Diffuse, fracturing systemic skeletal histiocytosis of unknown type: a novel metabolic bone disease.

We describe a novel disease of diffuse skeletal histiocytosis associated with multiple fragility fractures and high osteoclast activity. Clinical, radiographic, biochemical, genetic, and histopathological investigations were performed to characterize the diagnosis of an Asian man who presented with hip fracture and diffuse skeletal lytic lesions. After excluding malignancy and other common metabolic bone diseases, open bone biopsy yielded several pathological samples all showing extensive skeletal histiocytosis likely to explain the diffuse axial and appendicular lytic lesions. Rare disorders such as Langerhans histiocytosis, Erdheim-Chester disease, and diffuse cystic skeletal angiomatosis were excluded through careful pathological examination and lack of CD1a and S-100 staining. Whole exome sequencing did not yield diagnostic findings to explain this likely acquired disease. High markers of osteoclast activity suggested excessive focal bone resorption but normalized after zoledronic acid treatment. A novel disease of skeletal histiocytosis with high bone turnover is differentiated from other histiocytic and lytic skeletal diseases.

Suppression of ING1 expression in sporadic breast cancer.

Down regulation of the ING1 candidate tumour suppressor promotes growth in soft agar and focus formation in vitro and tumour formation in vivo. ING1 encodes a nuclear, cell cycle-regulated protein, overexpression of which efficiently blocks cell growth and is capable of inducing apoptosis in different experimental systems. Here we present the first report of ING1 mutation and expression analysis in a total of 452 cancer samples. One germline missense alteration and three germline silent alterations were detected in 377 primary breast cancers while marked (2 - 10-fold) decreases in ING1 mRNA expression were seen in 44% of primary breast cancers and in ten of ten breast cancer cell lines examined. Furthermore, the majority of breast cancers (58%) showing decreased ING1 expression had metastasized to regional lymph nodes whereas only 9% of cancers with elevated ING1 expression, compared to adjacent normal tissues, were metastatic. Thus, ING1 mutation is very rare in breast or ovarian cancers, however, repression of ING1 expression frequently accompanies tumour development of breast cancer.

Lipochondral degeneration of capsular tissue in osteoarthritic hips.

Lipochondral degeneration (LCD) was found in the capsular tissue of 33 of 74 resected osteoarthritic hips studied retrospectively and in 14 of 35 studied prospectively, but never in a control group (n = 46). The process arose in the ligamentous structures that had undergone nodular chondroid metaplasia. The lesion was characterized by vacuolar distention of chondrocytes, eventual necrobiosis, and formation of acellular pools of lipid material. The latter was shown by oil red O staining and electron microscopy. Matrix alterations included glycosaminoglycan depletion, formation of elastin-related material, and degeneration of collagen fibers. There was no significant correlation (p = 0.05) between the occurrence of LCD and the severity of the osteoarthritis; neither was any association found with age, sex, calcium pyrophosphate dihydrate deposition, diabetes mellitus, or coronary artery disease.

Successful treatment of post-transplant lymphoproliferative disorder in autologous blood stem cell transplant recipients.

We report three cases of post-transplant lymphoproliferative disorder (PTLD) in the context of autologous stem cell transplantation (ASCT) for multiple myeloma (MM) and non-Hodgkin's lymphoma. The first two cases received ASCT for MM, one with a CD34-selected autograft and the other with an unmanipulated autograft. Both these cases of PTLD achieved a complete response following treatment with IVIG, gancyclovir, solumedrol and interferon (IFN). The third case received ASCT with an unmanipulated autograft for relapsed angioimmunoblastic lymphoma. He also achieved a complete response but only after rituximab was added to IVIG, gancyclovir, solumedrol and IFN. None of these patients experienced a relapse of their PTLD with follow-up ranging from 1.5 to 5 years. These cases highlight the importance of considering PTLD in the differential diagnosis of lymphadenopathy and fever post ASCT. They also demonstrate the possibility of durable complete remission of post-ASCT PTLD following antiviral and immune modulating therapy.

The effect of fasting time on plasma total cholesterol concentration in Mongolian gerbils.

This study investigated the effect of length of fasting time on plasma total cholesterol response of male Mongolian gerbils (Meriones unguiculatus). Plasma cholesterol levels from fed and fasted gerbils were also compared with those reported for humans under similar metabolic states. Plasma total cholesterol response showed a significant quadratic relationship with time over a 15-hour period. Between 6 and 9 hours of fasting (the time during which plasma triglyceride concentration became relatively constant), the average plasma total cholesterol concentration was 178 mg/dl, compared with a zero hour (fed) cholesterol level of 265 mg/dl. The difference in plasma cholesterol levels observed in fed and fasted gerbils is unlike what has been reported for humans. Results from most human studies show no differences in plasma total cholesterol concentrations for fed and fasted subjects. Failure to consider species differences in metabolic responses may have implications when results from animal experiments are extrapolated to humans.

The accuracy and interobserver reproducibility of endometrial dating.

Although controversial, diagnosis of luteal phase defect (LPD) includes the morphological assessment of endometrial development. This study was conducted to determine if refresher training in the histological criteria could improve the accuracy and interobserver reproducibility of endometrial dating. Seventy-eight endometrial biopsies were dated by a reference panel of two pathologists and then reviewed twice by a study panel of four pathologists. In the first review, usual practice was applied. Prior to the second review, they studied a standard document of histological criteria. Samples were dated as proliferative, secretory (post-ovulatory day, POD), menstrual, and undatable. Accuracy levels based on the reference dating and agreement levels using kappa values were calculated per review and compared. The kappa for overall dating was 0.683 in the first review and 0.696 in the second. The respective first and second review kappa values were 0.736 and 0.771 for proliferative, and 0.794 and 0.764 for secretory. Amongst those dated as secretory in the first and second reviews, respectively, 31 and 28% were assigned the same POD by any two panellists, 68 and 63% were dated to within 1 day, and 77 and 71% were dated to within 2 days. Accuracy levels per panellist for overall dating were very high in both reviews but were low for individual PODs. Accuracy and interobserver reproducibility were unaffected by refresher training, suggesting the limits of histological dating have been reached.

Detailed immunohistologic evaluation of a methotrexate-induced nodule.

Accelerated nodulosis in patients with rheumatoid arthritis who are receiving methotrexate has become a well-recognized phenomenon, and it appears to occur in both individuals with seropositive and seronegative findings. No histologic differences permit a distinction between seronegative and seropositive nodulosis--either occurring during the natural history of rheumatoid arthritis or when "induced" by methotrexate. We examined such a nodule in a man with seronegative rheumatoid arthritis. Results of immunofluorescence examination were not contributory, but studies of the inflammatory cell populations within the nodule showed 5% of the cells to be lymphocytes with a CD4/CD8 ratio of 25:1. Of the total mononuclear cells, 85% were reactive for Leu-10 (HLA-DQ) and 95% were reactive for HLA-DR, and about 75% of the macrophages were reactive for CD4+. The strong expression of CD4, in conjunction with macrophage markers, and the high T-helper/suppression ratio are of note. We discuss the implications of these findings and the role that they play in the pathogenesis of methotrexate-induced nodules.

Long-term feeding of casein or soy protein with or without cholesterol in Mongolian gerbils. I. Morphologic effects.

This study was designed to determine whether male Mongolian gerbils (Meriones unguiculatus) develop atherosclerosis (AS) during long-term feeding of diets similar to those consumed by humans. Gerbils were fed diets containing 16% casein (C) or soy (S) protein +/- 0.1% cholesterol (CH) for 15 months. The energy contribution from protein, fat and carbohydrate was similar to the energy distribution reported for the average North American (NA) diet and the level of added dietary CH resembled the average NA intake. At mo 0, 3, 6, 9, 12 and 15, animals were killed and tissue sections were prepared for histologic examination. Microscopic observations of cardiovascular tissues did not reveal any evidence of AS in any of the diet groups. Liver fatty infiltration (FI) was evident in the C+CH and C groups at mo 3 and 9, respectively, and continued to occur at all subsequent sampling times. Livers from gerbils fed S+CH also began to exhibit FI at mo 9, while livers from S-fed gerbils did not show any significant morphologic changes. Biochemical liver total lipid results supported the histological liver findings. Other tissues examined did not reveal any morphological changes related to diet. The gerbil may be a useful animal model to study mechanisms which inhibit AS development.

Long-term feeding of casein or soy protein with or without cholesterol in Mongolian gerbils. II. Plasma lipid and liver cholesterol responses.

Male Mongolian gerbils (Meriones unguiculatus) were fed casein or soy protein in the presence and absence of dietary cholesterol for 15 months. Diets resembled the average North American diet in energy contributions from protein, fat and carbohydrate, cholesterol content and fatty acid profile. At month 0, 3, 6, 9, 12 and 15, plasma samples were analyzed for total cholesterol (TC), HDL cholesterol (HDLC) and triglyceride (TG) concentrations. Plasma LDL cholesterol (LDLC) was estimated indirectly. Liver TC was also determined at these time points. Comparisons of protein source and cholesterol level were averaged over the 15 month period. Casein-fed gerbils had significantly higher plasma TC and TG levels and lower HDLC levels (as a percent of TC) compared to soy-fed animals, independent of the presence or absence of dietary cholesterol. LDLC was significantly elevated in casein-fed gerbils only when cholesterol was present in the diet. Elevations in plasma TC levels were reflected by elevations in liver TC. Despite plasma lipid elevations that are consistent with the development of atherosclerosis (AS) and coronary heart disease (CHD) in humans, hyperlipidemic gerbils do not develop AS. Further characterization of gerbil lipid metabolism responses to dietary alterations aimed at the prevention of CHD in humans is necessary to elucidate the mechanism for the gerbil's resistance to AS.

Preoperative chemoradiation and flap reconstruction provide high local control and low wound complication rates for patients undergoing limb salvage surgery for upper extremity tumors.

BACKGROUND AND OBJECTIVES: Neoadjuvant protocols in the management of upper extremity sarcoma have improved local control rates but have been associated with high complication rates. We present a refinement of the Eilber protocol using judicious preoperative chemoradiation, limb salvage surgery, and flap coverage to achieve high local control rates with acceptable wound healing complications. METHODS: Patients presenting with upper extremity neoplasms from 1986 to 2002 were treated with a modified Eilber protocol, consisting of 3 days of adriamycin (30 mg/day) and sequential radiotherapy (300 cGy/day for 10 days). Limb salvage surgery with flap coverage where needed was performed 4-8 weeks later. Patients were followed prospectively for recurrence. RESULTS: Fifty-three consecutive patients with upper extremity tumors were treated and followed for a mean of 6.1 years. This cohort included 44 sarcomas and nine non-metastasizing, locally aggressive tumors. There were two local recurrences (3.8%). Limb salvage was achieved in all patients. Flaps were required in 43.4% of patients. Major complications occurred in 11%, were all flap related (partial flap loss, venous congestion), and went on to heal promptly with treatment. CONCLUSION: This modified Eilber protocol achieved 96% local control for upper extremity tumors with a wound complication rate of 11%. The liberal use of flaps of resulted in healed, stable wounds in all patients.

Use of tissue expanders and pre-operative external beam radiotherapy in the treatment of retroperitoneal sarcoma.

INTRODUCTION: We report our experience of treating retroperitoneal sarcoma (RPS) using pre-operative external beam radiotherapy (EBRT) in combination with radical resectional surgery from 1990 to 2005. METHODS: Twenty-eight primary and 10 recurrent tumors were identified from a prospective database. RESULTS: The resection rate was 71% overall; 82% in primary (23/28) and 40% (4/10) in recurrent cases. EBRT was administered preoperatively in 25 patients, postoperatively in 1, and palliatively in 11. In 33 patients a saline-filled tissue expander was inserted into the abdomen before radiotherapy to displace small bowel from the radiation field. 4,500-5,000 cGy was administered in fractions of 180-200 cGy over a 5-week period; surgery followed 6-8 weeks later. Expander insertion was associated with minimal morbidity; 31/37 patients received a dose of 4,000 cGy or more (median 4,650 cGy). Median resected tumor diameter was 13 cm, and a median of three adjacent organs was resected per patient. Complete macroscopic resection was achieved in 25/27 patients (93%); R0 in 9 (33%) and R1 in 13 (48%) (microscopic margins unclear in 5). There was no postoperative mortality. Tumors were high-grade in 20 patients, low-grade in 14 and ungraded in 4. Actuarial 5- and 10-year survival for all patients was 74 and 60%. For operable primary tumors, the 5-year survival and disease-free rates were 90 and 80%. In four patients with operable recurrent tumors, median disease-free interval was 91 months (27-160). In the 11 inoperable cases, median survival after radiotherapy was 48 months (9-77). CONCLUSIONS: We conclude that a combination of pre-operative tissue expander placement, high-dose EBRT and radical resectional surgery can achieve acceptable morbidity, extended survival and low long-term recurrence in patients with RPS. STATISTICS: Median (interquartile range).

Reversal of combination nondepolarized neuromuscular block.

The antagonism of a pancuronium-curare (P + C) neuromuscular block was assessed and compared to the antagonism of a pancuronium (P) block. One group of seven patients received P + C (0.024 mg/kg + 0.144 mg/kg); another similar group of seven patients received P (0.07 mg/kg). Both groups were anesthetized with nitrous oxide/oxygen/narcotic anesthesia. Each patient received 0.025 mg/kg of neostigmine when a train-of-four revealed only one twitch (90% block). The resultant antagonism of the pancuronium-curare blocks was the same as the antagonism of the pancuronium blocks (train-of-four ratio, 0.38 vs 0.32; P = 0.5). The authors conclude that neostigmine requirements for combination blocks are the same as those for single agent blocks.

Laser capture microdissection-guided fluorescence in situ hybridization and flow cytometric cell cycle analysis of purified nuclei from paraffin sections.

Laser capture microdissection (LCM) has recently been identified as a quick, simple, and effective method by which microdissection of complex tissue specimens for molecular analysis can be routinely performed. Assessment of gene copy number by fluorescence in situ hybridization (FISH) is useful for the analysis of molecular genetic alterations in cancer. Unfortunately, the application of FISH to paraffin sections of tumor specimens is fraught with technical difficulty and potential artifacts. Our results demonstrate that LCM-microdissected nuclei are suitable for FISH gene copy analysis. Amplification of genes in cancer specimens can be detected as easily in LCM-prepared nuclei as in fresh nuclei from cancer tissue specimens. Furthermore, contamination of tumor specimens by normal cells can make interpretation of flow cytometric cell cycle analysis difficult. Our results show that LCM-microdissected nuclei can also be used for flow cytometric cell cycle and ploidy analysis. LCM/FISH offers the advantages of multicolor FISH in a morphologically defined cell population, without the technical problems of FISH performed on paraffin sections. This technique should further simplify the methodology required to perform copy number analysis of tumor suppressor or protooncogenes in archived cancer specimens. The use of LCM specimens will also improve the specificity and simplify the interpretation of flow cytometric cell cycle and ploidy analysis of breast cancer specimens.

Hypopigmentation of a papillary carcinoma arising in a black thyroid.

We report a case of an unpigmented papillary carcinoma arising in a black thyroid induced by minocycline. Black thyroid syndrome is an unusual pigmented change seen almost exclusively in patients on minocycline, apparently resulting from an oxidative interaction between thyroid peroxidase and the drug. Twenty-six cases have previously been reported in the English literature, nine of which described an associated thyroid neoplasm. Four of these nine neoplasms were described as pale or hypopigmented. The nature of the lesion against the background of pigmentation suggests diminished function of the thyroid peroxidase in this clonal population.

Characteristics of the snoring noise in patients with and without occlusive sleep apnea.

We analyzed snoring noise from 10 nonapneic heavy snorers and nine patients with obstructive sleep apnea (OSA). Sound was recorded simultaneously through two microphones, one attached to the manubrium sterni and one suspended in the air 15 cm from the patient's head. Signals were stored on magnetic tape, digitized, and displayed in the time and frequency domains. Most of the power of snoring noise was below 2,000 Hz, and the peak power was usually below 500 Hz. When snores were generated during nose-only breathing (nasal snores), the sound spectrum was made up of a series of discrete, sharp peaks, with a fundamental note and harmonics similar to the spectrum of voiced sounds. When snores were generated during breathing through nose and mouth (oronasal snores), the spectra showed a mixture of sharp peaks and broad-band white noise. Patients with apnea showed a sequence of snores with spectral characteristics that varied markedly through an apnea-respiration cycle. The first postapneic snore consisted mainly of broad-band white noise with relatively more power at higher frequencies, so that the ratio of power above 800 Hz to power below 800 Hz could be used to separate snorers from patients with OSA. Other breaths in the cycle resembled oronasal or nasal snores in nonapneic subjects. Characteristics of the noise give information about the possible mechanism of sound generation and thus about the behavior of the pharynx during snoring. Quality of snoring sound may help to separate patients with obstructive apnea from those with simple snoring.

Clinical manifestations and molecular epidemiology of late recurrent candidemia, and implications for management.

The aim of this study was to define the epidemiology and clinical manifestations of late recurrent candidemia. For this purpose, late recurrent candidemia was defined as an episode of candidemia occurring at least 1 month after the apparent complete resolution of an infectious episode caused by the same Candida sp. A total of five patients with recurrent candidemia were investigated. For all patients, isolates from the initial and recurrent episodes of candidemia were available for in vitro susceptibility testing and genetic characterization by DNA-based techniques. The results revealed the following salient features: prolonged duration between the initial and recurrent episodes (range, 1-8 months); recurrence of candidemia despite anti-fungal therapy; importance of retained intravascular catheters, neutropenia, and corticosteroids as factors predisposing to recurrence; high morbidity and mortality; no emergence of antifungal drug resistance between the initial and recurrent episodes; and relapse of infection due to the original infecting strain, rather than reinfection with a new strain. These findings raise several issues about the management and follow-up of patients with candidemia, which require assessment in future studies.

Carcinoid syndrome symposium on treatment modalities for gastrointestinal carcinoid tumours: symposium summary.

OBJECTIVE: To develop a collaborative approach for the treatment of gastrointestinal carcinoid tumours and carcinoid syndrome. PARTICIPANTS: Leaders in the medical, endocrine, radiologic and surgical treatment of carcinoid disease were selected to present papers at the Carcinoid Syndrome Symposium on Treatment Modalities for Gastrointestinal Carcinoid Tumours and participate in the workshop that followed. EVIDENCE: A multidisciplinary symposium with experts in the field of carcinoid syndrome was organized at the University of Calgary. Data presented, participation of the attendees and a review of the literature were used in the workshop to develop a collaborative approach to the management of carcinoid tumours. BENEFITS: Carcinoid tumours are rare and few centres have large experiences in their treatment. Before the development of this collaboration, patients with carcinoid tumours received a unidisciplinary approach depending on referral patterns. The development of a multidisciplinary neuroendocrine clinic helped to unify the approach to these patients, yet a consensus on the treatment of carcinoid tumours was lacking. The expertise at the symposium allowed for consensus and the development of treatment algorithms, including biochemical screening, radiographic localization and surgical intervention, for gastrointestinal carcinoid tumours. The role of medical and hormonal therapy after cytoreducion is presented. RECOMMENDATION: Patients with carcinoid tumours require a multidisciplinary approach to their care.

Is primary CNS lymphoma really becoming more common? A population-based study of incidence, clinicopathological features and outcomes in Alberta from 1975 to 1996.

BACKGROUND: The incidence of primary CNS lymphoma (PCNSL) is believed to be increasing in immunocompetent patients but this may not be universally true. The objective of this study was to determine in a population if the incidence of PCNSL is increasing, if the histologic subtypes are changing, and to describe the clinicopathologic and outcome characteristics of PCNSL. PATIENTS AND METHODS: We identified all Alberta residents with a histologic diagnosis of PCNSL from 1 January 1975 to 31 December 1996 using the Alberta Cancer Registry. Annual age-standardized incidence rates (ASIR), clinicopathologic and outcome characteristics were determined. RESULTS: There were 50 immunocompetent PCNSL patients; the median age was 64 and 30 were male. Their median survival was 10.15 months. Histology was available for review in 37 (74%) patients: 19 (51%) were diffuse large cell, 16 (43%) were immunoblastic and 2 (5%) were unclassifiable malignant lymphomas. The ASIR ranged from 0.178-1.631/10(6) and no change in ASIR was found (test for trend, P = 0.26) for gender or age. The ASIR of malignant gliomas did not change either but increased for all other non-Hodgkin's lymphoma (94.95-138.7610(6); test for trend, P = 0.0001) The number of brain biopsies increased from 1979-1985 (test for trend, P < 0.0001) but remained stable from 1986-1996 (test for trend, P = 0.99). CONCLUSIONS: Unlike several other populations, PCNSL is not becoming significantly more common in Alberta. If this difference is real (i.e., not due to differences in cancer registry coding practices etc.) comparisons between Albertans and other populations in whom the incidence is rising may provide clues regarding the etiology of PCNSL.