The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis.

Synovial sarcomas are aggressive soft-tissue malignancies that express chromosomal translocation-generated fusion genes, SS18-SSX1 or SS18-SSX2 in most cases. Here, we report a mouse sarcoma model expressing SS18-SSX1, complementing our prior model expressing SS18-SSX2. Exome sequencing identified no recurrent secondary mutations in tumors of either genotype. Most of the few mutations identified in single tumors were present in genes that were minimally or not expressed in any of the tumors. Chromosome 6, either entirely or around the fusion gene expression locus, demonstrated a copy number gain in a majority of tumors of both genotypes. Thus, by fusion oncogene coding sequence alone, SS18-SSX1 and SS18-SSX2 can each drive comparable synovial sarcomagenesis, independent from other genetic drivers. SS18-SSX1 and SS18-SSX2 tumor transcriptomes demonstrated very few consistent differences overall. In direct tumorigenesis comparisons, SS18-SSX2 was slightly more sarcomagenic than SS18-SSX1, but equivalent in its generation of biphasic histologic features. Meta-analysis of human synovial sarcoma patient series identified two tumor-gentoype-phenotype correlations that were not modeled by the mice, namely a scarcity of male hosts and biphasic histologic features among SS18-SSX2 tumors. Re-analysis of human SS18-SSX1 and SS18-SSX2 tumor transcriptomes demonstrated very few consistent differences, but highlighted increased native SSX2 expression in SS18-SSX1 tumors. This suggests that the translocated locus may drive genotype-phenotype differences more than the coding sequence of the fusion gene created. Two possible roles for native SSX2 in synovial sarcomagenesis are explored. Thus, even specific partial failures of mouse genetic modeling can be instructive to human tumor biology.

The impact of osteoblastic differentiation on osteosarcomagenesis in the mouse.

Osteosarcomas remain an enigmatic group of malignancies that share in common the presence of transformed cells producing osteoid matrix, even if these cells comprise a minority of the tumor volume. The differentiation state of osteosarcomas has therefore become a topic of interest and challenge to those who study this disease. In order to test how the cell of origin contributes to the final state of differentiation in the transformed cells, we compared the relative tumorigenicity of Cre-LoxP conditional disruption of the cell cycle checkpoint tumor-suppressor genes Trp53 and Rb1 using Prx1-Cre, Collagen-1α1-Cre and Osteocalcin-Cre to transform undifferentiated mesenchyme, preosteoblasts and mature osteoblasts, respectively. The Prx1 and Col1α1 lineages developed tumors with nearly complete penetrance, as anticipated. Osteosarcomas also developed in 44% of Oc-Cre;Rb1(fl/fl);Trp53(fl/fl) mice. We confirmed using 5-ethynyl-2'-deoxyuridine click chemistry that the Oc-Cre lineage includes very few actively cycling cells. By assessing radiographic mineralization and histological osteoid production, the differentiation state of tumors did not correlate with the differentiation state of the lineage of origin. Some of the osteocalcin-lineage-derived osteosarcomas were among the least osteoblastic. Osteocalcin immunohistochemistry in tumors correlated well with the expression of DNA methyl transferases, suggesting that silencing of these epigenetic regulators may influence the final differentiation state of an osteosarcoma. Transformation of differentiated, minimally proliferative osteoblasts is possible but may require such an epigenetic reprogramming that the tumors no longer resemble their differentiated origins.

SS18-SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas.

Synovial sarcoma is a deadly malignancy with limited sensitivity to traditional cytotoxic chemotherapy. SS18-SSX fusion oncogene expression characterizes human synovial sarcomas and drives oncogenesis in a mouse model. Elevated expression of BCL2 is considered a consistent feature of the synovial sarcoma expression profile. Our objective was to evaluate the expression of apoptotic pathway members in synovial sarcomas and interrogate the impact of modulating SS18-SSX expression on this pathway. We show in human and murine synovial sarcoma cells that SS18-SSX increases BCL2 expression, but represses other anti-apoptotic genes, including MCL1 and BCL2A1. This repression is achieved by directly suppressing expression via binding through activating transcription factor 2 (ATF2) to the cyclic adenosine monophosphate (AMP) response element (CRE) in the promoters of these genes and recruiting TLE1/Groucho. The suppression of these two anti-apoptotic pathways silences the typical routes by which other tumors evade BH3-domain peptidomimetic pharmacotherapy. We show that mouse and human synovial sarcoma cells are sensitive in vitro to ABT-263, a BH3-peptidomimetic, much more than the other tested cancer cell lines. ABT-263 also enhances the sensitivity of these cells to doxorubicin, a traditional cytotoxic chemotherapy used for synovial sarcoma. We also demonstrate the capacity of ABT-263 to stunt synovial sarcomagenesis in vivo in a genetic mouse model. These data recommend pursuit of BH3-peptidomimetic pharmacotherapy in human synovial sarcomas.

Is There a Predisposition Gene for Ewing's Sarcoma?

Ewing's sarcoma is a highly malignant tumor of children and young adults. The molecular mechanisms that underlie Ewing's Sarcoma development are beginning to be understood. For example, most cases of this disease harbor somatic chromosomal translocations that fuse the EWSR1 gene on chromosome 22 with members of the ETS family. While some cooperative genetic events have been identified, such as mutations in TP53 or deletions of the CDKN2A locus, these appear to be absent in the vast majority of cases. It is therefore uncertain whether EWS/ETS translocations are the only consistently present alteration in this tumor, or whether there are other recurrent abnormalities yet to be discovered. One method to discover such mutations is to identify familial cases of Ewing's sarcoma and to then map the susceptibility locus using traditional genetic mapping techniques. Although cases of sibling pairs with Ewing's sarcoma exist, familial cases of Ewing's sarcoma have not been reported. While Ewing's sarcoma has been reported as a 2nd malignancy after retinoblastoma, significant associations of Ewing's sarcoma with classic tumor susceptibility syndromes have not been identified. We will review the current evidence, or lack thereof, regarding the potential of a heritable condition predisposing to Ewing's sarcoma.

The effects of dietary advice and vouchers on the intake of fruit and fruit juice by pregnant women in a deprived area: a controlled trial.

OBJECTIVE: To examine the effectiveness of two methods of increasing fruit and fruit juice intake in pregnancy: midwives' advice and vouchers exchangeable for juice. DESIGN: Pregnant women were randomly allocated to three groups: a control group, who received usual care; an advice group, given advice and leaflets promoting fruit and fruit juice consumption; and a voucher group, given vouchers exchangeable for fruit juice from a milk delivery firm. Dietary questionnaires were administered at ~16, 20 and 32 weeks of pregnancy. Serum beta-carotene was measured at 16 and 32 weeks. SETTING: An antenatal clinic in a deprived area. SUBJECTS: Pregnant women aged 17 years and over. RESULTS: The study comprised 190 women. Frequency of fruit consumption declined during pregnancy in all groups, but that of fruit juice increased substantially in the voucher group. Serum beta-carotene concentration increased in the voucher group, from 106.2 to 141.8 micromol l(-1) in women with measurements on both occasions (P = 0.003), decreased from 120.0 to 99.8 micromol l(-1) in the control group (P = 0.005), and was unchanged in the advice group. CONCLUSIONS: Pregnant women drink more fruit juice if they receive vouchers exchangeable for juice supplied by the milk delivery service. Midwives' advice to eat more fruit has no great effect. Providing vouchers for fruit juice is a simple method of increasing its intake in a deprived population and may be useful for other sections of the community.

Intracortical chondroma: a report of two cases.

Intracortical chondromas are exceedingly rare lesions that have the histopathologic appearance of enchondromas, but are located within cortical bone. Two new cases of intracortical chondroma, one symptomatic and the other found incidentally, are presented and the entity's brief literature reviewed.

Ankle fractures in patients with diabetes mellitus.

Diabetes mellitus is considered an indicator of poor prognosis for acute ankle fractures, but this risk may be specific to an identifiable subpopulation. We retrospectively reviewed 42 patients with both diabetes mellitus and an acute, closed, rotational ankle fracture. Patients were individually matched to controls by age, gender, fracture type, and surgical vs non-surgical treatment. Outcomes were major complications during the first six months of treatment. We contrasted secondarily 21 diabetic patients with and 21 without diabetic comorbidities. Diabetic patients and controls did not differ significantly in total complication rates. More diabetic patients required long-term bracing. Diabetic patients without comorbidities had complication rates equal to their controls. Diabetic patients with comorbidities had complications at a higher rate (ten patients; 47%) than matched controls (three patients; 14%, p = 0.034). A history of Charcot neuroarthropathy led to the highest rates of complication. An increased risk of complications in diabetic patients with closed rotational fractures of the ankle are specific to a subpopulation with identifiable related comorbidities.

Linking land cover and water quality in New York City's water supply watersheds.

The Catskill/Delaware reservoirs supply 90% of New York City's drinking water. The City has implemented a series of watershed protection measures, including land acquisition, aimed at preserving water quality in the Catskill/Delaware watersheds. The objective of this study was to examine how relationships between landscape and surface water measurements change between years. Thirty-two drainage areas delineated from surface water sample points (total nitrogen, total phosphorus, and fecal coliform bacteria concentrations) were used in step-wise regression analyses to test landscape and surface-water quality relationships. Two measurements of land use, percent agriculture and percent urban development, were positively related to water quality and consistently present in all regression models. Together these two land uses explained 25 to 75% of the regression model variation. However, the contribution of agriculture to water quality condition showed a decreasing trend with time as overall agricultural land cover decreased. Results from this study demonstrate that relationships between land cover and surface water concentrations of total nitrogen, total phosphorus, and fecal coliform bacteria counts over a large area can be evaluated using a relatively simple geographic information system method. Land managers may find this method useful for targeting resources in relation to a particular water quality concern, focusing best management efforts, and maximizing benefits to water quality with minimal costs.

Pattern of diabetic neuropathic arthropathy associated with the peripheral bone mineral density.

The relationship between the bone mineral density (BMD) and Charcot arthropathy is unclear. Prospectively, 55 consecutive diabetic patients presenting with a Charcot arthropathy of the foot or ankle were classified as having a fracture, dislocation, or a combination fracture-dislocation pattern of initial destruction. In these groups we used dual-energy x-ray absorptiometry to compare the peripheral bone of the affected and unaffected limbs. The clinical data relating to diabetes and related major comorbidities and the site of the arthropathy (ankle, hindfoot, midfoot, forefoot) were also compared. There were 23 patients with a fracture pattern, 23 with a dislocation pattern, and nine with a combination. The age-adjusted odds ratio for developing a Charcot joint with a fracture pattern as opposed to a dislocation pattern in patients with osteopenia was 9.5 (95% confidence interval 2.4 to 37.4; p = 0.0014). Groups also differed as to the site of the arthropathy. Fracture patterns predominated at the ankle and forefoot whereas dislocations did so in the midfoot. Diabetic Charcot arthropathy of the foot and ankle differs according to the pattern of the initial destruction. The fracture pattern is associated with peripheral deficiency of BMD. The dislocation pattern is associated with a normal BMD.

Revisional bariatric surgery--safe and effective.

BACKGROUND: Revision operations have traditionally been considered difficult and associated with a high complication and long-term failure rate. This paper demonstrates that revision and/or conversions to Roux-en-Y gastric bypass are generally safe as well as effective in long-term weight maintenance and control of co-morbidities. METHODS: A retrospective study from January 1989 through August 1999 was done involving 141 patients who had had various gastroplasty (118), gastric banding (6), jejunoileal bypass (3), or loop (2) and Roux-en-Y gastric bypass (RYGBP) procedures (12), with either technical failures or poor long-term maintained weight loss. RESULTS: The demographics were: mean pre-operative weight at original surgery 264 lbs (120 kg); postop weight at a mean elapsed time since surgery of 5 years, 4 months: 188 lbs (85 kg), or a mean excess weight loss of 59%. The mean BMI dropped from a pre-op 45 to a post-op 31. There were 7 complications which required emergency surgery (5%), which included 4 leaks, 2 subphrenic abscesses, and 1 wound dehiscence. Other complications included 4 hernias, 3 staple-line failures, 1 transient renal failure, and 3 incidences of peptic ulcer disease requiring surgery, giving a total major complication rate of 13% in 17 patients, with no deaths. An earlier experience of this author comparing conversion RYGBP vs revision gastroplasty found better morbidity rates and weight loss with those converted to RYGBP. CONCLUSION: Converting failed gastric limiting and other bariatric procedures to RYGBP was safe and effective. Technical approaches to each problem type encountered are presented.

The left subcostal incision revisited.

BACKGROUND: Since 1979, this author has used exclusively a left subcostal incision for gastroplasty (GP) and Roux-en-Y gastric bypass (RYGBP), with complication rates better than published reports in the literature for midline incisions. METHODS AND RESULTS: From July 1979 through March 1997, 1798 primary GP and RYGBP procedures have been done through the left subcostal incision, in addition to 42 conversions of GP to RYGBP, for a total of 1840 new left subcostal incisions. Comparison with an earlier series revealed no significant changes in results: incision hernias three (0.16%), dehiscence four (0.2%), splenectomy three (0.16%). No splenectomies have been necessary since 1983. Various wound healing problems occurred rarely (2.2%). CONCLUSION: The author believes that the left subcostal incision should be the gold-standard of bariatric surgery open procedures.

Roux-en-Y gastric bypass: an effective antireflux procedure in the less than morbidly obese.

BACKGROUND: Since Roux-en-Y gastric bypass (RYGBP) is an excellent antireflux procedure, why is it necessary to do it only for those who are morbidly obese: why not anyone who has had a longstanding severe weight problem with chronic disabling reflux esophagitis? METHODS: RYGBP was done primarily as an antireflux procedure in 332 patients late from 1987 through October 1996. Eighty-nine were less than 100 lb (45 kg) overweight. Forty-five were lost to follow-up. All but one had Visick ratings from 2 to 4 preoperatively. Thirty-one were primary RYGBP and 13 were conversions from previous gastroplasties. The diagnosis in each case was made by esophagogastroscopy with esophageal biopsy with or without the Bernstein test when indicated. RESULTS: Postoperatively, only one patient was symptomatic. The remaining had Visick ratings of 1. The average preoperative weight of 192 lb (87 kg) dropped to 145 lb (66 kg) postoperatively, or 67% of excess weight loss at a mean of 56 months. Compared to the morbidly obese group, there was no significant difference in 1-year postoperative laboratory values. CONCLUSION: This study supports the efficacy and safety of RYGBP for reflux esophagitis in the less than morbidly obese patient. Esophagitis is truly a comorbid condition of severe obesity, and it should be accepted as such. The arbitrary elimination from the consideration of candidacy for this procedure by those with a body mass index of less than 35 kg/m2 and unproven comorbidity appears unjustified.

Molecular systematics of short-horned lizards: biogeography and taxonomy of a widespread species complex.

We surveyed mitochondrial DNA (mtDNA) sequence variation in short-horned lizards (Phrynosoma douglasi) from throughout western North America and used these data to estimate an intraspecific phylogeny and to assess biogeographic scenarios underlying the geographic structure of lineages in this species. We sequenced 783 base pairs from 38 populations of P. douglasi and three putative outgroups (P. ditmarsi, P. orbiculare, P. platyrhinos). We detected high levels of nucleotide variation among populations and a spatial distribution of mtDNA lineages compatible with major geographic regions. The phylogenetic hypotheses best supported by the data suggest that P. douglasi, as currently described, is paraphyletic with respect to P. ditmarsi. Populations of P. douglasi from the Pacific Northwest (ID, CA, OR, WA) form a monophyletic group that is sister to the subsequent radiation of P. ditmarsi and other P. douglasi clades. These results suggest that divergences within this widespread species are fairly old. We focused on the genetic structure of populations of P. douglasi from a geographic perspective and interpreted the intraspecific phylogeny in light of geologic and climatic changes in western North America during the last 20 million years. The generally high levels of genetic variation found in these population comparisons are in accord with high levels of morphological variation in this species group; however, only in the Pacific Northwest region is there spatial congruence between these phylogenetic results and subspecific ranges based on previous morphological studies. We compared the evolutionary units delineated in this study with previously described subspecies of P. douglasi and evaluated the support (from morphology and mtDNA) for each population lineage in the phylogeny and the implications for the taxonomy of this group.

Taming the CAT Fund: two decades of challenges.

The CAT Fund on September 30 announced a 68 percent emergency surcharge to settle approximately $108 million in unpaid claims. Physicians across the state are asking how--and why--this happened. The Society's general counsel takes an historical look at the fund and offers a realistic solution to curtail similar "surprises" in the future.

A case for tort reform.

The current national debate on health care focuses on two issues: access and cost. While Pennsylvania Medical Society positions on health system reform and managed care--overviewed in this publication in January and June 1993 respectively--have dealt with both issues, this article analyzes one specific aspect of the cost issue: the need for tort reform.

AIDS law in effect in Pennsylvania.

The "Confidentiality of HIV-Related Information Act" signed by Governor Casey on November 29, 1990, became effective February 27, 1991. Hospitals have an additional 60 days--until April 28--to establish written confidentiality procedures. The Act's provisions are generally consistent with traditional medical consent and confidentiality concepts tailored to the special circumstances surrounding the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome (AIDS).