New algorithms for the staging of kidney cancer.
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Algorithms↗
Biomedical subjects
A Sella
Publications and source records attributed to A Sella.
Inhibition of contact hypersensitivity reaction to picryl chloride: effect of small molecular weight peptidomimetic compounds possessing inhibitory activity against metalloproteinases.
We have studied the effect of small molecular weight inhibitors of snake venom metalloproteinases (SVMP) and matrix metalloproteinases (MMPs) on the induction and effector phase of the contact hypersensitivity reaction (CHR) in a mouse model. Identification of nonsteroid small molecules is very important for the development of new anti-inflammatory drugs. The compounds that we tested were synthetically modified tripeptides (peptidomimetic compounds) POL-257, POL-509, POL-443, POL-491, and POL-647, with structures based on natural occurring peptides in snake venom. A well-known hydroxamate-based inhibitor of the MMPs, Batimastat (BB-94), was also used. We have shown that these peptidomimetics possess in vitro inhibitory activity against the MMP-2 (gelatinase-A), MMP-9 (gelatinase-B), and MMP-3 (stromelysin). They also inhibit metalloproteinases purified from the venom of Crotalus adamanteus and C. atrox snakes, which are very similar to the so-called A Desintegrine, A Metalloproteinase (ADAMs) enzymes. When injected intraperitonealy before the topical application of the contact sensitizer (picryl chloride) or before the challenge, these compounds significantly inhibited the development of CHR. BB-94 at doses 0.4 and 4 mg/kg before the sensitization or before the challenge almost completely abrogated the reaction. POL-257 and POL-443 were among the most active peptidomimetics tested. They inhibited the inflammatory reaction up to 70-80%, when applied either immediately before sensitization or before challenge. POL-509, a methylated derivative of POL-257, inhibited the CHR to 40-50% when administered at either challenge or sensitization. However, when applied 24 h before the challenge, it completely abrogated the inflammatory reaction. The results show that these small molecular weight peptidomimetic compounds, as well as BB-94, are able to significantly inhibit the CHR. This finding opens possibilities for using metalloproteinase inhibitors in the treatment of allergic contact dermatitis and other inflammatory diseases.
Animals↗
Chemotherapy with an every-2-week regimen of gemcitabine and paclitaxel in patients with transitional cell carcinoma who have received prior cisplatin-based therapy.
BACKGROUND: An every-2-week regimen of gemcitabine and paclitaxel was adapted for patients with advanced transitional cell carcinoma (TCC) who had received prior cisplatin-based chemotherapy. METHODS: Forty-one patients with advanced or metastatic TCC who had received prior cisplatin-based systemic chemotherapy were treated with an outpatient regimen of gemcitabine 2500-3000 mg/m(2) and paclitaxel 150 mg/m(2) every 2 weeks. RESULTS: Forty of 41 patients had measurable disease. Response was observed in 24 patients (60%; 95% confidence interval [CI], 45-75%). Eleven (28%) achieved complete response, and 13 (33%) obtained partial response. Twenty of 25 patients (80%; 95% CI, 64-96%) who had been previously treated in the neoadjuvant or adjuvant setting responded versus 4 of 15 (27%; 95% CI, 5-49%) in patients who received prior methotrexate, vinblastine, doxorubicin, cisplatin (M-VAC) for metastatic disease. The median duration of survival for patients given gemcitabine and paclitaxel after failing neoadjuvant or adjuvant M-VAC was 12 months (range, 2-43+), as compared with only 8 months (range, 2-28) for patients who had been treated after failure of prior therapy for metastatic disease. For all patients, the median duration of response was 6.4 months (range, 2-43.3+ months), and the median survival was 14.4 months (range, 2-43+). Thirteen patients (32%) developed World Health Organization Grade 3-4 neutropenia, with febrile neutropenia in 3 (7%) patients. Granulocyte colony-stimulating factor was given to 10 (24%) patients. There was no Grade 3-4 anemia or thrombocytopenia. CONCLUSIONS: The combination of gemcitabine and taxol in previously treated patients with recurrent TCC is highly effective and produces objective durable responses. This every-2-week schedule is a well tolerated outpatient regimen with minimal toxicity.
Adult↗
Synthesis and structural comparison of a series of divalent Ln(Tp(R,R)')2 (Ln = Sm, Eu, Yb) and trivalent Sm(Tp(Me2))2X (X = F, Cl, I, BPh4) complexes.
Reaction of LnI2 (Ln = Sm, Yb) with two equivalents of NaTp(Me2) or reduction of Eu(Tp(Me2))2OTf gives good yields of the highly insoluble homoleptic Ln(II) complexes, Ln(Tp(Me2))2 (Ln = Sm (1a), Yb (2a), Eu (3a)). Use of the additionally 4-ethyl substituted Tp(Me2,4Et) ligand produces the analogous, but soluble Ln(Tp(Me2,4Et))2 (1-3b) complexes. Soluble compounds are also obtained with the Tp(Ph) and Tp(Tn) ligands (Tn = thienyl), Ln(Tp(Ph))2 (Ln = Sm, 1c; Yb, 2c) and Ln(Tp(Tn))2 (Ln = Sm, 1d; Yb, 2d). To provide benchmark parameters for structural comparison the series of Sm(Tp(Me2))2X complexes (X = F, 1e; Cl, 1f; Br, 1g; I, 1h; BPh4, 1j) were prepared either via oxidation of the Sm(Tp(Me2))2 or salt metathesis from SmX3 (X = Cl, Br, I). The solid-state structures of 1-3a, 1b, 1-2c and 1e, 1f, 1h, and 1j were determined by single-crystal X-ray diffraction. The homoleptic bis-Tp complexes are all six-coordinate with trigonal antiprismatic geometries, planes of the kappa(3)-Tp ligands are parallel to one another. In the series of Sm(Tp(Me2))2X complexes the structure changes from seven-coordinate molecular compounds, with intact Sm-X bonds, for X = F, Cl, to six-coordinate ionic structures [Sm(Tp(Me2))2]X (X = I, BPh4), suitable crystals of the bromide compound could not be obtained. The dependence of the structures on the size of X is understandable in terms of the interplay between the size of the cleft that the [Sm(Tp(Me2))2](+) fragment can make available and the donor ability of the anionic group toward the hard Sm(III) center.
Journal Article↗
Solid-state structure and solution behavior of eight-coordinate Sm(III) poly(pyrazolyl)borate compounds.
[Sm(Tp(Me2)(2)(kappa(2)-S(2)CNR(2))] compounds (R = Et (1), Me (2); Tp(Me2) = HB(3,5-Me2pz)(3)) have been isolated from reaction of (R(2)NC(S)S)(2) with 2 equiv of [Sm(Tp(Me2)(2)]. Reductive cleavage of 2,2'-dipyridyl disulfide or 2,2'-dipyridyl diselenide by [Sm(Tp(Me2)(2)] afforded good yields of [Sm(Tp(Me2)(2)(kappa(2)-Y)] compounds (Y = 2-SC(5)H(4)N (3), 2-SeC(5)H(4)N (4)). 4 is the first selenopyridine complex of an f-block element. Sm(Tp(Me2)(2)(2-OC(5)H(4)N) (5) has been synthesized by salt metathesis of [Sm(Tp(Me2)(2)Cl] with the sodium salt of the 2-hydroxypyridine. The solid-state structures of 1, 3, 4, and 5 were determined by single-crystal X-ray diffraction analysis and revealed that the compounds are all eight-coordinate with dodecahedral geometry. The samarium atoms are bound in tridentate fashion to two pyrazolylborate ligands and in bidentate fashion by the third ligand. The solution behavior of the compounds was studied by (1)H NMR techniques. (1)H-(1)H exchange spectroscopy experiments give evidence for two distinct dynamic regimes occurring in solution.
Journal Article↗
Sperm extraction at orchiectomy for testis cancer.
OBJECTIVE: To evaluate the value of aspirating sperm from the vas and epididymis at orchiectomy in azoospermic patients. DESIGN: Retrospective clinical study. SETTING: Tertiary care academic hospital. PATIENT(S): Three patients with known azoospermia who presented with testicular masses suspected to be cancerous. INTERVENTION(S): At orchiectomy, immediately after ligation of the spermatic cord, the contents of the epididymis and vas deferens were extracted into preserving media. MAIN OUTCOME MEASURE(S): Fertility rate. RESULT(S): Sperm retrieval was successful in all three patients. The mean total sperm count was 2.3 x 10(6)/mL with 20% motility. Intracytoplasmic injection of sperm harvested by using this method was successful in two couples, one of which delivered a healthy infant. CONCLUSION(S): Sperm can be aspirated from the vas deferens and epididymis at orchiectomy for preservation. In azoospermic patients, this procedure may salvage enough sperm for successful use in micromanipulation techniques. It may be worthwhile to perform sperm aspiration during orchiectomy for testis cancer in any patient with known or suspected infertility.
Cryopreservation↗
Bladder neck involvement at radical prostatectomy: positive margins or advanced T4 disease?
OBJECTIVES: To assess the prognosis of patients with bladder neck (BN) involvement in radical prostatectomy specimens and compare it with patients with seminal vesicle invasion (SVI) presumed to have an inferior stage according to the TNM classification. METHODS: Two hundred eighty-six case files of consecutive radical prostatectomies were reviewed. The records of patients with pathologic BN involvement (pT4a) or SVI (pT3c) were thoroughly analyzed and compared. The mean and median follow-up periods were 30.8 and 35.5 months (range 9 to 40), respectively, for the patients with Stage pT4a and 40.8 and 44.1 months (range 8 to 86), respectively, for the patients with Stage pT3c. Particular attention was paid to the preoperative clinical and pathologic evaluation, the pathologic analysis of the prostatectomy specimen, and the postoperative follow-up data. Progression was defined as a prostate-specific antigen level of 0.2 ng/mL and rising. Adjuvant therapy was not initiated unless prostate-specific antigen failure had occurred. RESULTS: BN involvement was identified in 25 patients (8.7%) and SVI was found in 26 patients (9.1%). In 7 patients (2.4%), the BN was the only site of positive margins. Thirty-six percent of patients with BN involvement and 62% of patients with SVI demonstrated biochemical progression. Disease-free survival and metastasis-free survival rates were significantly better for the patients with Stage pT4a than for the patients with Stage pT3c at 24 and 36 months after surgery. Univariate analysis identified the prostate-specific antigen nadir to be the most significant predictor of prognosis. CONCLUSIONS: In this study, BN involvement in the surgical specimen carried a lower risk of progression than SVI. On the basis of our preliminary results and those in other studies, a conceivable downstaging of BN involvement in the TNM staging system should be considered. Possibly, additional modification of the TNM staging system should be contemplated on the basis of the results of pathologic analysis and prognosis. The significance of BN involvement and the role of adjuvant therapy in this group of patients need further evaluation.
Aged↗
Lanthanide chalcogenolate complexes: synthesis and crystal structures of the isoleptic series [Sm(TpMe,Me)2ER] (E = O, S, Se, Te; TpMe,Me = tris-3,5-dimethylpyrazolylborate).
A series of lanthanide complexes containing a chalcogenolate ligand supported by two TpMe,Me (tris-3,5-dimethylpyrazolylborate) groups has been prepared and crystallized and provides direct comparisons of bonding to hard and soft ligands at lanthanide centers. Reaction of [Sm(TpMe,Me)2Cl] with NaOR (R = Ph, Ph-Bu(t)) gives [Sm(TpMe,Me)2OR] (1a and 1b, respectively) in good yields. Reductive cleavage of dichalcogenides by samarium(II) was used to prepare the heavier congeners. Complexes of the type [Sm(TpMe,Me)2ER] for E = S, R = Ph (2a), E = S, R = Ph-4-Me (2b), E = S, R = CH2Ph (2c), E = Se, R = Ph (3a), E = Se, R = Ph-4-Bu(t) (3b), E = Se, R = CH2Ph (3c), and E = Te, R = Ph (4) have been prepared together with the corresponding complexes with TpMe,Me,4-Et as ancillary. The X-ray crystal structures of 1b, 2b, 3a, 3b, and 4 have been determined. The crystal of 1b (C40H57B2N12OSm.C7H8) was monoclinic, P2(1)/c, a = 10.6845(6) A, b = 18.5573(11) A, c = 24.4075(14) A, beta = 91.616(2) degrees, Z = 4. The crystal of 2b (C37H51B2N12SSm) was monoclinic, P2(1)/n, a = 15.0154(9) A, b = 13.1853(8) A, c = 21.1254(13) A, beta = 108.628(2) degrees, Z = 4. The crystal of 3a (C36H49B2N12SeSm.C7H8) was triclinic, P1, a = 10.7819(6) A, b = 19.3011(10) A, c = 23.0235(12) A, alpha = 79.443(2) degrees, beta = 77.428(2) degrees, gamma = 89.827(2) degrees, Z = 4. The crystal of 3b (C40H57B2N12SeSm) was triclinic, P1, a = 10.1801(6) A, b = 10.2622(6) A, c = 23.4367(14) A, alpha = 88.313(2) degrees, beta = 86.268(2) degrees, gamma = 62.503(2) degrees, Z = 2. The crystal of 4 (C36H49B2N12TeSm.C7H8) was monoclinic, P2(1)/c, a = 18.7440(10) A, b = 10.3892(6) A, c = 23.8351(13) A, beta = 94.854(2) degrees, Z = 4. The compounds form an isoleptic series of seven-coordinate complexes with terminal chalcogenolate ligands. Examination of 1b and other crystallographically characterized lanthanide alkoxides suggests that there is little correlation between bond angle and bond length. The structures of 3a and 3b, however, contain molecules in which one of the pyrazolylborate ligands undergoes a major distortion arising from twisting around a B-N bond so as to give an effectively eight-coordinate complex with pi-stacking of the phenyl group with one pyrazolyl ring. These distortions shed light on the fluxionality of these systems.
Journal Article↗
[Alopecia due to Seroxat therapy].
There are 2 stages of alopecia, anagen and telogen effluvium, both of which may be associated with medication-related alopecia. We describe massive hair loss in a 51-year-old woman during treatment with Seroxat (paroxetine), which remitted after it was discontinued. Pathological mechanisms of drug-associated alopecia are complex and have yet to be fully elucidated.
Alopecia↗
[Psychogenic polydipsia leading to water intoxication].
Psychogenic polydipsia and its frequent complication, water intoxication, are well-known to psychologists. There are biochemical and psychiatric theories of psychogenic polydipsia which often correlate with each other. A 48-year-old man with chronic paranoid schizophrenia developed symptoms of psychogenic polydipsia. This provoked disturbances in electrolyte balance, resulting in a rapid decrease in serum sodium concentration and eventual death. There is a paucity of information and little awareness of this problem in the professional literature.
Drinking Behavior↗
Phase II EORTC trial with 5-fluorouracil, cisplatin and interferon-alpha as second-line treatment of advanced transitional cell cancer of the urothelial tract.
BACKGROUND: Based on the favorable results of the combination 5-fluorouracil (5-FU), cisplatin and interferon-alpha as second-line treatment in advanced metastatic transitional-cell carcinoma of the urothelial tract a confirmatory study was executed in a multicenter setting. PATIENTS AND METHODS: In this open label phase II study 43 patients failing adequate previous chemotherapy were treated with IFN-alpha2b 5 MU/m2 subcutaneously for 5 consecutive days starting on day 1 and 22 simultaneous with 5-FU 500 mg/m2 daily as a continuous infusion. In between the same dose of IFN-alpha2b was given 3 times weekly with CDDP 25 mg/m2 on days 1, 8, 15 and 22. This cycle was repeated every six weeks. RESULTS: In 40 eligible patients 5 PR were seen (12.5%; 95% confidence interval (95% CI): 4.1%-26.8%). The major toxicity was hematological. Two toxic deaths were seen due to gastrointestinal hemorrhage. CONCLUSIONS: In view of these results this combination can not be recommended as second line treatment for metastatic transitional-cell carcinoma of the urothelial tract.
Aged↗
Low PSA metastatic androgen- independent prostate cancer.
OBJECTIVES: To describe the clinical parameters of low PSA, progressive metastatic androgen-independent prostate cancer. METHODS: From April 1995 to May 1999, we selected 18 patients with clinically progressive androgen-independent prostate cancer and low PSA (</=10 ng/ml). Patients received cisplatin-based therapy. Specimens from the primary tumor were reviewed and neuroendocrine differentiation was determined with chromogranin-A and neuron-specific enolase immunocytochemical staining. RESULTS: The median initial PSA level was 1.6 ng/ml (0-9.5). Each patient demonstrated elevation of at least one of the following markers: carcinoembryonic antigen, CA 19-9, CA15-3 and CA 125 CA. Metastases involved bone in 11 patients (61.1%) - 5 (27.7%) blastic, 2 (11.1%) lytic, and 4 (22.2%) combined - liver in 10 patients (55.5%), lymph nodes in 8 (44.4%), and lung in 6 (33.3%); solitary sites as orbit, skin and spleen were noted as well. A prostatic pelvic mass was detected in 13 patients (72.2%). Of the 12 patients who consented to chemotherapy, 8 (66.6%) achieved an objective response (95% CI, 34. 8-90%), including 1 patient with complete response. Hematoxylin and eosin evaluation revealed two major groups: neuroendocrine tumors, either pure small cell cancer in 6 patients (37.5%) or combined small cell cancer and adenocarcinoma in 8 (50%), and predominant poorly differentiated prostate cancer in 2 (12.5%). Neuroendocrine immunoreactivity was detected in all the specimens. CONCLUSIONS: Progressive androgen-independent prostate cancer with low serum PSA is characterized by visceral metastases, high proportion of lytic bone disease, sensitivity to cisplatin-based chemotherapy, and histological features of small cell or poorly differentiated prostate cancer. In this subgroup of patients, selection of the therapeutic approach can be based on clinical parameters. The rise of the serum markers may aid in the diagnosis and follow-up of these patients.
Androgens↗
Combination chemotherapy following adrenal suppression in androgen- independent prostate cancer.
OBJECTIVES: Recent trials with modern chemotherapy have demonstrated activity in androgen-independent prostate cancer, but all focused on patients with progression following androgen suppression or antiandrogen withdrawal. Limited data are available on the activity of chemotherapy in androgen-independent, hormone-refractory (progressing following adrenal suppression) prostate cancer. We evaluated the activity of estramustine combined with vinblastine in this subset of androgen-independent prostate cancer. METHODS: From January 1995 until April 1999, 19 patients with hormone-refractory prostate cancer received estramustine 140 mg p.o., three times daily along with weekly vinblastine 5 mg/m(2). RESULTS: A decrease in prostate-specific antigen of 50% or more was noted in 12 patients (63.1%, 95% CI 38.3-83.7%). The median decrease in prostate-specific antigen was 71.2% (range 50.5-85.2%). None of the 7 patients with measurable soft-tissue disease showed an objective response. The median survival from onset of chemotherapy was 6 (range 1.4-27.7) months and from initiation of adrenal suppression 16.9 (range 3.8-40. 5) months. CONCLUSIONS: The combination of estramustine and vinblastine is capable of inducing activity in androgen-independent prostate cancer progressing after adrenal suppression. In our small sample, the survival rate was low, and we obtained no response in soft-tissue sites. Future prospective trials are needed to determine the benefit of sequential versus simultaneous incorporation of adrenal suppression with chemotherapy in the management of androgen-independent prostate cancer.
Adult↗
[Information provided in writing for "informed consent" in clinical trials].
The Helsinki Declaration contains recommendations guiding physicians who conduct clinical trials. One is that the requirement for informed consent is essential for approval of a trial. An important component of the informed consent doctrine is that all data required for the participant's decision must be provided. We analyze data of a therapeutic trial, and define 12 data components outlined in, or directly derived from the Helsinki Declaration. 61 instances of informed consent for therapeutic clinical trials from various fields of medicine, from 1994 to 1997, were analyzed. In each the presence of the 12 components was evaluated. The data demonstrated that there were only 5 components cited in most cases of informed consent: trial objectives, methods, treatment plan, risks, and the option of withdrawing. Benefit to the participant was mentioned in half the cases, while only limited information was provided about other components such as life-threatening and unpredictable risks, and alternative treatment. Examples of informed consent from 1997 showed statistical improvement since 1994 in the data concerning trial objectives, methods, risks and alternative therapy. Informed consent documents of international multicenter trials compared with local trials showed statistical improvement in the data components of the trial objectives, methods, and risks, including those of potentially life-threatening and unpredictable risks, and alternative therapy. Analysis of informed consent showed that not all components required for a comprehensive decision regarding participation in a clinical trial are included. These data emphasize the need to design a structured informed consent protocol in which all the required data components are specifically outlined for potential participants.
Clinical Trials as Topic↗
[Combination chemotherapy with M-VAC protocol in metastatic urothelial cancer].
The treatment of metastatic urothelial cancer is based on the combination of cisplatin, methotrexate, vinblastine and adriamycin (M-VAC). From November 1994 to May 1997 we treated 25 patients (51 men, 3 women, aged 50-77) with M-VAC. The tumor originated from the urinary bladder in 14 (56%) and the upper urinary tract in 11 (44%). Disease sites included: primary--5 (25%), lymph nodes--17 (68%), lungs--10 (40%), bones--8 (32%), pelvic mass and liver each--4 (16%), with an overall median of 2 (1-5) sites per patient. 9 patients (38%) had complete responses and 8 (32%) had partial responses, for an overall response rate of 68% (95% CI 48.5%-85%). The median duration of response was 15.3 (1.6-29.6+) months. Median survival of responders was 19.1 (4.8-35.7+) months compared to 6.2 (0.7-11.2) for the non-responders (p < 0.05). 13 (52%) of patients are alive, of whom 8 (32%) are free of disease and 5 with a single metastatic site on presentation at follow-up. In the 118 treatment cycles we observed grade III-IV toxicity: myelosuppression 53 (45%), thrombocytopenia 4 (3%), stomatitis 8 (6.7%), diarrhea 3 (2.5%). There were 22 infectious episodes and 1 patient died of sepsis. We achieved a high response rate with the combination M-VAC. However, only a third had long-term disease-free states and treatment was associated with excessive toxicity. Therapeutic approaches with new agents are required to improve the response rate and toxicity.
Aged↗
Complications of retroperitoneal lymph node dissection in testicular cancer: primary and post-chemotherapy.
Retroperitoneal lymph node dissection (RPLND) is utilized in low-stage testis cancer as a primary diagnostic and therapeutic procedure. In the post-chemotherapy setting, it serves as an adjuvant procedure to resect residual tumor. Primary RPLND entails minimal resection of lymphatic tissue in the retroperitoneum; the complications are minor and insignificant. Wound infection is the main complication, affecting less than 5% of patients. Atelectasis and small bowel obstruction may occur in less than 2% of patients. In post-chemotherapy RPLND, the template and the surgical challenge are much larger. Extensive tumor size, difficult location, adherence to major vessels, and vital structures, together with inferior pre-operative status, are probably the main reasons for complications. The overall complication rate is 20% to 35% and mortality is 0.8% to 1%. Pulmonary insufficiency secondary to bleomycin-induced interstitial fibrosis is the cause of the most severe side effects and mortality in these operations. Chylous ascites may occur, especially where resection of the inferior vena cava is necessary. Other complications occur to a lesser extent. A summary of all complications is presented and measures to avoid or manage them are depicted.
Antineoplastic Combined Chemotherapy Protocols↗
Inhibition of adamalysin II and MMPs by phosphonate analogues of snake venom peptides.
Phosphonate analogues of the peptidomimetic N-(Furan-2-yl)carbonyl-Leu-Trp-OH were prepared with the goal of evaluating the effect of phosphonate for carboxylate replacement on binding with snake venom metalloproteinases and MMPs. N-(Furan-2-yl)carbonyl-Leu-L-Trp(P)-(OH)2 showed a 75-fold increase of the inhibiting activity against adamalysin II, a snake venom metalloproteinase structurally related to MMPs and TACE. Both the phosphonate and carboxylate peptidomimetics fit into the active site adopting a retrobinding mode and provide the structural base for a new class of metalloproteinases inhibitors.
Inhibitory Concentration 50↗
(PhTe)(3)(-): The Anionic Tellurium Analogue of I(3)(- ).
The missing link between solid-state tellurium chemistry and polyhalide ions is provided by the synthesis of the almost linear (PhTe)(3)(-) ion, whose structure is shown. Tritelluride units are a recurring motif in the solid state and are related to the structures of polyhalides.
Journal Article↗