Metastasectomy for renal cell carcinoma.
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Carcinoma, Renal Cell↗
Biomedical subjects
D A Swanson
Publications and source records attributed to D A Swanson.
Surgery for metastases of renal cell carcinoma.
The role of surgery for RCC in the era of emerging effective systemic therapy (usually immunotherapy) is not yet defined except for solitary metastasis. The retrospective analysis of patients subjected to aggressive surgical management after systemic therapy reinforces the need to find better therapeutic modalities in order to achieve complete eradication of metastatic disease. In the meantime, however, we propose these guidelines. First, we would encourage aggressive surgical resection of the clinically solitary metastasis, whether synchronous or metachronous. Continue to follow those patients indefinitely, because relapse is quite likely, but do not give adjuvant systemic therapy unless on protocol. Second, limited metastases in only one organ may behave similarly to a solitary metastasis, and if the metastases are in a site amenable to surgical resection, e.g., lung, initial surgery might be reasonable. Systemic therapy for these patients is highly recommended and need not necessarily wait for recurrence. Third, for patients with multiple metastases, initial systemic therapy followed then by resection of any residual disease in selected patients seems to be supported by the experience at several medical centers. Apparently prolonged survival times have been observed after systemic therapy followed by surgery in highly selected patients, despite finding viable cancer in the overwhelming majority of specimens. One must be mindful of the morbidity of an attempt to remove all known disease, however, and try to weigh this against potential benefit. Only a prospective, randomized trial could ever confirm the value of an aggressive surgical approach to metastatic RCC. In the meantime, however, metastasectomy offers, at the very least, the opportunity to confirm the histologic response to systemic therapy, render some patients disease-free, and possibly promote long-term survival in selected patients.
Carcinoma, Renal Cell↗
Expression levels of genes that regulate metastasis and angiogenesis correlate with advanced pathological stage of renal cell carcinoma.
We examined the expression levels of a number of metastasis-related genes to determine the relationship of these levels to the development of metastasis in renal cell carcinoma. Gene expression was examined in 46 formalin-fixed, paraffin-embedded, archival specimens of primary organ-confined, clear-cell, renal cell carcinoma from patients who had undergone radical nephrectomy. Twenty samples were from patients who did not have metastasis after a median of 48 months; 26 were from patients with either synchronous or metachronous metastases. Microvessel density was assessed by anti-CD-34 immunohistochemical analysis. The expression levels of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), matrix metalloproteinases (MMP)-2 and -9, and E-cadherin were examined at the periphery of the tumor by a colorimetric in situ mRNA. The expression levels of bFGF, VEGF, IL-8, MMP-2, and MMP-9 were significantly higher in primary renal tumors from patients with either synchronous or metachronous metastases than those who were disease-free at a median of 48 months of follow-up. Multivariate analysis of disease-free survival showed that the ratio of MMP-9 to E-cadherin (P = 0.012) and the expression level of bFGF expression (P = 0.045), were independent predictors for the development of metastases. The expression levels of bFGF, VEGF, and IL-8 did not correlate with microvessel density, which in itself was not a significant predictor of progression (P = 0.21). In summary, expression levels of genes that regulate metastasis angiogenesis can predict the metastatic potential in individual patients with organ-confined clear-cell renal carcinoma.
Cadherins↗
Targeted disruption of the methionine synthase gene in mice.
Alterations in homocysteine, methionine, folate, and/or B12 homeostasis have been associated with neural tube defects, cardiovascular disease, and cancer. Methionine synthase, one of only two mammalian enzymes known to require vitamin B12 as a cofactor, lies at the intersection of these metabolic pathways. This enzyme catalyzes the transfer of a methyl group from 5-methyl-tetrahydrofolate to homocysteine, generating tetrahydrofolate and methionine. Human patients with methionine synthase deficiency exhibit homocysteinemia, homocysteinuria, and hypomethioninemia. They suffer from megaloblastic anemia with or without some degree of neural dysfunction and mental retardation. To better study the pathophysiology of methionine synthase deficiency, we utilized gene-targeting technology to inactivate the methionine synthase gene in mice. On average, heterozygous knockout mice from an outbred background have slightly elevated plasma homocysteine and methionine compared to wild-type mice but seem to be otherwise indistinguishable. Homozygous knockout embryos survive through implantation but die soon thereafter. Nutritional supplementation during pregnancy was unable to rescue embryos that were completely deficient in methionine synthase. Whether any human patients with methionine synthase deficiency have a complete absence of enzyme activity is unclear. These results demonstrate the importance of this enzyme for early development in mice and suggest either that methionine synthase-deficient patients have residual methionine synthase activity or that humans have a compensatory mechanism that is absent in mice.
5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
Pubourethral sling simultaneous with radical retropubic prostatectomy for patients at high risk for postprostatectomy incontinence.
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Journal Article↗
A note on the measurement of accuracy for subnational demographic estimates.
Mean absolute percentage error (MAPE), the measure most often used for evaluating subnational demographic estimates, is not always valid. We describe guidelines for determining when MAPE is valid. Applying them to case study data, we find that MAPE understates accuracy because it is unduly influenced by outliers. To overcome this problem, we calculate a transformed MAPE (MAPE-T) using a modified Box-Cox method. Because MAPE-T is not in the same scale as the untransformed absolute percentage errors, we provide a procedure for calculating MAPE-R, a measure in the same scale as the original observations. We argue that MAPE-R is a more appropriate summary measure of average absolute percentage error when the guidelines indicate that MAPE is not valid.
Censuses↗
PHR1 encodes an abundant, pleckstrin homology domain-containing integral membrane protein in the photoreceptor outer segments.
We cloned human and murine cDNAs of a gene (designated PHR1), expressed preferentially in retina and brain. In both species, PHR1 utilizes two promoters and alternative splicing to produce four PHR1 transcripts, encoding isoforms of 243, 224, 208, and 189 amino acids, each with a pleckstrin homology domain at their N terminus and a transmembrane domain at their C terminus. Transcript 1 originates from a 5'-photoreceptor-specific promoter with at least three Crx elements ((C/T)TAATCC). Transcript 2 originates from the same promoter but lacks exon 7, which encodes 35 amino acids immediately C-terminal to the pleckstrin homology domain. Transcripts 3 and 4 originate from an internal promoter in intron 2 and either include or lack exon 7, respectively. In situ hybridization shows that PHR1 is highly expressed in photoreceptors, with lower expression in retinal ganglion cells. Immunohistochemistry localizes the PHR1 protein to photoreceptor outer segments where chemical extraction studies confirm it is an integral membrane protein. Using a series of PHR1 glutathione S-transferase fusion proteins to perform in vitro binding assays, we found PHR1 binds transducin betagamma subunits but not inositol phosphates. This activity and subcellular location suggests that PHR1 may function as a previously unrecognized modulator of the phototransduction pathway.
Alternative Splicing↗
Specific androgen receptor activation by an artificial coactivator.
Transcription activation of steroid receptors, such as the androgen receptor (AR), is mediated by coactivators, which bridge the receptor to the preinitiation complex. To develop a tool for studying the role of the AR in normal development and disease, we constructed artificial coactivators consisting of the transcription activation domains of VP16 or p65/RelA and the AR hinge and ligand-binding domain (ARLBD), which has been shown to interact with the AR N-terminal domain. The artificial VP16-ARLBD and ARLBD-p65 coactivators interacted with the AR N terminus and wild-type AR in an androgen-dependent and androgen-specific manner. VP16-ARLBD and ARLBD-p65 enhanced the AR transactivity up to 4- and 13-fold, respectively, without affecting the expression of the AR protein. The coactivators did not enhance the transcription activity of the progesterone receptor (PR) or the glucocorticoid receptor (GR), showing their specificity for the AR. In addition, to construct PR- and GR-specific coactivators, the VP16 activation domain was fused to the PR and GR hinge/ligand-binding domain. Although VP16-PRLBD and VP16-GRLBD interacted with the C-terminal portion of steroid receptor coactivator-1, they did not enhance the transcription activity of their receptor. The presented strategy of directing activation domains or other protein activities into the DNA-bound AR complex provides a novel means of manipulating AR function in vitro and in vivo.
Binding Sites↗
Methionine synthase: high-resolution mapping of the human gene and evaluation as a candidate locus for neural tube defects.
Periconceptual folate supplementation has been found to prevent the occurrence of many neural tube defects (NTDs). Consequently, genetic variation in folate metabolism genes is expected to contribute to the risk for neural tube defects. Methionine synthase catalyzes the vitamin B(12)-dependent conversion of homocysteine and 5-methyltetrahydrofolate to methionine and tetrahydrofolate. The observation that homocysteine and vitamin B(12) levels are independent predictors of NTD risk suggested that methionine synthase could be a candidate gene for NTDs. To assess the role of the MS gene in NTDs, we performed high-resolution physical mapping of the MS locus, isolated highly polymorphic markers linked to the MS gene, and tested for an association between specific MS alleles and NTDs. We mapped the MS gene to a position between 909 and 913 cR(10000) on chromosome 1 by radiation hybrid mapping. Polymorphic markers D1S1567 and D1S1568 map to locations no more than 900 and 194 kb from the MS gene, respectively. The segregation of these polymorphic markers was measured in 85 Irish NTD families. No allele of either marker showed a significant association with NTDs using the transmission disequilibrium test. A lack of association was also observed for the D1919G missense mutation within the gene. Our results suggest that inherited variation in the MS gene does not contribute to NTD risk in this population.
5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
A stage specific approach to tumor surveillance after radical cystectomy for transitional cell carcinoma of the bladder.
PURPOSE: Surveillance protocols after radical surgery for genitourinary tumors typically do not consider that the risk of recurrence is stage dependent. We describe the development of a stage specific protocol for monitoring patients with transitional cell carcinoma for tumor recurrence and conduit complications after radical cystectomy. MATERIALS AND METHODS: The records of 382 patients with transitional cell carcinoma who underwent cystectomy in 1986 to 1994 were reviewed for the dates and presenting symptoms of local and distant recurrences, and the results of radiological imaging studies and liver function tests. Based on the division of patients into pathological stages of pT1, pT2 and pT3 groups, we developed a new transitional cell carcinoma surveillance protocol. RESULTS: Of 97 patients with transitional cell carcinoma metastases 72 (74%) were asymptomatic, including 43 with metastases detected by routine chest x-rays (30) or blood tests (13). Surveillance computerized tomography identified isolated asymptomatic intra-abdominal metastases in 10 patients (10%), of whom 90% had pT3 disease. Based on these results we recommend a stage specific surveillance protocol for pT1--annual history, physical examination, chest x-ray and laboratory studies, pT2-same studies at 6, 12, 18, 24, 30, 36, 48 and 60 months after cystectomy, and pT3-same studies at 3, 6, 12, 18, 24, 30, 36, 48 and 60 months plus computerized tomography at 6, 12 and 24 months after cystectomy. A radiographic study of the upper tract should be performed in all patients every 1 to 2 years to evaluate for recurrences and complications of the ileoureteral anastomosis. CONCLUSIONS: A stage driven surveillance strategy for monitoring patients after radical cystectomy can reduce costly imaging studies while efficiently detecting recurrences and complications.
Carcinoma, Transitional Cell↗
Early nasogastric tube removal combined with metoclopramide after radical cystectomy and urinary diversion.
PURPOSE: Prolonged nasogastric decompression increases pulmonary complications by inhibiting clearance of respiratory secretions. The literature supports early nasogastric tube removal following bowel resection. Metoclopramide stimulates bowel activity, promoting return of function. We examined combining early nasogastric tube removal with metoclopramide after radical cystectomy. MATERIALS AND METHODS: From 1994 to 1996, 27 prospective cystectomy patients received intravenous metoclopramide (metoclopramide group) combined with early nasogastric tube removal (less than 24 hours). A total of 54 concurrent cystectomy controls received no metoclopramide and nasogastric tubes remained until return of normal bowel function. RESULTS: Preoperative and perioperative factors were comparable between the 2 groups. Nasogastric tubes were removed from 78% of the metoclopramide group in less than 24 hours, 11% on day 2 and 11% on day 3 compared to none on day 1, 50% on day 2 and 50% on day 3 or greater in controls. The metoclopramide group had a more rapid return of normal bowel sounds (2.9 versus 4.0 days, p = 0.0002) and earlier tolerance of solid food (6.7 versus 7.9 days, p = 0.04). Nasogastric tube replacement was required in 3 of 27 metoclopramide cases versus 5 of 54 controls. Atelectasis occurred more often in the control group (33 versus 15%). There were no bowel related complications in the metoclopramide group but partial small bowel obstruction in 2 controls was treated conservatively. CONCLUSIONS: This preliminary study suggests that combining intravenous metoclopramide with early nasogastric tube removal after cystectomy and urinary diversion may reduce postoperative atelectasis and speed return of bowel function while posing no danger to the small bowel anastomosis. This regimen may result in fewer complications and shorter hospitalizations, translating into lower costs without compromising quality of care.
Aged↗
Identification and characterization of the human ortholog of rat STXBP1, a protein implicated in vesicle trafficking and neurotransmitter release.
In a screen designed to identify genes expressed preferentially in retina, we identified a cDNA encoding the human ortholog of rat STXBP1 (n-Sec1, Munc-18-1, rbSec1), a protein implicated in vesicle trafficking and neurotransmitter release. This protein also has similarity to Drosophila Rop (65% aa identity) and Caenorhabditis elegans UNC-18 (58% aa identity). The major human cDNA encodes a protein of 594 amino acids which has 100 % amino acid identity with its rat and murine counterparts. Additionally, there is an alternative splice form in humans, arising from the inclusion of an additional exon, which encodes a protein of 603 amino acids and is also 100% identical to the corresponding rat isoform. We found expression of the shorter cDNA in all tissues and cell lines we examined with highest levels in retina and cerebellum. By RT-PCR analysis, we found expression of the longer cDNA in neural tissues only. We mapped the structural gene to 9q34.1, a region without obvious candidate phenotypes. However, due to its evolutionary conservation and abundant expression in retina and brain, STXBP1 should be considered a candidate gene for retinal and/or neural disorders mapping to 9q34.1.
Amino Acid Sequence↗
The tragedy of the census.
The author discusses the debate on how to reduce the undercount error in the 2000 U.S. census. He reviews the history of the census, and considers the impact of the "opposing ¿interest groups' represented in Congress and elsewhere debating methodological issues that can affect the distribution of census-allocated resources [who] tend to favor methodological choices that will increase their resources."
Americas↗
K-12 enrollment forecasting: merging methods and judgment.
"This article describes an enrollment forecasting process in which technical experts and local community stakeholders [in Oregon] worked together to produce data that were cost-efficient and yet accurate enough to serve as the basis for sound decisions. The large school district that employed this process gained valuable insights to guide its attendance zone and facilities planning decisions, and also created a group of key communicators to ensure community understanding and support."
Americas↗
Stage specific guidelines for surveillance after radical nephrectomy for local renal cell carcinoma.
PURPOSE: We report stage specific followup guidelines based on our evaluation of the pattern of recurrence in 286 patients treated for local N0 or Nx renal cell carcinoma. MATERIALS AND METHODS: We retrospectively reviewed the clinical records of 286 patients with pT1 to pT3N0 or Nx renal cell carcinoma who underwent nephrectomy at our center between February 1985 and December 1994. In cases of later metastases the median interval to first metastasis, site of metastasis and method of diagnosis were correlated with the primary lesion stage. RESULTS: Metastases developed in 68 patients a median of 23 months after nephrectomy. Eight of the 113 patients with pT1 disease had metastases (median time to diagnosis 38 months), while 17 of 64 with pT2 disease and 43 of 109 with pT3 disease had metastases (medians 32 and 17 months, respectively). Of the 92 metastases 59 (64%) were asymptomatic, including 44 detected on routine chest x-rays (32) and blood tests (12). Isolated asymptomatic intra-abdominal metastases were diagnosed by surveillance computerized tomography in only 6 patients (9%). The remaining patients with metastases had associated clinical symptoms and/or abnormal results on interval tests that prompted further diagnostic studies. CONCLUSIONS: We confirmed that the risk of metastatic renal cell carcinoma is stage dependent. Therefore, surveillance protocols should be based on the pathological stage of the primary tumor. We recommend an annual chest x-ray, and serum liver function and alkaline phosphatase level tests for patients with pT1 disease. These studies are indicated beginning at 6 and 3 months for pT2 and pT3 disease, respectively, continuing every 6 months for 3 years and then annually. Surveillance computerized tomography should be performed at 24 and 60 months in patients with pT2 and pT3 disease or earlier when the results of any routine study are abnormal or clinical symptoms are present. Bone and brain surveillance studies should be prompted by site specific symptoms, elevated alkaline phosphatase levels or the diagnosis of metastasis at another site.
Adult↗
Timely delivery of biological therapy after cytoreductive nephrectomy in carefully selected patients with metastatic renal cell carcinoma.
PURPOSE: We determine whether cytoreductive surgery delays or precludes the administration of systemic biological therapy in patients with previously untreated metastatic renal cell carcinoma. MATERIALS AND METHODS: We evaluated 79 patients 22 to 73 years old with untreated renal cell carcinoma for possible cytoreductive surgery before the administration of systemic biological therapy. Based on performance status, overall disease burden and subjective clinical assessment 13 patients were referred for initial systemic biological therapy and 66 underwent cytoreductive surgery as initial treatment. We evaluated patient ability to receive postoperative biological therapy, time to therapy, surgical complications and mortality. RESULTS: Cytoreductive surgery had a minimal impact on the administration of timely systemic biological therapy in these carefully selected patients. Of the 66 patients 54 (82%) received postoperative systemic biological therapy beginning a median of 40 days after nephrectomy. Two patients (3%) died postoperatively (within 30 days) and in 1 (1.5%) postoperative deterioration in performance status precluded the administration of systemic therapy. The other 9 patients did not have measurable residual disease postoperatively, did not need or refused systemic therapy, or were followed elsewhere. CONCLUSIONS: Systemic biological therapy can be administered in a timely manner (median 40 days) to the majority of patients (82% treated) after cytoreductive surgery. Surgery alone does not preclude the administration of systemic biological therapy in carefully selected patients.
Adult↗
Mammalian orthologs of C. elegans unc-119 highly expressed in photoreceptors.
PURPOSE: To characterize orthologous human and murine cDNAs isolated through separate screens designed to identify genes expressed preferentially in retina. METHODS: By screening bovine, murine, and human retinal cDNA libraries, human UNC-119 clones of two varieties and a murine cDNA clone corresponding to the most abundant human transcript were isolated. Northern blot and reverse transcription-polymerase chain reaction analyses were used to determine tissue distribution of UNC-119 expression; in situ hybridization localized it in retina to photoreceptors. Fluorescence in situ hybridization was used to map the human structural gene, and its intron- exon boundaries were elucidated by polymerase chain reaction amplification and sequencing genomic DNA. RESULTS: UNC-119 was expressed at high levels in photoreceptors and at low levels elsewhere. The most abundant transcript encoded a protein of 240 amino acids with homology to Caenorhabditis elegans UNC-119. Rat and human cDNAs of UNC-119 have been previously reported as human retinal gene 4 and rat retinal gene 4 (HRG4 and RRG4). An alternative splice form in humans arose from retention of the 3'-most intron, seemed to be retina-specific, and encoded a protein of 220 amino acids. The human structural gene mapped to 17q 1.2 and comprised at least five exons and four introns. A patient with neurofibromatosis type 1, which also maps to 17q11.2, and cone-rod dystrophy was examined for a deletion of UNC-119 but no abnormalities were found. CONCLUSIONS: Given its strong degree of evolutionary conservation and abundant and nearly exclusive expression in photoreceptors, it is likely that UNC-119 plays an important role in vision and is a strong candidate gene for retinal diseases that map to 17q11.2.
Amino Acid Sequence↗
Future prognostic factors for renal cell carcinoma: Workgroup No. 5. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC).
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Biomarkers, Tumor↗