Protocol of the HISTOTHERM study: assessing the response to hyperthermia and hypofractionated radiotherapy in recurrent breast cancer.

Introduction: Breast cancer is globally the leading cancer in women, and despite the high 5-year survival rate the most frequent cause of cancer related deaths. Surgery, systemic therapy and radiotherapy are the three pillars of curative breast cancer treatment. However, locoregional recurrences frequently occur after initial treatment and are often challenging to treat, amongst others due to high doses of previous radiotherapy treatments. Radiotherapy can be combined with local hyperthermia to sensitize tumor cells to radiation and thereby significantly reduce the required radiation dose. Therefore, the combination treatment of mild local hyperthermia, i.e. locally heating of the tissue to 39-43°C, and re-irradiation with a reduced total dose is a relevant treatment option for previously irradiated patients. The mechanisms of this effect in the course of the therapy are to date not well understood and will be investigated in the HISTOTHERM study. Methods and analyses: Patients with local or (loco)regional recurrent breast cancer with macroscopic tumors are included in the study. Local tumor control is evaluated clinically and histologically during the course of a combination treatment of 60 minutes mild superficial hyperthermia (39 - 43°C) using water-filtered infrared A (wIRA) irradiation, immediately followed by hypofractionated re-irradiation with a total dose of 20-24 Gy, administered in weekly doses of 4 Gy. Tumor and tumor stroma biopsies as well as blood samples will be collected prior to treatment, during therapy (at a dose of 12 Gy) and in the follow-up to monitor therapy response. The treatment represents the standard operating procedure for hyperthermia plus re-irradiation. Various tissue and blood-based markers are analyzed. We aim at pinpointing key mechanisms and markers for therapy response which may help guiding treatment decisions in future. In addition, quality of life in the course of treatment will be assessed and survival data will be evaluated. Registration: The study is registered at the German Clinical Trials Register, Deutsches Register Klinischer Studien (DRKS00029221).

Peliosis lienalis with atraumatic splenic rupture in a patient with chronic myelomonocytic leukemia: A case report.

INTRODUCTION: Atraumatic splenic rupture is a rare but life-threatening condition which may be associated with hematological malignancies. PRESENTATION OF CASE: We present the case of a 63-year-old male patient with a history of chronic myelomonocytic leukemia and sarcoidosis under therapy with prednisone, who suffered an atraumatic splenic rupture with hemodynamic instability. He was managed with proximal splenic artery embolization and secondary open splenectomy. On pathology the diagnosis of peliosis lienalis was established. DISCUSSION: Peliosis is a rare pathological entity, which presents with multiple blood-filled cavities within parenchymatous organs and is of unknown etiology and pathogenesis. In retrospect a rapid increase in splenomegaly and inhomogeneous parenchyma of the spleen on sonography was realized. CONCLUSION: Sonographic changes in size and parenchyma of the spleen in patients with hematological malignancies might help suspecting peliosis lienalis with impending splenic rupture and could alter clinical management towards a prophylactic splenectomy.

Human intestinal spirochetosis--a review.

Human intestinal spirochetosis (IS) is a condition defined histologically by the presence of spirochetal microorganisms attached to the apical cell membrane of the colorectal epithelium. Intestinal spirochetes comprise a heterogeneous group of bacteria. In humans, Brachyspira aalborgi and Brachyspira pilosicoli predominate. Prevalence rates of IS are low where living standards are high, in contrast to poorly developed areas where IS is common. Homosexuals and HIV-infected individuals are at high risk of being colonized. Clinical significance in individual cases has remained unclear up to now. A review of the literature assumes that invasion of spirochetes beyond the surface epithelium may be associated with gastrointestinal symptoms which respond to antibiotic treatment (metronidazole), whereas individuals lacking this feature may be mostly asymptomatic. Of unknown reason, homosexual and HIV-positive men as well as children are more likely to be symptomatic irrespective of invasion. Rare cases of spirochetemia and multiple organ failure have been reported in critically ill patients with IS.

[Eosinophilic granuloma of the mandible--a case report]. / Eosinophiles Granulom des Unterkiefers. Fallbericht.

BACKGROUND: Langerhans cell histiocytosis is characterized by a clonal proliferation of Langerhans cells. The clinical manifestation varies from a localized lesion (eosinophilic granuloma) to a systemic disease. The diagnosis can only be confirmed histopathologically. A comprehensive staging is necessary to determine the extent of the disease and to establish an adequate therapy. CASE REPORT: We report on a 27 years old patient who was referred to our clinic with the diagnosis of an osteomyelitis of the mandibular angle and a pathological fracture after extraction of tooth 38 one month before. Curettage and primary bone grafting were performed. In the histological examination of the specimen infiltrates of a Langerhans cell histiocytosis were found. The clinical and radiological staging demonstrated a solitary mandibular lesion (eosinophilic granuloma). After wound healing a low-dose radiotherapy with 6 Gray was performed. Two years after completion of the therapy the patient is asymptomatic and does not show any evidence of recurrence. CONCLUSION: Langerhans cell histiocytosis has to be included in the differential diagnosis of osteolytic lesions of the mandible. A low-dose radiotherapy is a reasonable and well-tolerated treatment option.

Changing incidence of gastric and oesophageal cancer subtypes in central Switzerland between 1982 and 2007.

Several Western countries have reported a decrease in the incidence of noncardia gastric adenocarcinoma and a strong increase in the incidence of oesophageal and cardia adenocarcinoma. We examined incidence rates of gastric and oesophageal cancer by subsite and histology in Central Switzerland over the last 26 years. Data on biopsy-diagnosed gastric and oesophageal carcinoma incidence during 1982-2007 were obtained from the Cancer Registry of the Institute of Pathology, Lucerne, the Medical Centre for Central Switzerland. Age-adjusted (standardized to the European standard population), and sex-specific incidence rates were calculated. In total, 2,322 cancers were diagnosed: 1,240 noncardia gastric adenocarcinomas, 459 cardia gastric adenocarcinomas, 248 oesophageal adenocarcinomas, and 375 squamous cell carcinomas. From 1982 to 2007, the incidence rates of noncardia adenocarcinoma decreased substantially from 17.9 (per 100,000) to 6.0 in men and 10.3 to 5.5 in women. In men, the incidence of gastric cardia adenocarcinoma decreased from 7.5 to 4.3, the incidence of oesophageal adenocarcinoma increased from 3.3 to 4.8, and the incidence of oesophageal squamous cell carcinoma decreased from 6.6 to 4.1; the incidence rates of these cancers were low in women (1.1-2.4). In conclusion, the incidence of gastric noncardia carcinoma has decreased substantially over the past 26 years. In contrast to other Western countries, the incidence of gastric cardia adenocarcinoma did not increase in Central Switzerland. Whereas the rate of oesophageal adenocarcinoma increased, the rate of squamous cell carcinoma decreased. These results suggest substantial changes in environmental and life-style risk factors over the past 26 years.

Atherosclerosis, cholesterol, nutrition, and statins--a critical review.

Atherosclerosis, which causes approximately half of all deaths of adults over age 60 in industrialized nations, is a pandemic among inappropriately nourished and/or physically hypoactive children, adolescents, and adults world wide. Although nowadays statins are widely prescribed to middle age and elderly adults with high blood lipid levels as pharmacological prevention for the late complications of atherosclerosis, from a critical point of view statins seem not to solve the problem, especially when compared with certain natural ingredients of our nutrition like micronutrients as alternative strategy. Statin ingestion is associated with lowering of serum cholesterol and low-density lipoprotein concentrations; some prospective studies have shown statistical associations with subsequent modest reduction of mortality from cardiovascular disease. However, specific biochemical pathways and pharmacological roles of statins in prevention of atherosclerosis, if any, are unknown. Moreover, there have been no systematic cost-benefit analyses of life-style prophylaxis versus statin prophylaxis versus combined life-style plus statin prophylaxis versus neither life-style nor statin prophylaxis for clinically significant complications of cardiovascular diseases in the elderly. Further, in the trials of effectiveness statins were not compared with management of nutrition, which is the most appropriate alternative intervention. Such studies seem to be important, as the ever increasing world population, especially in developing countries, now demand expensive statins, which may be unaffordable for mitigating the pandemic. Studies of this kind are necessary to identify more precisely those patients for whom cardiovascular benefits will outweigh the risks and costs of the statin treatment in comparison with nutritional interventions. Against the background of the current pathogenetic concept of atherogenesis some of its possible risk factors, particularly the roles of cholesterol and homocysteine, and the effects of statins versus nutritional (micronutrients) interventions in prevention and treatment of the disease are discussed. The prevailing opinion that serum cholesterol as a mediator of the disease is increased by eating saturated fats and decreased by eating polyunsaturated fats is being challenged. Evidently, the beneficial effects of statins in atherosclerosis are not mainly due to its cholesterol lowering effect, rather than to its "pleiotropic effects". Other pathogenetic factors in atherosclerosis are involved, like inflammatory and immunologic processes, that can be modulated by statins as well as by other drugs or by the Mediterranean-style nutrition and by micronutrients (folate, B-vitamins).

Role of the different isoforms of cyclooxygenase and nitric oxide synthase during gastric ulcer healing in cyclooxygenase-1 and -2 knockout mice.

Traditional NSAIDs, selective cyclooxygenase (COX)-2 inhibitors, and inhibitors of nitric oxide synthase (NOS) impair the healing of preexisting gastric ulcers. However, the role of COX-1 (with or without impairment of COX-2) and the interaction between COX and NOS isoforms during healing are less clear. Thus we investigated healing and regulation of COX and NOS isoforms during ulcer healing in COX-1 and COX-2 deficiency and inhibition mouse models. In this study, female wild-type COX-1(-/-) and COX-2(-/-) mice with gastric ulcers induced by cryoprobe were treated intragastrically with vehicle, selective COX-1 (SC-560), COX-2 (celecoxib, rofecoxib, and valdedoxib), and unselective COX (piroxicam) inhibitors. Ulcer healing parameters, mRNA expression, and activity of COX and NOS were quantified. Gene disruption or inhibition of COX-1 did not impair ulcer healing. In contrast, COX-2 gene disruption and COX-2 inhibitors moderately impaired wound healing. More severe healing impairment was found in dual (SC-560 + rofecoxib) and unselective (piroxicam) COX inhibition and combined COX impairment (in COX-1(-/-) mice with COX-2 inhibition and COX-2(-/-) mice with COX-1 inhibition). In the ulcerated repair tissue, COX-2 mRNA in COX-1(-/-) mice, COX-1 mRNA in COX-2(-/-) mice, and, remarkably, NOS-2 and NOS-3 mRNA in COX-impaired mice were more upregulated than in wild-type mice. This study demonstrates that COX-2 is a key mediator in gastric wound healing. In contrast, COX-1 has no significant role in healing when COX-2 is unimpaired but becomes important when COX-2 is impaired. As counterregulatory mechanisms, mRNA of COX and NOS isoforms were increased during healing in COX-impaired mice.

Development, characterization, and use of a fetal skin cell bank for tissue engineering in wound healing.

Wound healing in fetal skin is characterized by the absence of scar tissue formation, which is not dependent on the intrauterine environment and amniotic fluid. Fetal cells have the capacity of extraordinary expansion and we describe herein the development of a fetal skin cell bank where from one organ donation (2-4 cm2) it is possible to produce several hundred million fetal skin constructs of 9 x 12 cm2. Fetal cells grow three to four times more rapidly than older skin cells cultured in the same manner and these banked fetal cells are very resistant against physical and oxidative stress when compared to adult skin cells under the same culture conditions. They are up to three times more resistant to UVA radiation and two times more resistant towards hydrogen peroxide treatment. This mechanism may be of major importance for fetal cells when they are delivered to hostile wound environments. For fetal cell delivery to patients, cells were associated with a collagen matrix to form a three-dimensional construct in order to analyze the capacity of these cells for treating various wounds. We have seen that fetal cells can modify the repair response of skin wounds by accelerating the repair process and reducing scarring in severe bums and wounds of various nature in children. Hundreds of thousands of patients could potentially be treated for acute and chronic wounds from one standardized and controlled cell bank.

Gastrin-releasing peptide receptors in normal and neoplastic human uterus: involvement of multiple tissue compartments.

CONTEXT: Bombesin-like neuropeptides including gastrin-releasing peptide (GRP) and their corresponding receptors, mediate multiple physiological actions and have biological significance in cancer. However, information about the function of these neuropeptides and the incidence, distribution, density, and subtype of their receptors in human uterine tissues is scarce. OBJECTIVE: The objective of the study was to investigate normal and neoplastic human uterine tissues for their bombesin receptor status. DESIGN: In vitro subtype-specific bombesin receptor autoradiography was used in this study. PATIENTS: The following tissue samples were taken immediately after surgery: myometrium (n = 41), endometrium (n = 29), leiomyomas (n = 26), leiomyosarcomas (n = 6), endometrial adenocarcinomas (n = 28), and carcinosarcoma (n = 1). RESULTS: Normal uterine tissues expressed GRP receptors (GRP-Rs) in the myometrium, in subsets of secretory endometrial glands, and in subsets of endometrial blood vessels of the late proliferative and the secretory phase. Most leiomyomas (20 of 26) expressed GRP-R but not the leiomyosarcomas. GRP-Rs were also detected in 10 of 28 adenocarcinomas, one of one carcinosarcoma, and in blood vessels surrounding the adenocarcinomas. No other bombesin receptor subtypes (neuromedin B receptors and bb3) were detected. CONCLUSIONS: These findings may be of physiological and pathophysiological significance. The expression of GRP-R in glands and vessels during specific phases of the cycle suggests a timely precise physiological action of GRP in these targets; in certain uterine neoplasms, the GRP-R overexpression may contribute to tumor development because GRP is a potent growth factor. Furthermore, these findings may be diagnostically and therapeutically relevant. The expression of GRP-R in leiomyomas may allow distinguishing them from receptor-negative leiomyosarcomas; GRP-R in leiomyomas, in a subset of endometrial adenocarcinomas, carcinosarcomas, and in peritumoral vessels may be candidates for receptor targeting in vivo.

Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer.

BACKGROUND & AIMS: Germline mutations in the DNA mismatch repair (MMR) genes MSH2, MSH6, or MLH1 predispose to colorectal cancer (CRC) with an autosomal dominant inheritance pattern. The protein encoded by PMS2 is also essential for MMR; however, alterations in this gene have been documented only in extremely rare cases. We addressed this unexpected finding by analyzing a large series of CRCs. METHODS: Expression of MSH2, MSH6, MLH1, and PMS2 was studied by immunohistochemistry in 1048 unselected, consecutive CRCs. Where absence of MMR proteins was detected, microsatellite instability and cytosine methylation of the respective gene promoter were analyzed. The DNA of patients presenting with PMS2-deficient cancers was examined for germline and somatic alterations in the PMS2 gene. RESULTS: An aberrant pattern of MMR protein expression was detected in 13.2% of CRCs. Loss of expression of MSH2, MSH6, or MLH1 was found in 1.4%, 0.5%, and 9.8%, respectively. PMS2 deficiency accompanied by microsatellite instability was found in 16 cases (1.5%) with a weak family history of cancer. The PMS2 promoter was not hypermethylated in these cases. Despite interference of the PMS2 pseudogenes, we identified several heterozygous germline mutations in the PMS2 gene. CONCLUSIONS: PMS2 defects account for a small but significant proportion of CRCs and for a substantial fraction of tumors with microsatellite instability. However, the penetrance of heterozygous germline mutations in PMS2 is considerably lower than that of mutations in other MMR genes. The possible underlying causes of this unorthodox inheritance pattern are discussed.

Bacterial translocation in the normal human appendix parallels the development of the local immune system.

Experimental modes and pathological conditions may result in bacterial translocation (BT), that is, the passage of indigenous bacteria colonizing the intestine through the intestinal mucosa to mesenteric lymph nodes. Yet no data are available on BT in the normal human gut. We determined the occurrence of BT and its extent in histologically normal, incidentally removed human vermiform appendices (VA) from individuals of different ages and correlated the findings with the development with age of associated lymphatic tissue. BT appears to pertain to normal antigen-sampling processes of the GALT in the VA. It also parallels the development of the GALT and its maintenance during adulthood. In the first two weeks after birth, when bacterial colonization of the gut evolves and when the VA lacks the protection of secretory IgA, BT was not detected. Thereafter, BT occurs along with development of the local GALT, which is fully built up after the first year. A physiological uptake of, or invasion by, bacteria may be instrumental (1) for tolerance induction against the indigenous flora and (2) for the stimulation and normal development of the GALT.

Local pathogenic bacteria in allergic rhinitis: a novel concept of its pathogenesis.

BACKGROUND: It is still unclear to what extent microorganisms are involved in the pathogenesis of allergic rhinitis. OBJECTIVE: Therefore, we examined the mucosal colonization with potential pathogenic bacteria (PPB) of the nasal cavity in allergic and nonallergic subjects. METHODS: In an open prospective study of 389 office workers (297 men, mean age 42.5 years, and 92 women, mean age 36.7 years), bacterial swabs were taken selectively from both nasal cavities. Standard skin tests for various aeroallergens and negative control tests were conducted in parallel in these subjects. RESULTS: In the 389 subjects, we found positive skin tests in 58 (15%); 37 of these revealed a high level of sensitivity, whilst the other 21 persons had low to moderate levels. Ninety percent of the 58 sensitive persons had PPB in their nasal cavity while only 36% (119) of the remaining 331 subjects with negative skin tests were shown to have PPB in nasal cultures (p < 0.001). Sixty-four percent of the sensitized subjects with PPB were found to have more than 2 PPB species and a positive correlation with the intensity of the skin reaction. In contrast, only 18% (22) of the 119 nonallergic test persons with PPB had more than 1 PPB species. CONCLUSIONS: This finding of an unusually high frequency of nasal PPB in subjects with positive skin tests to aeroallergens may indicate an involvement of PPB in the pathogenesis of allergic rhinitis. Yet, further data are still lacking to support this novel concept.

Cytopathology of the nasal mucosa in chronic exposure to diesel engine emission: a five-year survey of Swiss customs officers.

The simple and cheap technique of nasal cytology was used to assess possible adverse effects of chronic exposure to diesel engine emission (DEE) on respiratory mucous membranes. Brush cytology probes were taken from the noses of 194 male, nonsmoking customs officers twice a year (January and July) over a period of 5 years. The study group of 136 officers was solely occupied with clearing of diesel trucks (8.4 hr/day, 42 hr/week). Measured DEE concentrations varied between 31 and 60 microg/m3) and of benzo[a]pyrene concentrations were between 10 and 15 ng/m3). The control group of 58 officers worked only in the office. Over the 5-year period, similar results were obtained in summer and winter. In contrast to those not exposed to DEE, those who were had clear goblet cell hyperplasia with increased metaplastic and dysplastic epithelia and an increase in leukocytes. We found no evidence of progression of the cytopathologic changes. The findings may be described as a chronic inflammation of the nasal mucous membrane in the presence of chronic DEE exposure (chemical-induced rhinitis). Additionally, the findings of metaplastic and dysplastic nasal epithelia in the exposed subjects may indicate a genotoxic effect of chronic DEE exposure in humans.

Ingested probiotics reduce nasal colonization with pathogenic bacteria (Staphylococcus aureus, Streptococcus pneumoniae, and beta-hemolytic streptococci).

BACKGROUND: As a bacterial reservoir, the nose may harbor potentially pathogenic bacteria (PPB: Staphylococcus aureus, Streptococcus pneumoniae, beta-hemolytic streptococci, and Haemophilus influenzae). In patients carrying PPB, antiseptic regimens could be crucial for infection control after major operations on or injuries of the head, nasal sinuses, or lungs. Such regimens may also be important for diabetic patients and persons receiving hemodialysis, in intensive care units, or with impaired immunity due to various other causes. OBJECTIVE: We tested a possible effect of the ingestion of probiotics on the bacterial flora of the nose. DESIGN: In an open, prospective trial, 209 volunteers were randomly assigned to consume either a probiotic, fermented milk drink [65 mL with Lactobacillus GG (ATCC 53103), Bifidobacterium sp B420, Lactobacillus acidophilus 145, and Streptococcus thermophilus; n = 108] or standard yogurt (180 g; n = 101) daily for 3 wk. Nasal microbial flora were analyzed on days 1, 21, and 28. The microbial examination was blinded to the source of the samples. RESULTS: We found a significant reduction (19%; P < 0.001) in the occurrence of nasal PPB in the group who consumed the probiotic drink but not in the group who consumed yogurt. The effect was mainly on gram-positive bacteria, which decreased significantly (P < 0.05). CONCLUSIONS: The results indicate that regular intake of probiotics can reduce PPB in the upper respiratory tract. The results also indicate a linkage of the lymphoid tissue between the gut and the upper respiratory tract.