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1.
Curr Psychiatry Rep ; 24(12): 889-896, 2022 12.
Article in English | MEDLINE | ID: mdl-36422834

ABSTRACT

PURPOSE OF REVIEW: As maternal mortality climbs in the USA with mental health conditions driving these preventable deaths, the field of reproductive psychiatry must shift towards identification of women and other birthing individuals at risk and facilitating access. This review brings together recent studies regarding risk of perinatal depression and highlights important comorbidities that place individuals at higher vulnerability to poor perinatal outcomes. RECENT FINDINGS: Recent research suggests that identifying risk for perinatal depression including historical diagnoses of depression, anxiety, trauma, and comorbid substance use and intimate partner violence may move the field to focus on preventive care in peripartum populations. Emerging data shows stark health inequities in racial and ethnic minority populations historically marginalized by the health system and in other vulnerable groups such as LGBTQ+ individuals and those with severe mental illness. Innovative models of care using systems-level approaches can provide opportunities for identification and risk analyses of vulnerable peripartum patients and facilitate access to therapeutic or preventive interventions. Utilizing intergenerational approaches and leveraging multidisciplinary teams that thoughtfully target high-risk women and other birthing individuals could promote significant changes to population-level care in maternal health.


Subject(s)
Depression, Postpartum , Pregnancy , Female , Humans , Depression, Postpartum/diagnosis , Depression, Postpartum/therapy , Ethnicity , Minority Groups , Anxiety Disorders , Anxiety , Depression/therapy , Postpartum Period
2.
Br J Cancer ; 104(12): 1869-76, 2011 Jun 07.
Article in English | MEDLINE | ID: mdl-21610703

ABSTRACT

BACKGROUND: Thiothymidine (S(4)TdR) can be incorporated into DNA and sensitise cells to DNA damage and cell death following exposure to UVA light. Studies were performed to determine if the combination of S(4)TdR and UVA could be an effective treatment for bladder cancer. METHODS: Uptake and incorporation of S(4)TdR was determined in rat and human bladder tumour cell lines. Measures of DNA crosslinking and apoptosis were also performed. In vivo activity of the combination of S(4)TdR and UVA was investigated in an orthotopic model of bladder cancer in rats. RESULTS: Thiothymidine (200 µM) replaced up to 0.63% of thymidine in rat and tumour bladder cancer cells. The combination of S(4)TdR (10-200 µM) and UVA (1-5 kJ m(-2)) caused apoptosis and cell death at doses that were not toxic alone. Addition of raltitrexed (Astra Zeneca, Alderley Edge, Cheshire, UK) increased the incorporation of S(4)TdR into DNA (up to 20-fold at IC(5)) and further sensitised cells to UVA. Cytotoxic effect was associated with crosslinking of DNA, at least partially to protein. Intravenous administration of S(4)TdR, in combination with UVA delivered directly to the bladder, resulted in an antitumour effect in three of five animals treated. CONCLUSION: These data indicate that the combination of S(4)TdR and UVA has potential as a treatment for bladder cancer, and give some insight into the mechanism of action. Further work is necessary to optimise the delivery of the two components.


Subject(s)
Radiation-Sensitizing Agents/therapeutic use , Thymidine/analogs & derivatives , Ultraviolet Therapy , Urinary Bladder Neoplasms/therapy , Animals , Apoptosis/radiation effects , Cell Line, Tumor , DNA Damage , Female , Humans , Quinazolines/pharmacology , Rats , Rats, Inbred F344 , Thiophenes/pharmacology , Thymidine/metabolism , Thymidine/therapeutic use , Thymidine/toxicity , Urinary Bladder Neoplasms/pathology
3.
Br J Cancer ; 102(3): 553-60, 2010 Feb 02.
Article in English | MEDLINE | ID: mdl-20051956

ABSTRACT

BACKGROUND: The standard treatment of choice for malignant pleural mesothelioma is chemotherapy with pemetrexed and platinum, but the clinical outcome is poor. This study investigates the response to pemetrexed in a panel of eight mesothelioma cell lines and the clinical outcome for patients treated with pemetrexed in relation to folate receptor alpha (FRalpha). METHODS: Cell lines were treated with pemetrexed to determine the concentration that reduced growth to 50% (GI(50)). FRalpha expression was determined by western blotting and that of FRalpha, reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) by real-time quantitative RT-PCR. Immunohistochemistry for FRalpha was carried out on 62 paraffin-embedded samples of mesothelioma from patients who were subsequently treated with pemetrexed. RESULTS: A wide range of GI(50) values was obtained for the cell lines, H2452 cells being the most sensitive (GI(50) 22 nM) and RS5 cells having a GI(50) value greater than 10 microM. No FRalpha protein was detected in any cell line, and there was no relationship between sensitivity and expression of folate transporters. FRalpha was detected in 39% of tumour samples, generally in a small percentage of cells. There was no correlation between the presence of FRalpha and the outcome of pemetrexed treatment, and no significant difference between histological subtypes. CONCLUSION: Response to treatment with pemetrexed does not depend on the presence of FRalpha.


Subject(s)
Carrier Proteins/physiology , Folic Acid Antagonists/therapeutic use , Glutamates/therapeutic use , Guanine/analogs & derivatives , Mesothelioma/drug therapy , Pleural Neoplasms/drug therapy , Receptors, Cell Surface/physiology , Blotting, Western , Carrier Proteins/analysis , Carrier Proteins/genetics , Cell Line, Tumor , Folate Receptors, GPI-Anchored , Guanine/therapeutic use , Humans , Immunohistochemistry , Pemetrexed , Receptors, Cell Surface/analysis , Receptors, Cell Surface/genetics , Reverse Transcriptase Polymerase Chain Reaction
4.
J Clin Pathol ; 61(10): 1098-103, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18682419

ABSTRACT

BACKGROUND: MYCN is the most commonly amplified gene in human neuroblastomas. This proto-oncogene has been overexpressed in a mouse model of the disease in order to explore the role of MYCN in this tumour. AIMS: To report the histopathological features of neuroblastomas from MYCN transgenic mice. METHODS: 27 neuroblastomas from hemizygous transgenic mice and four tumours from homozygous mice were examined histologically; Ki67 and MYCN immunocytochemistry was performed in 24 tumours. RESULTS: Tumours obtained from MYCN transgenic mice resembled human neuroblastomas, displaying many of the features associated with stroma-poor neuroblastoma, including heterogeneity of differentiation (but no overt ganglionic differentiation was seen), low levels of Schwannian stroma and a high mitosis karyorrhexis index. The tumours had a median Ki67 labelling index of 70%; all tumours expressed MYCN with a median labelling index of 68%. The most striking difference between the murine and human neuroblastomas was the presence of tingible body macrophages in the transgenic mouse tumours reflecting high levels of apoptosis. This has not previously been described in human or other murine neuroblastoma models. CONCLUSIONS: These studies highlight the histological similarities between tumours from MYCN transgenic mice and human neuroblastomas, and reaffirm their role as a valuable model to study the biology of aggressive human neuroblastoma.


Subject(s)
Abdominal Neoplasms/pathology , Neuroblastoma/pathology , Nuclear Proteins , Oncogene Proteins , Abdominal Neoplasms/genetics , Animals , Biomarkers/analysis , Blotting, Western , Female , Gene Amplification , Humans , Immunohistochemistry , Ki-67 Antigen/analysis , Male , Mice , Mice, Transgenic , N-Myc Proto-Oncogene Protein , Neuroblastoma/genetics , Nuclear Proteins/analysis , Nuclear Proteins/genetics , Oncogene Proteins/analysis , Oncogene Proteins/genetics , Proto-Oncogene Mas , Ubiquitin Thiolesterase/analysis
5.
J Pediatr Surg ; 36(12): 1781-4, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11733906

ABSTRACT

BACKGROUND/PURPOSE: Antiangiogenic agents offer a new approach to the treatment of aggressive neoplasms, yet very few agents are available for current use. The authors have shown previously the efficacy of antiangiogenic therapy in experimental Wilms tumor, using an investigative antibody. They hypothesized that topotecan, administered in a regimen targeting endothelial cells, would suppress tumor growth and angiogenesis in experimental Wilms tumor. METHODS: Experimental tumors were induced in the left kidneys of athymic mice by injection of cultured Wilms tumor cells. Topotecan (0.36, 0.6, 1.0, 2.0, and 3.0 mg/kg) or vehicle was injected intraperitoneally in 2 cycles over a 6-week period. Fluorescein angiograms and platelet endothelial cell adhesion molecule-1 staining of primary tumors were performed to ascertain vascular architecture. Endothelial apoptosis was assessed by TdT-mediated dUTP nick end labeling assay. RESULTS: Tumor weights were reduced significantly in treated versus control animals, even in the lowest-dose group. Endothelial cell staining and angiography results showed relatively sparse vascularity in treated xenografts. Endothelial apoptosis was observed in treated but not control tumors. CONCLUSIONS: Topotecan, delivered in an "antiangiogenic" regimen, even at very low doses, significantly inhibited growth of experimental Wilms tumors. No adverse effects were noted at low doses. Thus, the established chemotherapy agent topotecan may be useful in a novel role: as antiangiogenic therapy. J Pediatr Surg 36:1781-1784.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Topotecan/therapeutic use , Wilms Tumor/drug therapy , Angiogenesis Inhibitors/pharmacology , Animals , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Mice , Mice, Nude , Neovascularization, Pathologic/prevention & control , Topotecan/pharmacology , Wilms Tumor/pathology
6.
J Pediatr Surg ; 36(8): 1177-81, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11479851

ABSTRACT

BACKGROUND/PURPOSE: Antibody to vascular endothelial growth factor (anti-VEGF) suppresses tumor growth and metastasis in experimental Wilms tumor. However, tumor growth accelerates if antibody is withdrawn. As recently shown, low-dose, frequently administered topotecan, a topoisomerase-1 inhibitor, has anti-angiogenic activity. The authors hypothesized that combined topotecan/anti-VEGF therapy would suppress tumor growth and metastasis more durably than either agent alone. METHODS: Xenografts were induced by intrarenal injection of human Wilms tumor cells in athymic mice (n = 59). Mice were divided into control (n = 10), anti-VEGF (n = 16), topotecan (n = 17), and topotecan plus anti-VEGF (n = 16) groups. All control and half the treated mice were killed at week 6. Remaining ("rebound") mice were maintained without treatment until week 8. Tumor vasculature was mapped by fluorescein angiography/PECAM immunostaining. Endothelial apoptosis was assessed by TUNEL assay. RESULTS: 6 weeks: Tumor weights were reduced significantly in treated mice (P <.003 v control). Seven of ten control and 1 of 25 treated mice displayed lung metastases (P <.003). Rebound tumors were largest in topotecan-only, intermediate in antibody-treated, and smallest in combination-treated mice. Immunostaining and angiography results showed sparse vascularity in treated xenografts. Endothelial apoptosis was observed only in treated tumors. CONCLUSION: Combination low-dose topotecan and anti-VEGF antibody therapy is antiangiogenic and suppresses tumor growth and metastasis in experimental Wilms tumor more durably than either agent alone.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Kidney Neoplasms/drug therapy , Neovascularization, Pathologic/prevention & control , Wilms Tumor/drug therapy , Animals , Antibodies, Monoclonal/pharmacology , Biopsy, Needle , Disease Models, Animal , Endothelial Growth Factors/administration & dosage , Endothelial Growth Factors/immunology , In Situ Nick-End Labeling , Injections, Intraperitoneal , Kidney Neoplasms/pathology , Lymphokines/administration & dosage , Lymphokines/immunology , Mice , Mice, Nude , Neoplasm Transplantation , Reference Values , Sensitivity and Specificity , Survival Rate , Topotecan/administration & dosage , Treatment Outcome , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors , Wilms Tumor/pathology
7.
J Pediatr Surg ; 36(2): 287-90, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11172417

ABSTRACT

BACKGROUND/PURPOSE: Neuroblastoma and Wilms tumor exhibit different patterns of metastasis, invasion, and therapeutic response. Vascular endothelial growth factor (VEGF) is an angiogenic factor expressed in both tumors. The authors hypothesized that because the clinical behavior of these tumors differs, the response to anti-VEGF therapy would be distinct, and tumor vascular architectures would reflect this distinction. METHODS: Xenografts were induced by intrarenal injection of cultured cells in athymic mice. After 1 week, anti-VEGF antibody or vehicle were administered for 5 weeks before sacrifice. Additional animals were maintained for 3 weeks after termination of antibody injections to assess rebound growth of tumors. Fluorescein angiography was performed in selected animals. RESULTS: Neuroblastoma control and treated tumor weights were not significantly different (1.48 g v 0.77 g, P =.34). By comparison, as previously reported, antibody-treated Wilms tumors were growth inhibited. Angiograms of treated (but not control) neuroblastomas displayed novel rounded structures at vessel branches, which the authors term terminal vascular bodies (TVBs). Wilms tumor vessels displayed no such alteration. CONCLUSIONS: Neuroblastoma xenografts are less effectively suppressed by anti-VEGF antibody than Wilms tumors. Neuroblastoma vascular architecture displays a novel alteration during antibody administration, which attenuates when antibody is withdrawn. These studies suggest that angiogenesis is differently regulated in experimental neuroblastoma and Wilms tumor.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antibodies, Monoclonal/therapeutic use , Brain Neoplasms/therapy , Endothelial Growth Factors/antagonists & inhibitors , Kidney Neoplasms/therapy , Neovascularization, Pathologic , Neuroblastoma/therapy , Wilms Tumor/therapy , Animals , Brain Neoplasms/blood supply , Endothelial Growth Factors/physiology , Humans , Kidney Neoplasms/blood supply , Mice , Mice, Nude , Models, Animal , Neoplasm Invasiveness/physiopathology , Neuroblastoma/blood supply , Treatment Outcome , Wilms Tumor/blood supply
8.
J Pediatr Surg ; 36(2): 357-61, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11172434

ABSTRACT

BACKGROUND/PURPOSE: Pathologic angiogenesis in tumors is a potential target for novel therapies. Vascular endothelial growth factor (VEGF) is an angiogenic promoter present in a wide variety of human tumors. VEGF is expressed as 4 isoforms; one of these, VEGF165, predominates in human tumors. The authors hypothesized that antagonism of VEGF165 by a specific aptamer would block tumor growth in an experimental model of Wilms tumor. METHODS: VEGF isoform expression in clinical (n = 2) and experimental tumors were evaluated by reverse transcription polymerase chain reaction (RT-PCR). Tumors were induced in NCR nude mice (n = 32) by intrarenal injection of 10(6) cultured Wilms tumor cells. At 1 week, aptamer (n = 16) or vehicle (n = 16) treatment was started and continued daily for 5 weeks. RESULTS: At 6 weeks tumors weighed 84% less in treated versus control animals (0.69 v 4.41 g; P <.028), without observed adverse effects and similar to suppression previously reported using nonisoform-specific anti-VEGF antibody (94% to 96%). CONCLUSIONS: Anti-VEGF165 aptamer effectively suppressed primary tumor growth in experimental animals with no observed adverse effects. Development of highly specific antiangiogenic therapies may be of particular benefit to pediatric patients.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Kidney Neoplasms/therapy , Wilms Tumor/therapy , Animals , Endothelial Growth Factors/antagonists & inhibitors , Mice , Models, Animal , Reverse Transcriptase Polymerase Chain Reaction , Treatment Outcome , Tumor Cells, Cultured
9.
Am J Surg Pathol ; 24(12): 1634-40, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11117784

ABSTRACT

The grading system for prostate carcinoma devised by Gleason is a strong prognostic indicator. The primary and secondary patterns are combined to give a tumor score, referred to as Gleason score or sum. Gleason scores on biopsy correlate with the prostatectomy Gleason scores, and in combination with pretreatment serum prostate-specific antigen and digital rectal examination results, predict tumor stage and lymph node status. However, when only a minute focus of tumor is present on biopsy, the Gleason score is assigned by doubling the Gleason pattern. The goal of this study was to determine if a Gleason score assigned to a minimal focus of adenocarcinoma had predictive value. Paired biopsies and prostatectomy specimens from 963 cases of men with clinically localized prostate cancer were examined. Minimal tumor on biopsy was defined as less than 1 mm or 5% involvement of one biopsy core; excluded from this definition were biopsies where two Gleason patterns could be identified and/or tumor was seen on more than one biopsy core. Terms often used to describe these lesions include "single minute focus of carcinoma" or "adenocarcinoma, too small to give a Gleason grade." One hundred five cases (10.9%) met the above criteria for minimal carcinoma. The correlation of Gleason scores between biopsies and prostatectomy specimens overall was good with exact agreement for 57% of cases and a difference of +/-1 unit in 92% of cases. The correlation for the minimal tumors on biopsy and prostatectomy was slightly worse with exact agreement in 52.4% (55 of 105) and a difference of +/-1 unit in 87.6% (92 of 105). The majority of minimal tumors (83.8% or 88 of 105) were assigned a Gleason score of 6. A total of 31.8% of these 88 cases were upgraded and 5.7% were downgraded. Multivariate analysis on all cases looking for predictors of tumor stage found biopsy Gleason score, perineural invasion, pretreatment prostatic-specific antigen, and digital rectal examination all predicted higher tumor stage with odds ratios of 1.86 (95% confidence interval [CI], 1.53-2.27; p = 0.0001), 2.06 (95% CI, 1.43-2.95; p = 0.0001), 1.08 (95% CI, 1.05-1.11; p = 0.0001), and 1.41 (95% CI, 1.04-1.91; p = 0.0289), respectively. In a model restricted to the 105 cases with minimal carcinoma, pretreatment prostatic-specific antigen was the only independent predictor of higher tumor stage with an odds ratio of 1.15 (95% CI, 1.01-1.31; p = 0.0380); Gleason score was not found to significantly predict higher tumor stage (odds ratio, 1.156; p = 0.6680). The results of this study confirm that biopsy Gleason score in most cases predicts prostatectomy Gleason score and tumor stage. However, for cases with minimal tumor on biopsy, the assigned Gleason score did not predict tumor stage. To properly convey this uncertainty to clinicians, a cautionary note should accompany Gleason scores derived from a minimal focus of carcinoma.


Subject(s)
Adenocarcinoma/pathology , Biopsy, Needle/methods , Prostatic Neoplasms/pathology , Adenocarcinoma/surgery , Adult , Aged , Aged, 80 and over , Biopsy, Needle/standards , Endpoint Determination , Humans , Male , Middle Aged , Multivariate Analysis , Neoplasm Staging , Prognosis , Prostatectomy , Prostatic Neoplasms/surgery , Reproducibility of Results
10.
Pharmacotherapy ; 20(9): 1045-50, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10999495

ABSTRACT

STUDY OBJECTIVES: To examine the psychometric and cardiac effects of pseudoephedrine at 1 and 3 atmospheres (atm) of pressure (0 and 66 feet of sea water, respectively), and to make recommendations about the agent's safety in the diving environment. DESIGN: Double-blind, placebo-controlled, crossover study. SETTING: Monoplace hyperbaric chamber of a university hospital. SUBJECTS: Thirty active divers (mean age 38 yrs). INTERVENTION: A bank of seven tests was used to assess cognitive function during four different simulated dive combinations: placebo-1 atm, placebo3 atm, pseudoephedrine-1 atm, and pseudoephedrine-3 atm. MEASUREMENTS AND MAIN RESULTS: Heart rate and cardiac rhythm were recorded during all dives. Repeated-measures analysis of variance was used to analyze the effects of pseudoephedrine, depth, and drug-depth interaction. No significant, independent effects of pseudoephedrine were seen on any of the seven psychometric test scores (p>0.05), although the drug tended to increase anxiety scores (p=0.092). Depth resulted in a significant increase in anxiety scores (p=0.021) and a significant decrease in verbal fluency test scores (p=0.041); it had no significant effects on the other five psychometric tests (p>0.05). Pseudoephedrine caused a significant increase (p=0.036) in mean heart rate, and depth caused a significant decrease (p=0.013). Neither pseudoephedrine nor depth affected cardiac rhythm. CONCLUSION: Pseudoephedrine does not cause significant alterations in psychometric performance at 3 atm of pressure that might increase the risk of diving. Depth causes significant adverse effects on anxiety levels and semantic memory at 3 atm. Pseudoephedrine and depth have significant but opposite effects on heart rate; although, these effects are unlikely to be clinically significant during diving. It is unlikely that pseudoephedrine adds significant risk to the diver.


Subject(s)
Atmospheric Pressure , Bronchodilator Agents/pharmacology , Cognition/drug effects , Diving/physiology , Ephedrine/pharmacology , Heart Rate/drug effects , Adult , Aged , Analysis of Variance , Anxiety/physiopathology , Atmosphere Exposure Chambers , Atrial Premature Complexes/chemically induced , Cognition/physiology , Cross-Over Studies , Double-Blind Method , Female , Heart Rate/physiology , Humans , Male , Middle Aged , Psychometrics , Ventricular Premature Complexes/chemically induced
11.
Pharmacotherapy ; 20(9): 1051-4, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10999496

ABSTRACT

STUDY OBJECTIVES: To examine the psychometric and cardiac effects of dimenhydrinate at 1 and 3 atmospheres (atm) of pressure (0 and 66 feet of sea water, respectively), and to make recommendations about the drug's safety in the diving environment. DESIGN: Double-blind, placebo-controlled, crossover study SETTING: Monoplace hyperbaric chamber of a university hospital. SUBJECTS: Thirty active divers (mean age 38 yrs). INTERVENTIONS: A bank of seven tests was used to assess cognitive function during four different dive combinations: placebo-1 atm, placebo-3 atm, dimenhydrinate-1 atm, and dimenhydrinate-3 atm. MEASUREMENTS AND MAIN RESULTS: Heart rate and cardiac rhythm were recorded during all dives. Repeated-measures multivariate analysis of variance was used to analyze the effects of dimenhydrinate, depth, and drug-depth interaction. Dimenhydrinate resulted in a significant decrease in scores of mental flexibility (trail-making, part B, p<0.05) but had no effect on scores in the six other psychometric tests (p>0.05). It had no effect on mean heart rate (p>0.05), although frequent unifocal ventricular ectopic beats occurred in two subjects after ingestion of the drug. Depth resulted in a significant decrease in verbal memory test scores (p=0.001) and mean heart rate (p<0.001). CONCLUSION: Dimenhydrinate adversely affects mental flexibility. This effect, when added to the adverse effect of depth on memory, may contribute to the dangers of diving.


Subject(s)
Atmospheric Pressure , Dimenhydrinate/pharmacology , Diving/physiology , Heart Rate/drug effects , Histamine H1 Antagonists/pharmacology , Memory/drug effects , Mental Processes/drug effects , Aged , Analysis of Variance , Atmosphere Exposure Chambers , Cross-Over Studies , Double-Blind Method , Female , Heart Rate/physiology , Humans , Male , Memory/physiology , Mental Processes/physiology , Middle Aged , Psychometrics , Trail Making Test/statistics & numerical data , Ventricular Premature Complexes/chemically induced
12.
J Pediatr Surg ; 35(6): 977-81, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10873048

ABSTRACT

BACKGROUND/PURPOSE: Neuroblastoma is the most common tumor of the abdomen in children. Consistently effective treatments are lacking for aggressive disease. The authors previously reported that therapy with anti-vascular endothelial growth factor (VEGF) antibodies suppresses both growth and metastasis in an experimental model of Wilms' tumor. The authors hypothesized that, in a parallel model of neuroblastoma, anti-VEGF treatment would inhibit (1) growth and (2) metastasis. METHODS: Primary tumors were established in the kidneys of nude mice. In cohort 1 (n = 42), mice were killed at 3 time-points, and tissues were evaluated histologically. Tumors were assayed for VEGF. In cohort 2 (n = 28), anti-VEGF antibody or vehicle was administered. Tumor weights and the incidence of metastases in the 2 groups were compared. VEGF deposition was evaluated by immunohistochemistry. RESULTS: Mice displayed large tumors with liver and lung metastases. VEGF levels in tumors increased over time. Antibody-treated animals displayed significantly smaller tumors, but incidence and size of metastases were unaffected. VEGF was localized to tumor stroma immunohistochemically, with no difference in pattern observed in control and antibody-treated tumors. CONCLUSIONS: Anti-VEGF antibodies inhibit primary tumor growth in experimental neuroblastoma, but not metastasis. This may contrast with the effect of the same antibody in a parallel model of Wilms' tumor.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Endothelial Growth Factors/immunology , Kidney Neoplasms/therapy , Lymphokines/immunology , Neuroblastoma/therapy , Animals , Endothelial Growth Factors/analysis , Female , Humans , Immunohistochemistry , Kidney Neoplasms/chemistry , Kidney Neoplasms/pathology , Lymphokines/analysis , Mice , Mice, Nude , Neoplasm Transplantation , Neuroblastoma/chemistry , Neuroblastoma/pathology , Neuroblastoma/secondary , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
13.
Urology ; 56(1): 76-80; discussion 81, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10869628

ABSTRACT

OBJECTIVES: To determine the patient tolerance and thermal ablation pattern in human prostatic tissue after treatment with a hot water, catheter-based system. METHODS: Twenty-seven men scheduled for surgery for symptomatic benign prostatic hyperplasia or adenocarcinoma of the prostate underwent water-induced thermotherapy. The patients were randomly assigned to one of four treatment groups. Lidocaine gel was the sole means of pain control. The patients and an observer recorded patient discomfort during therapy. A Foley catheter was left in place until surgery (n = 13) or successful voiding (n = 14). Prostates were subsequently enucleated or removed, whole mounted, and examined. RESULTS: Patients reported mild treatment discomfort, the level of which did not correlate with the extent of necrosis, balloon diameter, or water temperature (all P >0. 05). Distal penile burning was the most commonly reported discomfort. All 14 patients successfully voided within 12 days of treatment. Prostates were enucleated (n = 24) or removed (n = 3) at a mean of 27 days (range 4 to 120) after thermotherapy, except for a single adenectomy 17 months after therapy. Pathologic findings included periurethral hemorrhagic necrosis, with focal or extensive urothelial denudation and mild inflammation. The mean maximal depth of necrosis from the urethral lumen was 7, 9, 10.33, and 11 mm in groups 1, 2, 3, and 4, respectively. The extent of necrosis was similar in all groups (P = 0.11), regardless of the water temperature; conversely, the balloon diameter correlated with the depth of necrosis (P = 0.024). CONCLUSIONS: This system of tissue ablation appears to be well tolerated, and it produced consistent pathologic results.


Subject(s)
Hyperthermia, Induced , Prostatic Hyperplasia/pathology , Prostatic Hyperplasia/therapy , Adenocarcinoma/therapy , Aged , Catheterization , Humans , Hyperthermia, Induced/instrumentation , Hyperthermia, Induced/methods , Male , Middle Aged , Patient Satisfaction , Prostatic Neoplasms/therapy , Urethra , Urinary Catheterization , Water
14.
J Pediatr Surg ; 35(1): 30-2; discussion 32-3, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10646769

ABSTRACT

BACKGROUND/PURPOSE: Vascular endothelial growth factor (VEGF) has been shown previously to correlate with tumor growth and metastasis in an experimental model of anaplastic Wilms' tumor. The authors hypothesized that treatment with anti-VEGF antibodies would suppress both primary tumor growth and metastasis in this model. METHODS: Tumors were induced in the right kidneys of nude mice by the injection of cultured Wilms' tumor cells. After 1 week, anti-VEGF treatment was begun with injection of either vehicle or an anti-VEGF antibody intraperitoneally. Mice were killed after 4.5 weeks of treatment and tumor weights and the incidence of metastases evaluated. RESULTS: Anti-VEGF treatment resulted in a greater than 95% reduction in tumor weight (P < .0001). Anti-VEGF treatment also abolished the establishment of lung metastases (40% in control animals, P < .003). Cessation of treatment resulted in rebound tumor growth. CONCLUSION: Anti-VEGF therapy can suppress both primary tumor growth and the establishment of metastases in experimental anaplastic Wilms' tumor.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Endothelial Growth Factors/immunology , Kidney Neoplasms/therapy , Lymphokines/immunology , Wilms Tumor/therapy , Animals , Endothelial Growth Factors/physiology , Female , Kidney Neoplasms/pathology , Lung Neoplasms/secondary , Lymphokines/physiology , Mice , Mice, Nude , Neoplasm Transplantation , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors , Wilms Tumor/pathology , Wilms Tumor/secondary
15.
J Urol ; 163(5): 1413-8, 2000 May.
Article in English | MEDLINE | ID: mdl-10751847

ABSTRACT

PURPOSE: Trials have demonstrated decreased relapse with perioperative methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) chemotherapy in patients with muscle invasive bladder cancer. We evaluated whether the benefit of chemotherapy correlates with its effects on distant or pelvic relapse. MATERIALS AND METHODS: We retrospectively evaluated the records of all 107 patients who underwent cystectomy for muscle invasive bladder cancer at our institution between 1988 and 1994. Factors predicting relapse were identified and used to group patients at high or low risk. The outcome in each group with and without M-VAC chemotherapy was then analyzed in terms of overall, metastatic and pelvic relapse. Univariate analysis was performed using the Kaplan-Meier method and log rank statistic, and multivariate analysis was done using the Cox proportional hazards model. Median survival was 29 months for patients free of disease. RESULTS: Pathological stage T3 or greater according to the American Joint Committee on Cancer, tumor greater than 3 cm. and creatinine greater than 1.5-fold normal were independent poor prognostic factors in patients treated with cystectomy only. Patients with any of these factors or metastatic involvement of the pelvic lymph nodes were considered at high risk. All 35 low risk patients were treated with cystectomy only and had an excellent outcome with a 3-year relapse-free survival plus or minus standard error of 93% +/- 5%. The 3-year rates in 52 and 20 high risk patients treated without and with chemotherapy, respectively, were 42% +/- 8% versus 57% +/- 13% for relapse-free survival (p = 0.17), 38% +/- 9% versus 8% +/- 8% for pelvic failure (p = 0.02) and 39% +/- 9% versus 38% +/- 13% for distant metastases (not significant). Multivariate analysis of patients who underwent pelvic lymphadenectomy revealed that perioperative chemotherapy improved relapse-free survival and pelvic control but not metastatic control (p = 0.03, 0.02 and 0.31, respectively). CONCLUSIONS: Low risk patients have excellent disease control when treated with cystectomy only. Those with high risk features are at substantial risk for pelvic failure (38% at 3 years) after cystectomy only. Perioperative M-VAC chemotherapy has a profound impact on pelvic but not on metastatic failure.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cystectomy , Muscle Neoplasms/drug therapy , Muscle Neoplasms/surgery , Neoplasm Recurrence, Local/prevention & control , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/surgery , Aged , Cisplatin/therapeutic use , Combined Modality Therapy , Disease-Free Survival , Doxorubicin/therapeutic use , Female , Humans , Male , Methotrexate/therapeutic use , Middle Aged , Muscle Neoplasms/pathology , Muscle, Smooth , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplasm Staging , Retrospective Studies , Risk Factors , Treatment Failure , Urinary Bladder Neoplasms/pathology , Vinblastine/therapeutic use
16.
Urology ; 54(6): 1039-43, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10604705

ABSTRACT

OBJECTIVES: To examine the significance of perineural invasion (PNI) in predicting pathologic findings in patients treated by radical prostatectomy, because a recent study concluded that PNI on needle biopsy has no independent predictive value. METHODS: Between 1993 and 1998, radical prostatectomy was performed in 319 consecutive patients. Prostate needle biopsies were reviewed in all cases. We compared PNI with other preoperative parameters, including digital rectal examination, PSA, and biopsy Gleason score, for the ability to predict tumor stage. Clinical records and pathologic findings were reviewed for all cases. Tumor stage was defined as either pT2 (organ confined) or pT3 (extraprostatic extension and/or seminal vesicle invasion). RESULTS: The median age was 61.4 years (range 40 to 75.6). Seventy-two percent of the 95 men with nonpalpable disease and 67% of the 224 men with palpable disease had organ-confined prostate cancer on final pathologic staging. Of 205 men with a Gleason score on biopsy of 6 or less, 159 (78%) had organ-confined disease compared with 59 (52%) of 114 with a Gleason score of 7 to 9 (P <0.001, chi-square test). PNI was identified in 77 (24%) of 319 patients, with 83% specificity and 40% sensitivity for Stage pT3 disease (odds ratio 3.49). Of men with pT3 disease on final pathologic staging, 18%, 27%, and 56% had preoperative PSA levels of 0 to 4, more than 4 to 10, and greater than 10 ng/mL, respectively (P <0.001, Mantel-Haenszel chi-square test). On multivariate analysis, PNI (P = 0.0031), PSA (P = 0.0004), and Gleason score (P = 0.0003) independently predicted stage (pT3 disease). CONCLUSIONS: PNI is an important preoperative predictor of pathologic stage and should be reported when adenocarcinoma is diagnosed on prostate needle biopsies.


Subject(s)
Biopsy, Needle , Prostatic Neoplasms/pathology , Adult , Aged , Humans , Male , Middle Aged , Multivariate Analysis , Neoplasm Invasiveness , Neoplasm Staging , Predictive Value of Tests , Prostate/innervation
17.
Liver Transpl Surg ; 5(5): 429-36, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10477845

ABSTRACT

Early hepatic artery thrombosis (HAT) after pediatric orthotopic liver transplantation (OLT) can cause significant morbidity and mortality, leading to liver failure or septic complications requiring urgent retransplantation. Experimental evidence that hyperbaric oxygen (HBO) may ameliorate hepatic ischemic-reperfusion injury led to this study of HBO in pediatric liver transplant recipients who developed HAT. Children undergoing OLT under primary tacrolimus immunosuppression and University of Wisconsin organ preservation between August 1, 1989, and December 31, 1998, who developed HAT were the basis for this study. Patients who developed HAT between March 1, 1994, and December 31, 1998, were treated with HBO therapy until signs of ischemia resolved (absence of fever, normalizing liver injury test results) or for 2 weeks. The pediatric OLTs performed from August 1, 1989, to February 28, 1994, who developed HAT served as a control group. Primary outcome measures were survival, retransplantation rate, time to retransplantation, incidence of hepatic gangrene, and days to collateral formation. Three hundred seventy-five consecutive pediatric patients underwent 416 OLTs between August 1, 1989, and December 31, 1998. Thirty-one patients (7.5%) developed HAT at a mean time of 8.2 days (range, 1 to 52 days) post-OLT. In 17 patients, HBO treatment was begun within 24 hours of HAT or immediately after the revascularization attempt and performed twice daily for 90 minutes at 2.4 atmospheres pressure. Fourteen patients were treated without HBO. None of the HBO-treated patients developed hepatic gangrene. Eight HBO patients (47%) were bridged to retransplantation at a mean time of 157 days (range, 3 to 952 days) after initial OLT and all survived. Mean time to retransplant in the control group was 12.7 days (range, 1 to 64 days). HBO was well tolerated without significant complications. Although there was no significant difference in survival or retransplantation rates, HBO significantly delayed retransplantation, potentially by hastening the development of hepatic artery collaterals.


Subject(s)
Arterial Occlusive Diseases/therapy , Hepatic Artery , Hyperbaric Oxygenation , Liver Transplantation/adverse effects , Thrombosis/therapy , Arterial Occlusive Diseases/etiology , Arterial Occlusive Diseases/physiopathology , Blood Flow Velocity , Child, Preschool , Female , Hepatic Artery/diagnostic imaging , Humans , Infant , Liver/blood supply , Liver/diagnostic imaging , Male , Retrospective Studies , Thrombosis/etiology , Thrombosis/physiopathology , Treatment Outcome , Ultrasonography, Doppler
18.
J Pediatr Surg ; 34(5): 676-9, 1999 May.
Article in English | MEDLINE | ID: mdl-10359162

ABSTRACT

BACKGROUND/PURPOSE: Pathological vascular architecture is a feature of neoangiogenic processes such as diseases of the retina and tumor growth. The authors hypothesized that experimental human Wilms' tumors would display a vascular architecture similar to retinal diseases that are driven by vascular endothelial growth factor (VEGF). METHODS: Human Wilms' tumors were established in the right kidneys of nude mice. After 4.5 weeks of tumor growth, fluorescein angiograms were performed before death. Representative sections of tumors and contralateral, control kidneys were evaluated by fluorescent microscopy. RESULTS: Fluorescein angiograms demonstrated a characteristic pathological architecture. Vascular tortuosity, capillary tufting, and hemorrhage were noted. These features were not present in normal kidneys. CONCLUSIONS: Vascular architecture of Wilms' tumor displays the specific features previously described in diseases of the retina, which have been shown to be driven by VEGF, suggesting that neoangiogenesis in this model is also VEGF driven.


Subject(s)
Endothelial Growth Factors/physiology , Kidney Neoplasms/blood supply , Lymphokines/physiology , Neovascularization, Pathologic , Wilms Tumor/blood supply , Animals , Disease Models, Animal , Kidney Neoplasms/pathology , Mice , Mice, Inbred Strains , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors , Wilms Tumor/pathology
19.
J Pediatr Surg ; 34(5): 743-7; discussion 747-8, 1999 May.
Article in English | MEDLINE | ID: mdl-10359175

ABSTRACT

BACKGROUND/PURPOSE: The growth and spread of solid tumors are critically dependent on the induction of angiogenesis. We hypothesized that vascular endothelial growth factor (VEGF) would be detected in Wilms' tumors, and that both growth and metastasis would parallel VEGF levels in a murine model. METHODS: Primary tumors were established in the right kidneys of nude mice (n = 21). Mice were killed at 3, 4.5, or 6 weeks. Tumor-bearing and control kidneys were subjected to enzyme-linked immunosorbent assay (ELISA) for VEGF. Representative sections were assessed by histology and immunohistochemistry. Lungs were examined for metastases. Clinical specimens of Wilms' tumor (n = 12) also were assayed for VEGF. RESULTS: The authors detected VEGF by ELISA with increasing frequency, and in increasing quantity, as experimental Wilms' tumors were grown over time. Immunohistochemistry demonstrated accumulation of VEGF in areas of viable tumor. Lung metastases occurred in 8 of 10 animals with VEGF-positive tumors, but in only 3 of 11 animals with VEGF-negative tumors, an association that was statistically significant. VEGF was found in 10 of 12 clinical Wilms' tumor specimens tested. CONCLUSIONS: VEGF is present in both clinical and experimental Wilms' tumors. In a murine model, absolute VEGF levels increase as primary tumors grow, and VEGF production is significantly associated with tumor metastasis.


Subject(s)
Endothelial Growth Factors/metabolism , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Lung Neoplasms/secondary , Lymphokines/metabolism , Wilms Tumor/metabolism , Wilms Tumor/secondary , Animals , Female , Humans , Immunohistochemistry , Lung Neoplasms/metabolism , Mice , Mice, Nude , Neovascularization, Pathologic , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
20.
J Urol ; 162(1): 103-6, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10379750

ABSTRACT

PURPOSE: We evaluated the role of perineural invasion identified on prostate needle biopsy as a predictor of prostate specific antigen (PSA) recurrence after radical prostatectomy. MATERIALS AND METHODS: Between 1993 and 1998 radical prostatectomy was performed in 319 consecutive patients. Prostate needle biopsies were reviewed in all cases. We compared perineural invasion with other preoperative parameters, including digital rectal examination, PSA and biopsy Gleason score, for the ability to predict PSA recurrence with recurrence defined as any serum PSA level greater than 0.2 ng./ml. RESULTS: Perineural invasion was identified on 77 of 319 preoperative prostate biopsies (24%). There was PSA recurrence in 46 patients (14.4%) at a mean followup of 25.4 months (range 0.2 to 62.1). Perineural invasion statistically correlated with PSA recurrence. Kaplan-Meier analysis revealed disease-free survival rates of 24 versus 64% when perineural invasion was and was not present in the prostate biopsy (p = 0.0003, log rank 12.92). Multivariate analysis demonstrated that perineural invasion (p = 0.012) and PSA (p = 0.005) were independent preoperative predictive factors of PSA recurrence. When perineural invasion was compared with postoperative parameters, including disease stage, surgical margins and seminal vesicle invasion, it was not an independent predictor because it closely correlated with tumor stage. CONCLUSIONS: Perineural invasion on preoperative prostate needle biopsy is a strong independent predictor of PSA recurrence in patients in whom prostate cancer was treated with radical prostatectomy.


Subject(s)
Biopsy, Needle , Neoplasm Recurrence, Local/blood , Neoplasm Recurrence, Local/epidemiology , Prostate-Specific Antigen/blood , Prostate/innervation , Prostate/pathology , Prostatectomy , Prostatic Neoplasms/pathology , Prostatic Neoplasms/surgery , Adult , Aged , Humans , Male , Middle Aged , Neoplasm Invasiveness , Predictive Value of Tests , Prostatic Neoplasms/blood
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