural history of restenosis, both with respect to neointimal formation and remodeling, resemble the human disease quite closely.     

Long-term visual outcome of choroidal neovascularization in pathologic myopia: natural history and laser treatment

Tumour-endothelial cell adhesion forms a key role in the establishment of distant metastases. This study examined the effect of gamma linolenic acid (GLA), an anti-cancer polyunsaturated fatty acid (PUFA), on both the gap junction communication of human vascular endothelial cells and tumour cell-endothelial interactions. By using scrape loading of Lucifer yellow dye, we showed that GLA at non-toxic levels increased Lucifer yellow transfer, indicating improved gap junction communication. The fatty acid also corrected the communication that was reduced by the mitogenic and motogenic factor HGF/SF. GLA inhibited the tyrosine phosphorylation of connexin-43, a protein that formed gap junction in this cell. When human tumour cells were added to quiescent or HGF/SF-activated endothelial cells, the presence of GLA reduced adhesion of tumour cells to the endothelium. It is concluded that GLA reduces tumour-endothelium adhesion, partly by improved gap junction communications of the endothelium.     

Differences in blood-tumour-barrier leakage of human intracranial tumours: quantitative monitoring of vasogenic oedema and its response to glucocorticoid treatment

The objective of this paper is to summarize the goals, technical requirements, advantages, and potential risks of gastroplasty for treatment of severe obesity. Gastroplasty is preferred to more complex operations, as it preserves normal digestion and absorption and avoids complications that are peculiar to exclusion operations. The medical literature and a 30-year experience at the University of Iowa Hospitals and Clinics (UIHC) provides an overview of vertical banded gastroplasty (VBG) evolution. Preliminary 10-year results with the VBG technique currently used at UIHC are included. At UIHC the VBG is preferred to other gastroplasties because it provides weight control that extends for at least 10 years and the required objective, intraoperative quality control required for a low rate of reoperation. It is recommended that modifications of the operative technique not be attempted until a surgeon has had experience with the standardized operation--and then only under a carefully designed protocol. Realistic goals for surgery and criteria of success influence the choice of operation and the optimum, lifelong risk/benefit ratio. In conclusion, VBG is a safe, long-term effective operation for severe obesity with advantages over complex operations and more restrictive simple operations.     

Gaucher's disease: clinical features and natural history

Gaucher's disease is an inherited disorder characterized by pathological storage of glycolipid in mononuclear phagocytes: it is a multi-system disease associated with striking variation in its clinical manifestations, severity and course. Although molecular analysis of the glucocerebrosidase gene in patients with Gaucher's disease has permitted broad correlations between genotype and phenotype to be made, with few exceptions genetic variation at this locus does not allow confident prediction of clinical phenotype or prognosis. Partial deficiency of glucocerebrosidase is associated principally with parenchymal disease of the liver, spleen, bone marrow and, in severe cases, the lung, in non-neuronopathic, Type 1, Gaucher's disease: here storage material in macrophages originates from turnover of exogenous glycolipids. Severe deficiency of glucocerebrosidase caused by disabling mutations is additionally associated with neurological manifestations that in part reflect a failure to degrade endogenous neuronal glycosphingolipids, the so-called neuronopathic, Type 2 and Type 3 disease categories. Here we describe the clinical features, complications and natural history principally of Type 1 Gaucher's disease: emphasis is placed on emerging pulmonary, osseous and other manifestations of obscure pathogenesis that respond poorly to enzyme-replacement therapy.     

Biliary dyskinesia: natural history and surgical results

Patients with biliary dyskinesia have symptoms consistent with biliary colic and an abnormal gallbladder ejection fraction (GEF) in the absence of cholelithiasis. Cholecystokinin hepatobiliary scan quantifies gallbladder function and may assist in selecting patients with acalculous biliary pain who would benefit from cholecystectomy. Seventy-eight patients with an abnormal GEF (< 35%) on cholecystokinin hepatobiliary scan without cholelithiasis were studied retrospectively. Patients were divided into groups based on diagnosis and treatment. In Group I, the patients who underwent cholecystectomy, 80 per cent (35 of 44) had complete symptomatic resolution whereas the remaining 20 per cent (9 of 44) had symptomatic improvement. Pathology reports demonstrated chronic cholecystitis in 95 per cent of specimens. Group II were patients with symptoms attributable to biliary dyskinesia, but did not undergo cholecystectomy. Persistence of symptoms was noted in 75 per cent (18 of 24) of patients whereas 25 per cent (6 of 24) had symptomatic resolution without any treatment. Group III consisted of patients with an abnormal ejection fraction who had improvement of symptoms after treatment for an alternative diagnosis (n = 10). These findings suggest that an abnormal ejection fraction does not always indicate gallbladder disease. Alternative diagnoses must be investigated and treated. Patients with persistent biliary type symptoms in combination with an abnormal GEF in the absence of other attributable causes can expect a favorable response to cholecystectomy.     

The dromedary: ancestry, history of domestication and medical treatment in early historic times

Research on camel bones from archaeological excavations in North Africa and the Near East contradict the current opinion in textbooks that the dromedary and the Bactrian camel are domesticated forms derived from a single species, the two-humped wild camel (C. ferus). The probable ancestor of the domestic one-humped camel is Thomas' camel (C. thomasi). The wild dromedary was probably domesticated on the Arabian peninsula, perhaps as early as the 4th millennium BC. From the 2nd millennium BC onward there is evidence for the use of the one-humped camel for riding and transport purposes. Camel-keeping also implied the therapy of diseased animals, the main source of information about their treatment being medieval arabic texts dealing with veterinary medicine. An expert of such an early 13th century text is presented and discussed. From this it can be seen that the medieval camel treatment fits the principles of the so-called humoral theory, a medical concept which at that time already existed for more than 1500 years.     

The natural history of amphibian skin secretions, their normal functioning and potential medical applications

Amphibians occupy a wide range of habitat types from arid deserts to deep freshwater lakes; they may spend most of their life underground or high in cloud forest canopy. Some are found north of the Arctic Circle and can tolerate freezing conditions, while others have evolved a range of adaptations to avoid desiccation in some of the hotter areas of the world. The skin plays key roles in the everyday survival of amphibians and their ability to exploit a wide range of habitats and ecological conditions. The normal functions of the skin are surveyed and Eisner's biorational approach to chemical prospecting--seeking clues from an animal's behaviour and its interactions with its environment to reveal the presence of chemical compounds with potential medical or veterinary applications--is applied to amphibians. The biology and natural history of amphibian skin, its glands and their secretions are briefly reviewed. Four categories of compounds are found in the granular or poison glands, these are: biogenic amines, bufodienolides (bufogenins), alkaloids and steroids, peptides and proteins. Toads, particularly members of the genus Bufo, are identified as a particularly convenient and useful source of granular gland secretions. The potential medical-pharmaceutical significance of products derived from amphibian skin secretions is discussed. The need for a humane approach to this work is noted.     

Apoptosis and its role in the myelodysplastic syndromes: implications for disease natural history and treatment

Apoptosis (programmed cell death) is an active cellular process which regulates cell population size by decreasing cell survival. In this review the underlying cellular and molecular mechanisms of apoptosis in hemopoietic and non-hemopoietic cells are described, with specific focus on these issues in the myelodysplastic syndrome (MDS), a myeloid clonal hemopathy. Apoptosis-regulating genes exist as families whose protein products are either anti-apoptotic or pro-apoptotic. Numerous stimuli can serve as initiators of the cell death pathway, including essentially all chemotherapeutic drugs, irradiation, certain inhibitory cytokines and deprivation of relevant growth factors. Morphological evidence of increased apoptosis in marrow hemopoietic cells has been demonstrated in patients with MDS. The reviewed data provide support for the hypothesis that early in MDS, increased apoptosis is associated with ineffective progenitor and maturing hemopoietic cell survival, and occurs concomitant with cytopenias/ineffective hemopoiesis; conversely, the progression of MDS toward AML occurs in concert with decreased apoptosis and an increased degree of neoplastic cell survival, leading to subsequent expansion of the abnormal precursor cells. These processes are associated with alterations in the balance between pro- and anti-apoptotic oncoprotein expression within the hemopoietic precursors, which may be modified by cytokine treatment. Investigations evaluating apoptotic events in MDS have improved our understanding of the biology of hemopoietic cell survival as related to pathogenetic features of this disease. By modifying levels of apoptosis, such studies provide a framework for future potentially beneficial therapeutic approaches to treat patients with MDS.     

Spontaneous pneumomediastinum in children: clinical and natural history

Investigation of the clinical characteristics and natural history of nine children with spontaneous pneumomediastinum (SPM) was conducted at the Tel Aviv University Sheba Medical Centre between 1984 and 1994. Most cases occurred in the setting of a valsalva-type manoeuvre, while symptoms and signs on admission were mainly chest pain, dyspnoea, neck pain, subcutaneous emphysema, and Hamman's sign. Three clinical patterns concerning longterm sequelae were identified: patients without any long-term sequelae, patients with a tendency to airway hyperreactivity and subclinical asthma, and patients in whom SPM was the presenting feature of their asthma. CONCLUSION: Close personal follow up, including pulmonary function tests, should be designed for all children with Spontaneous pneumomediastinum.