Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

On returning from a medical meeting, we learned that sadly a patient, "Mr. B.," had passed away. His death was a completely unexpected surprise. He had been doing well nine months after a course of intensive radiotherapy for a locally advanced head and neck cancer; in his most recent follow-up notes, he was described as a "complete remission." Nonetheless, he apparently died peacefully in his sleep from a cardiac arrest one night and was found the next day by a concerned neighbor. In our absence, after Mr. B. expired, his death certificate was filled out by a physician who didn't know him in detail, but did know why he recently was treated in our department. The cause of death was listed as head and neck cancer. It wasn't long after his death before we began to receive those notorious "requests for additional information," letters from the statistical office of a well-known cooperative group. Mr. B., as it turns out, was on a clinical trial, and it was "vital" to know further details of the circumstances of his passing. Perhaps this very large cancer had been controlled and Mr. B. succumbed to old age (helped along by the tobacco industry). On the other hand, maybe the residual "fibrosis" in his neck was actually packed with active tumor and his left carotid artery was finally 100% pinched off, or maybe he suffered a massive pulmonary embolism from cancer-related hypercoagulability. The forms and requests were completed with a succinct "cause of death uncertain," adding, "please have the Study Chairs call to discuss this difficult case." Often clinical reports of outcomes utilize and emphasize the endpoint "disease specific survival" (DSS). Like overall survival (OS), the DSS can be calculated by actuarial methods, with patients who have incomplete follow-up "censored" at the time of last follow-up pending further information. In the DSS, however, deaths unrelated to the index cancer of interest are censored at the time of death; thus, a death from intercurrent disease is considered a "success" (to the investigator, that is; obviously, not to the patient and his or her family). The DSS rate will always be superior to the OS rate. Obviously, for any OS curve, if one waits long enough it will ultimately come to zero. There is thus a very logical rationale for reporting the DSS separately, particularly in diseases where death from intercurrent disease is expected to be common. Analyzing the DSS allows researchers to better compare the biologic efficacy of two or more cancer treatments, since it does not necessarily come to zero. Unlike some other endpoints, including local-regional control or freedom from progression, it takes into account the possibility of salvage therapy. DSS also focuses on an endpoint of interest to the public-death from cancer. In a recent popular media survey in which people were asked how they would choose to die if they could, 0% selected cancer. However, there are two serious potential problems with heavy dependence on the DSS. First, since patients who die from intercurrent disease are considered "cured," it seriously inflates the apparent effectiveness of a cancer treatment. Given the same biologic disease and the same treatment, the DSS as calculated in an old, sick population at high risk of intercurrent death will be better than the DSS in a younger, healthier population whose major risk is from their cancer. This problem has been discussed with respect to early stage prostate cancer, in which the conservative approach of observation has been criticized. The studies at issue rely heavily on the DSS, suggesting a comparable DSS (90% at 10 years) with "watchful waiting" to other researchers' results with aggressive therapy. The problem is that these series of conservative management focus on a patient population (as opposed to individuals) with a high risk of competing causes of mortality, which is very different from the population of patients generally treated with aggressive therapy (in which some have shown overall survivals superior to age-matched controls). It is fallacious and illogical to compare nonrandomized series of observation to those of aggressive therapy. In addition to the above problem, the use of DSS introduces another potential issue which we will call the bias of cause-of-death-interpretation. All statistical endpoints (e.g., response rates, local-regional control, freedom from brain metastases), except OS, are known to depend heavily on the methods used to define the endpoint and are often subject to significant interobserver variability. There is no reason to believe that this problem does not occasionally occur with respect to defining a death as due to the index cancer or to intercurrent disease, even though this issue has been poorly studied. In many oncologic situations-for example, metastatic lung cancer-this form of bias does not exist. In some situations, such as head and neck cancer, this could be an intermediate problem (Was that lethal chest tumor a second primary or a metastasis?.Would the fatal aspiration pneumonia have occurred if he still had a tongue?.And what about Mr. B. described above?). In some situations, particularly relatively "good prognosis" neoplasms, this could be a substantial problem, particularly if the adjudication of whether or not a death is cancer-related is performed solely by researchers who have an "interest" in demonstrating a good DSS. What we are most concerned about with this form of bias relates to recent series on observation, such as in early prostate cancer. It is interesting to note that although only 10% of the "observed" patients die from prostate cancer, many develop distant metastases by 10 years (approximately 40% among patients with intermediate grade tumors). Thus, it is implied that many prostate cancer metastases are usually not of themselves lethal, which is a misconception to anyone experienced in taking care of prostate cancer patients. This is inconsistent with U.S. studies of metastatic prostate cancer in which the median survival is two to three years. It is possible that many deaths attributed to intercurrent disease in "watchful waiting" series were in fact prostate cancer-related, perhaps related to failure to thrive, urosepsis, or pulmonary emboli. We will not know without an independent review of the medical records of individual patients; in some cases, even the most detailed review, sometimes even an autopsy, will not be conclusive. There are only a few data available describing the problems created by cause-of-death-interpretation bias. One small study, presented only in abstract form, assessed the cause of death in 50 randomly selected prostate cancer patients who died. Five experts in prostate cancer were asked to assign the cause of death as due to or not due to prostate cancer. The DSS varied from 21% to 35% among the five reviewers, a relative difference of 66%. Studies of autopsies, which are now rarely done in the U.S., have shown that fatal malignant tumors were occasionally missed by clinicians and-even more sobering-an occasional patient thought to have died from metastatic cancer is found to have no tumor but to have died from a "benign" cause such as TB. One study suggested an error rate of approximately 8%. Clearly the use of DSS is here to stay and is a useful adjunct to OS in analyzing randomized trials. There needs to be more research on the validity and interobserver reproducibility of the DSS. In the meantime, researchers should not report DSS without reporting OS and the reasons for intercurrent deaths should be described-peer reviewers should enforce this. As with so many other problems with statistics in the medical literature, it is the job of the reader to remain skeptical. The rate of intercurrent deaths in a study should reflect the age and demographics of the study population. If the DSS is far superior to the OS, the population being studied may be unusually sick (and thus unrealistic), or there may be a bias in classifying the causes of death. Similarly, if the DSS and OS are identical (unless a highly virulent malignancy is being studied), it may suggest the researchers have only included an unusually healthy (and thus unrealistic) patient population. Finally, we would also be a bit suspicious of a sizeable series that did not have any deaths that were considered of "uncertain" cause, unless the researchers specifically included them as being due to the cancer. We honestly think that everybody has a few patients like Mr. B.
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PMID:"Just Another Statistic" 1038 5

Serine proteases of the chymotrypsin fold are of great interest because they provide detailed understanding of their enzymatic properties and their proposed role in a number of physiological and pathological processes. We have been developing the macromolecular inhibitor ecotin to be a "fold-specific" inhibitor that is selective for members of the chymotrypsin-fold class of proteases. Inhibition of protease activity through the use of wild-type and engineered ecotins results in inhibition of rat prostate differentiation and retardation of the growth of human PC-3 prostatic cancer tumors. In an effort to identify the proteases that may be involved in these processes, reverse transcription-PCR with PC-3 poly(A)+ mRNA was performed by using degenerate oligonucleotide primers. These primers were designed by using conserved protein sequences unique to chymotrypsin-fold serine proteases. Five proteases were identified: urokinase-type plasminogen activator, factor XII, protein C, trypsinogen IV, and a protease that we refer to as membrane-type serine protease 1 (MT-SP1). The cloning and characterization of the MT-SP1 cDNA shows that it encodes a mosaic protein that contains a transmembrane signal anchor, two CUB domains, four LDLR repeats, and a serine protease domain. Northern blotting shows broad expression of MT-SP1 in a variety of epithelial tissues with high levels of expression in the human gastrointestinal tract and the prostate. A His-tagged fusion of the MT-SP1 protease domain was expressed in Escherichia coli, purified, and autoactivated. Ecotin and variant ecotins are subnanomolar inhibitors of the MT-SP1 activated protease domain, suggesting a possible role for MT-SP1 in prostate differentiation and the growth of prostatic carcinomas.
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PMID:Reverse biochemistry: use of macromolecular protease inhibitors to dissect complex biological processes and identify a membrane-type serine protease in epithelial cancer and normal tissue. 1050 Jan 22

A 72-year-old man presented with pollakiuria and dysuria. His prostate was the size of an apple and hard on digital rectal examination and the serum prostate specific antigen (PSA) level was 73 ng/ml (RIA). Ultrasonography revealed bilateral hydronephrosis and the serum creatinine level was 13.2 mg/dl. CT scanning of the abdomen demonstrated swelling of paraaortic lymph nodes. Transrectal needle biopsy of the prostate gave a diagnosis of moderately differentiated adenocarcinoma. Accordingly, the final diagnosis was prostate cancer (cT3N4M1, stage D2). Immediately after bilateral percutaneous nephrostomy, treatment with an LH-RH agonist (goserelin) and flutamide was commenced. Serum creatinine was 6.6 mg/dl at the start of antiandrogen therapy and decreased to 1.8 mg/dl after 27 days. A 125 mg flutamide capsule was administered at 7 a.m., and blood samples were collected 4 hours later on days 1, 2, 3, 5, 6, 8, 12, 14, 17, 18 and 27. The OH-flutamide concentration was measured. There was no significant correlation between serum creatinine and the OH-flutamide concentration. After implantation of goserelin (3.6 mg depot), blood samples were obtained at 11 a.m. on days 8, 12, 14, 15 and 25. The serum goserelin level was measured. The serum goserelin level increased to a peak on day 14, as described previously, but the peak value of 9.63 ng/ml was higher than that reported before (mean +/- SD 2.848 +/- 0.199).
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PMID:[Serum concentrations of flutamide and goserelin in a prostate cancer patient with obstructive nephropathy: a case report]. 1050 Sep 60

A 78-year-old man admitted with clinical jaundice and pelvic pain had a total bilirubin level of 6.56 mg/dL, an alkaline phosphatase level of 855 U/L, and a prostate specific antigen (PSA) level of 9996 ng/mL. A computed tomogram demonstrated marked retroperitoneal, peripancreatic, periceliac, and periaortic lymphadenopathy. A bone scan revealed increased radiolabeled technetium uptake in the pelvis, vertebral column, parietooccipital region, ribs, and appendiceal skeleton. A biopsy of one pelvic lesion revealed metastatic prostate cancer. This man's obstructive jaundice and bone pain had a dramatic response to treatment with a gonadotropin-releasing hormone analog (leupro lide) and antiandrogen (bicalutamide). All bone pair and clinical signs of jaundice disappeared in 1 week His total bilirubin decreased to 0.84 mg/dL by 2 weeks His PSA values reflected this clinical response, decreasing to 4022 ng/mL in 1 week, 2680 ng/dL after 2 weeks and 1028 ng/mL after 1 month of the above therapy.
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PMID:Metastatic prostate cancer (with prostate-specific antigen of 9996) presenting as obstructive jaundice. 1069 97

Androgen receptors (ARs) belong to the family of hormone receptors that are ligand-dependent transcription factors. Endocrine therapy provides effective treatment for prostate cancer until mutations arise that alter the ligand responsiveness of AR. In this study, structural models were developed for the functional domains of human AR by homology modeling from crystal structures of closely related nuclear receptors. These models were used to locate the sites of two frequently occurring mutations in prostate cancer. The substitutions that develop in LNCaP (threonine-->alanine at residue 877) and CWR22 (histidine-->tyrosine at residue 874) tumor cell lines are both located on helix 11 that forms part of the ligand-binding pocket. However, the results suggest that these mutations influence ligand responsiveness by completely different mechanisms. Residue 877 contacts the ligand directly, and substitution at this site alters the stereochemistry of the binding pocket. Thus, the LNCaP mutation apparently broadens the specificity of ligand recognition. In contrast, residue 874 is located down the helical axis, projects away from the ligand pocket, and does not contact ligand. The side chain of residue 874 lies in a cavity between helices 11 and 12. Substitution of tyrosine for histidine 874 in CWR22 tumors may affect a conformational change of helix 12 and, thus, influence binding of coactivator proteins and their regulatory effect on transcriptional activation.
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PMID:Ligand responsiveness in human prostate cancer: structural analysis of mutant androgen receptors from LNCaP and CWR22 tumors. 1081 Nov

Factor VIII inhibitors are antibodies of the IgG class that block functional epitopes or antigenic sites of factor VIII. They occur in about 5-20% of hemophilia A patients after infusions of factor VIII concentrate. Antibodies to factor VIII can also arise spontaneously in association with various autoimmune and chronic inflammatory diseases, hematologic malignancies, solid tumors, certain drugs, dermatologic conditions, and in puerperium. In the majority of cases, the clinical course is characterized by severe hemorrhages. Strategies to treat such inhibitors are controversial. We present the case of a patient with prostatic cancer who developed acquired factor VIII inhibitor. His severe bleeding complications were treated successfully with cyclophosphamide in combination with methylprednisolone. Within a few months, moreover, the immunosuppressive therapy brought about complete disappearance of the inhibitor and normalization of coagulation parameters. Our case illustrates that, although the clinical course in patients with acquired factor VIII inhibitor is not predictable, and the inhibitor may disappear spontaneously, combined therapy with cyclophosphamide and methylprednisolone should be considered for patients with severe hemorrhages.
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PMID:Acquired factor VIII inhibitor associated with prostatic cancer: successful treatment with steroid and immunosuppressive therapy. 1092 May 9

The cellular form of human prostatic acid phosphatase (PAcP) is a neutral protein-tyrosine phosphatase (PTP) and may play a key role in regulating the growth and androgen responsiveness of prostate cancer cells. The functional role of the enzyme is at least due in part to its dephosphorylation of c-ErbB-2, an in vivo substrate of the enzyme. In this study, we investigated the molecular mechanism of phosphotyrosine dephosphorylation by cellular PAcP. We mutated several amino acid residues including one cysteine residue that was proposed to be involved in the PTP activity of the enzyme by serving as the phosphate acceptor. The cDNA constructs of mutant enzymes were transiently transfected into C-81 LNCaP and PC-3 human prostate cancer cells that lack the endogenous PAcP expression. The phosphotyrosine level of ErbB-2 in these transfected cells was subsequently analyzed. Our results demonstrated that the phosphotyrosine level of ErbB-2 in cells expressing H12A or D258A mutant PAcP is similar to that in control cells without PAcP expression, suggesting that these mutants are incapable of dephosphorylating ErbB-2. In contrast, cells expressing C183A, C281A, or wild-type PAcP had a decreased phosphotyrosine level of ErbB-2, compared with the control cells. Similar results were obtained from in vitro dephosphorylation of immunoprecipitated ErbB-2 by these mutant enzymes. Furthermore, transient expression of C183A, C281A, or the wild-type enzyme, but not H12A or D258A, decreased the growth rate of C-81 LNCaP cells. The data collectively indicate that His-12 and Asp-258, but not Cys-183 or Cys-281, are required for the PTP activity of PAcP.
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PMID:Characterization of a prostate-specific tyrosine phosphatase by mutagenesis and expression in human prostate cancer cells. 1106 47

Hemangiomas represent the most common primary tumor of the liver. Clinically the significance of these lesions is highly variable. The management of hemangiomas is controversial and is intimately related to the size, symptoms, and associated comorbidities of the patients who harbor these benign tumors. Series suggest that the vast majority of hemangiomas are less than 4 cm, asymptomatic, and clinically incidental findings. Symptomatic hemangiomas are large and associated with a constellation of vague upper abdominal complaints including pain, mass, distention, early satiety, and weight loss. A number of small series of surgically treated symptomatic hemangiomas have demonstrated enucleation as a safe and effective intervention. We report a collection of case reports using embolization as a primary treatment of symptomatic hemangiomas. The first patient is a 73-year-old black man previously treated for prostate cancer by radical prostatectomy and radiation. He developed weight loss, abdominal fullness, and early satiety. His symptoms were attributed to a large left lateral segmental liver mass that was biopsy proven to be a hemangioma. The second patient is a 49-year-old black women who complained of weakness, fatigue, night sweats, and anemia. The only abnormality discovered was a large right posterior hemangioma. The third patient is a 49-year-old black women with unexplained right upper quadrant pain and anemia who was found to have a 19 x 11 x 7.5-cm left hepatic hemangioma by CT. All three patients underwent elective treatment of their hemangiomas with highly selective hepatic embolization. There were no significant complications related to the procedures. Symptoms resolved for all patients acutely after treatment. The use of embolization for hepatic hemangiomas provides safe and effective treatment of the patient's symptoms while avoiding operative intervention, extended hospitalization, or postoperative recuperation. This treatment modality should be considered for the symptomatic hemangioma under elective conditions.
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PMID:Embolization for management of hepatic hemangiomas. 1124 41

Although prostate cancer is one of the most commonly encountered malignancies in clinical practice, it is very unusual for prostate cancer to metastasize to the small bowel. Our search of the literature found no such cases published from 1966 to the present. We report the case of a 69-year-old man who presented for evaluation of anasarca and anorexia. He had a history of prostate cancer diagnosed 9 years before and had undergone a radical prostatectomy with subsequent radiotherapy for positive tumor margins. He developed anasarca 2 years before presentation to us. His serum albumin ranged between 1.5 and 2.5 g/dL. Upper endoscopy was performed for possible protein-losing enteropathy and the appearance of gastric and duodenal mucosa was found to be normal. Random small bowel biopsies revealed submucosal infiltrating adenocarcinoma with positive prostate-specific antigen stains consistent with the diagnosis of prostate cancer metastatic to the small bowel. This is a rare presentation of metastatic prostate cancer. Even though prostate cancer is the most commonly diagnosed cancer in American men, antemortem diagnosis of small bowel metastasis has not been reported. In patients with unexplained anasarca, especially with a history of malignancy, an upper endoscopy with small bowel biopsy may be useful in establishing the diagnosis.
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PMID:Prostate cancer metastasizing to the small bowel. 1131 19

Acid phosphatases are enzymes capable of hydrolyzing orthophosphoric acid esters in an acid medium. Prostatic acid phosphatase has served as a tumor marker for metastatic prostate cancer for many years. We have cloned a new human acid phosphatase gene (named testicular acid phosphatase, ACPT), which is expressed mainly in testis and to a lower extent in the prostate, trachea, and other tissues. This gene maps to chromosome 19q13.4, in an area that harbors many cancer-related genes. The testicular acid phosphatase gene is composed of 11 exons, and the protein is predicted to have a luminal domain, a transmembrane domain, and a cytoplasmic domain. The N-terminal end of the protein encodes a signal peptide. The protein has approximately 50% homology with both the prostatic and the lysosomal acid phosphatases, and the position of the cysteine residues, the N-glycosylation sites, and the histidine catalytic site are conserved among the three proteins. The testicular acid phosphatase gene is up-regulated by androgens and is down-regulated by estrogens in the prostate cancer cell line LNCaP. Our preliminary results indicate that this gene exhibits a lower level of expression in testicular cancer tissues than in their normal counterparts.
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PMID:Molecular cloning of a novel human acid phosphatase gene (ACPT) that is highly expressed in the testis. 1141 67


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