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H Scher

Publications and source records attributed to H Scher.

At least 19 recordsLinked to original sources
PubMed2006

An electrodiagnostic evaluation of the effect of pre-existing peripheral nervous system disorders in patients treated with the novel proteasome inhibitor bortezomib.

AIMS: Bortezomib (Velcade), a novel proteasome inhibitor, has shown promise in the treatment of malignancies, including multiple myeloma and non-Hodgkin's lymphoma. Several studies have identified neuropathy as a potentially dose-limiting side effect of treatment with bortezomib. We report the clinical and electrodiagnostic data from four patients who developed signs and symptoms of peripheral neuropathy from treatment with bortezomib. MATERIALS AND METHODS: Patients were included if they were enrolled in active phase 2 trials of bortezomib for non-Hodgkin's lymphoma or prostate cancer, developed signs and symptoms of peripheral neuropathy, and were referred for electrodiagnostic evaluation. RESULTS: Four patients, including two with non-Hodgkin's lymphoma and two with prostate cancer, underwent electrodiagnostic testing. Electrodiagnostic evaluation showed pre-existing peripheral nervous system disorders in three out of four patients. Multiple peripheral nervous system disorders were present in two out of four patients. CONCLUSIONS: Bortezomib can cause a predominately sensory axonal polyneuropathy. Pre-existing peripheral nervous system disorders, such as neuropathy and radiculopathy, are common in patients with cancer, and may pre-dispose to the development of symptomatic neuronal toxicity when treated with bortezomib. Baseline electrodiagnostic evaluation may identify patients with pre-existing peripheral nervous system disorders at risk for additive neuronal toxicity from neurotoxic chemotherapeutic agents.

Aged↗
PubMed2001

Paclitaxel, estramustine phosphate, and carboplatin in patients with advanced prostate cancer.

PURPOSE: To determine the safety and activity of weekly paclitaxel in combination with estramustine and carboplatin (TEC) in patients with advanced prostate cancer. PATIENTS AND METHODS: In a dose-escalation study, patients with advanced prostate cancer were administered paclitaxel (weekly 1-hour infusions of 60 to 100 mg/m(2)), oral estramustine (10 mg/kg), and carboplatin (area under the curve, 6 mg/mL-min every 4 weeks). Paclitaxel levels were determined 0, 30, 60, 90, and 120 minutes and 18 hours after infusion, and a concentration-time curve was estimated. Once a safe dose was established, a multi-institutional phase II trial was conducted in patients with progressive androgen-independent disease. RESULTS: Fifty-six patients with progressive androgen-independent disease were treated for a median of four cycles. The dose of paclitaxel was escalated from 60 to 100 mg/m(2) without the occurrence of DLT. Posttherapy decreases in serum prostate-specific antigen levels of 50%, 80%, and 90% were seen in 67%, 48%, and 39% (95% confidence interval, 55% to 79%, 35% to 61%, 26% to 52%) of the patients, respectively. Of the 33 patients with measurable disease, two (6%) had a complete response and 13 (39%) had a partial response. The overall median time to progression was 21 weeks, and the median survival time for all patients was 19.9 months. Major grade 3 or 4 adverse effects were thromboembolic disease (in 25% of patients), hyperglycemia (in 38%), and hypophosphatemia (in 42%). Significant leukopenia, thrombocytopenia, and peripheral neuropathy were not observed. CONCLUSION: TEC has significant antitumor activity and is well tolerated in patients with progressive androgen-independent prostate cancer.

Aged↗
PubMed2001

Analysis of field observations of tracer transport in a fractured till.

We analyze a set of observations from a recently published, field-scale tracer test in a fractured till. These observations demonstrate a dominant, underlying non-Fickian behavior, which cannot be quantified using traditional modeling approaches. We use a continuous time random walk (CTRW) approach which thoroughly accounts for the measurements, and which is based on a physical picture of contaminant motion that is consistent with the geometric and hydraulic characterization of the fractured formation. We also incorporate convolution techniques in the CTRW theory, to consider transport between different regions containing distinct heterogeneity patterns. These results enhance the possibility that limitations in predicting non-Fickian modes of contaminant migration can be overcome.

Chlorides↗
PubMed2001

Local detection of prostate cancer by positron emission tomography with 2-fluorodeoxyglucose: comparison of filtered back projection and iterative reconstruction with segmented attenuation correction.

BACKGROUND: To compare filtered back projection (FBP) and iterative reconstruction with segmented attenuation correction (IRSAC) in the local imaging of prostate cancer by positron emission tomography with 2-fluorodeoxyglucose (FDG-PET). METHODS: We retrospectively identified 13 patients with primary (n=7) or recurrent (n=6) prostate cancer who had increased uptake in the prostate on FDG-PET performed without urinary catheterization, contemporaneous biopsy confirming the presence of active tumor in the prostate, and correlative cross-sectional imaging by MRI (n=8) or CT (n=5). FDG-PET images were reconstructed by FBP and IRSAC. Two independent nuclear medicine physicians separately rated FBP and IRSAC images for visualization of prostatic activity on a 4-point scale. Results were compared using biopsy and cross-sectional imaging findings as the standard of reference. RESULTS: IRSAC images were significantly better that FBP in terms of visualization of prostatic activity in 12 of 13 patients, and were equivalent in 1 patient (p<0.001, Wilcoxon signed ranks test). In particular, 2 foci of tumor activity in 2 different patients seen on IRSAC images were not visible on FBP images. In 11 patients who had a gross tumor mass evident on cross-sectional imaging, there was good agreement between PET and cross-sectional anatomic imaging with respect to tumor localization. CONCLUSIONS: In selected patients, cancer can be imaged within the prostate using FDG-PET, and IRSAC is superior to FBP in image reconstruction for local tumor visualization.

Aged↗
PubMed2000

Expression of c-kit and kit-ligand in benign and malignant prostatic tissues.

The tyrosine kinase receptor c-kit and its ligand [kit ligand (KL) or stem cell factor (SCF)] exert a broad range of biological activities during organogenesis and normal cell development. Recent studies have revealed that altered c-kit levels occur in a variety of malignancies and cancer cell lines. KL has also been shown to stimulate the growth of malignant cells, as well as to promote chemotaxis. We had previously reported expression of KL in stroma cells of normal human prostate. The present study was undertaken in order to analyze the patterns of expression of c-kit and KL in a well characterized set of prostatic tissues, including normal prostate (n=4), benign prostatic hyperplasia (BPH) (n=53) and adenocarcinoma (n=46) samples. The distribution of c-kit and KL proteins was studied by immunohistochemical analyses, while transcript levels were determined by in situ hybridization with specific RNA probes on a subset of the benign and malignant tissues referred above. In addition, reverse-transcriptase polymerase chain reaction (RT-PCR) was performed to determine levels of c-kit and KL expression in cultures of epithelial and stroma cells, as well as in the prostate cancer cell lines LNCaP, DU145 and PC3. c-kit protein in normal prostate was exclusively detected in mast cells by immunohistochemistry and in situ hybridization. However, c-kit transcripts, but not c-kit protein, were detected in low levels and with an heterogeneous pattern in basal epithelial cells of ducts and acini. c-kit in BPH was detected in epithelial cells in 9 of 53 (17%) specimens. c-kit protein expression in malignant epithelial cells was identified in 1 of 46 (2%) tumors. However, c-kit transcripts were detected in low levels by in situ hybridization in most of the tumors analyzed. KL protein and transcripts in normal prostate were detected in high levels in stroma cells. However, epithelial cells were unreactive for anti-KL antibody, but showed low levels of KL transcripts mainly in cells of the basal layer. Basal epithelial cells in hyperplastic glands showed KL expression in 13 of 53 (24%) specimens. KL protein in tumor cells was noted in 18 of 46 (39%) cases. c-kit transcripts were not found in normal prostate and in the 3 cancer cell lines analyzed by RT-PCR, however, it was present in cultured epithelial cells of BPH, and in cultures of stroma cells from both normal and BPH. The majority of cultured cell lines of epithelial and stromal origin displayed considerable levels of KL. In addition all prostate cell lines studied showed significant levels of KL transcripts. In summary, co-expression of c-kit and KL in a subset of BPH cases may suggest an autocrine mode of signaling. Data from this study reveals that altered patterns of c-kit and KL expression are associated with BPH and adenocarcinoma of prostate. It appears that KL induces mast cells proliferation and maturation and enhances their release of protease. This could explain the accumulation of mast cells at tumor sites, a phenomenon that was not observed in normal prostate or BPH samples.

Adenocarcinoma↗
PubMed2000

Evaluation of drug delivery and survival impact of dose-intense relative to conventional-dose methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy in urothelial cancer.

The efficacy of dose-intense methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) chemotherapy relative to conventional-dose M-VAC in patients with advanced transitional cell carcinoma is unknown. The outcomes of 33 patients on two successive protocols using dose-intense M-VAC with granulocyte colony-stimulating factor (G-CSF) support were compared with those of 129 patients treated with conventional-dose M-VAC to assess for an impact of dose-intense therapy on long-term survival. The mean relative dose intensity of chemotherapy delivered to the dose-intense cohort was 55% higher than that delivered to the conventional-dose cohort (p = 0.0001). However, no significant differences were observed with regard to response proportion (72% vs. 76%), median survival (13.3 vs. 16.7 months, p = 0.31), or 5-year survival (16% vs. 15%). Growth factor support enabled a statistically significant increase in the delivered dose intensity of M-VAC chemotherapy, but no survival advantage relative to conventional-dose M-VAC was observed.

Adult↗
PubMed1999

Phase II trial of intermediate dose methotrexate in combination with vinblastine, doxorubicin, and cisplatin in patients with unresectable or metastatic transitional cell carcinoma.

BACKGROUND: This study was undertaken to determine whether the use of intermediate dose methotrexate in combination with vinblastine, doxorubicin, and cisplatin as first-line therapy increases the proportion of major responders and overall survival in patients with unresectable or metastatic transitional cell carcinoma (TCC) of the urothelial tract. METHODS: Twenty-nine patients with histologically confirmed TCC received methotrexate at a dose of 1000 mg/m2 on Day 1 followed by leucovorin calcium rescue on Day 2 and vinblastine (3 mg/m2), doxorubicin (30 mg/m2), and cisplatin (70 mg/m2) (VAC) on Day 2. Therapy was recycled at 28-day intervals. RESULTS: Fourteen of 28 patients (50%; 95% confidence interval [CI], 31-69%) achieved a major response, including 6 pathologic or clinical complete responses (CR) and 8 partial responses (PR). Nine patients were rendered disease free after postchemotherapy surgical resection of residual disease (surgical CR), including five patients who had PR and four nonresponders to chemotherapy alone. Five of 18 patients with disease limited to lymph nodes attained CR, in contrast to only 1 of 10 patients with visceral metastatic disease. The median survival for the entire population was 13.6 months. CONCLUSIONS: The escalation of methotrexate to 1000 mg/m2 in combination with vinblastine, doxorubicin, and cisplatin did not result in a response proportion or median survival superior to that observed with standard dose M-VAC. As previously observed in a Phase II trial of M-VAC, only the attainment of CR was associated with prolongation of survival.

Adult↗
PubMed1999

Editorial.

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Journal Article↗
PubMed1999

Editorial.

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Journal Article↗
PubMed1999

Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group.

PURPOSE: Prostate-specific antigen (PSA) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells. For patients with metastatic disease, changes in PSA will often antedate changes in bone scan. Furthermore, many but not all investigators have observed an association between a decline in PSA levels of 50% or greater and survival. Since the majority of phase II clinical trials for patients with androgen-independent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting. We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters. RESULT: We defined four patient groups: (1) progressive measurable disease, (2) progressive bone metastasis, (3) stable metastases and a rising PSA, and (4) rising PSA and no other evidence of metastatic disease. The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials. We propose that investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period. Some investigators may want to report additional measures of PSA changes (ie, 75% decline, 90% decline). Response duration and the time to PSA progression may also be important clinical end point. CONCLUSION: Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point.

Androgens↗
PubMed1998

Evidence for extreme climatic warmth from late cretaceous arctic vertebrates

A Late Cretaceous (92 to 86 million years ago) vertebrate assemblage from the high Canadian Arctic (Axel Heiberg Island) implies that polar climates were warm (mean annual temperature exceeding 14 degreesC) rather than near freezing. The assemblage includes large (2.4 meters long) champsosaurs, which are extinct crocodilelike reptiles. Magmatism at six large igneous provinces at this time suggests that volcanic carbon dioxide emissions helped cause the global warmth.

Journal Article↗
PubMed1998

Uroplakin II gene is expressed in transitional cell carcinoma but not in bilharzial bladder squamous cell carcinoma: alternative pathways of bladder epithelial differentiation and tumor formation.

Uroplakins (UPs) are integral membrane proteins that are synthesized as the major differentiation products of mammalian urothelium. We have cloned the human UP-II gene and localized it on chromosome 11q23. A survey of 50 transitional cell carcinomas (TCCs) revealed a UP-II polymorphism but no tumor-specific mutations. Immunohistochemical staining using rabbit antisera against a synthetic peptide of UP-II and against total UPs showed UP reactivity in 39.5% (17 of 43 cases) of conventional TCCs, 12.8% (5 of 39) of bilharzial-related TCCs, and 2.7% (1 of 36) of bilharzial-related squamous cell carcinomas (SCCs). The finding that fewer bilharzial TCCs express UPs than conventional TCCs (12.8 versus 40%) raised the possibility that the former are heterogeneous, expressing SCC features to varying degrees. Our data strongly support the hypothesis that urothelium can undergo at least three pathways of differentiation: (a) urothelium-type pathway; (b) epidermis-type pathway; and (c) glandular-type pathway, characterized by the production of UPs, K1/K10 keratins, and secreted glycoproteins, respectively. Vitamin A deficiency and mesenchymal factors may play a role in determining the relative contributions of these pathways to urothelial differentiation as well as to the formation of TCC, SCC, and adenocarcinoma, or a mixture thereof.

Amino Acid Sequence↗
PubMed1998

Urinary bombesin-like peptide levels in infants and children with bronchopulmonary dysplasia and cystic fibrosis.

Compared to normal infants and children, there are increased numbers of neuroendocrine cells with bombesin-like peptide (BLP) immunostaining in the lungs of infants and children with bronchopulmonary dysplasia (BPD) and cystic fibrosis (CF). However, there are no data documenting levels of urinary BLP in normal infants and children, or in children with lung disease. We therefore determined the normal developmental pattern for urinary BLP excretion in healthy infants and children, and in infants and children with BPD and CF, and correlated these findings with the subjects' clinical course. We measured urinary BLP levels in 110 subjects: 54 controls, 33 with BPD, and 23 with CF. An age-dependent decline in urinary bombesin levels was evident in the control and BPD subjects, but not in those with CF. There were no statistically significant differences in BLP levels between normal infants and those with BPD. Mean BLP levels were higher in the more immature preterm infants with BPD who required increased ventilatory support. The highest mean BLP levels were documented in BPD infants under age 3 months (882 fmol/mg creatinine), in controls between 3 and 12 months of age (625 fmol/mg creatinine), and in 12-60-month-old CF subjects (486 fmol/mg creatinine). Thus there is an age-dependent decline in BLP levels in controls and BPD, but not in CF. We speculate that the elevated urinary BLP levels in infants and children with BPD and CF may reflect increased pulmonary neuroendocrine cell activity in these conditions, due to the epithelial regenerative response to airway damage and repair.

Aging↗
PubMed1998

NCCN urothelial cancer practice guidelines. National Comprehensive Cancer Network.

Urothelial tumors represent a spectrum of diseases with a range of prognoses. Once a diagnosis is established at any point on the urothelial tract, the patient remains at risk for developing a new lesion at a different or the same location, at a similar or more advanced stage. Continued monitoring for recurrence is an essential part of management, as most recurrences are superficial and can be managed by endoscopic means. Within each category of disease, more refined methods to determine prognosis and guide management, based on molecular staging, are under development. These methods are aimed at optimizing the individual patient's likelihood of cure and chance for organ preservation. For patients with more extensive disease, newer treatments typically involve combined-modality approaches using recently developed surgical procedures, or three-dimensional treatment planning for more precise delivery of radiation therapy. While these are not appropriate in all cases, they do offer the promise of an improved quality of life and prolonged survival. Finally, within the category of metastatic disease, a number of new agents have been identified that appear to be superior to those currently considered to be standard therapies. It is thought, therefore, that the treatment of urothelial tumors will evolve rapidly over the next few years, with improved outcomes for patients with all stages of disease.

Humans↗
PubMed1997

Chromosome 16 in primary prostate cancer: a microsatellite analysis.

Cytogenetic and molecular genetic analyses of prostate cancer specimens have revealed nonrandom chromosomal deletions, affecting chromosomes 7q, 8p, 10q and 16q. Based on these data, we designed this study to further characterize the altered region(s) on chromosome 16 by evaluating 16 microsatellite markers on a population composed of 32 paired normal and primary prostatic tumor samples. The 16 microsatellites selected mapped to 11 distinct loci on 16q and 5 loci on 16p. No alterations were identified affecting 16p. However, 16 of 31 (51%) informative cases showed molecular alterations in at least one of the loci analyzed on 16q, consisting of 18 deletions and 11 bandshifts. Moreover, most of the deletions clustered at 6 microsatellite loci, mapping to the 16q22.1-23.1 region. Our results suggest that microsatellite alterations on the long arm of chromosome 16 are frequent events in prostate cancer, and that the 16q22.1-23.1 region might harbor a tumor suppressor gene involved in prostate cancer.

Adenocarcinoma↗
PubMed1997

Assessment of hormone refractory prostate cancer.

OBJECTIVES: To define guidelines for the assessment of treatment in patients with hormone-refractory prostate cancer (HRPC). METHODS: In the light of modern research, and taking new treatment options into account, the Committee essays to specify different categories of patients entering clinical trials, and to define response criteria and those endpoints that are relevant in phase III studies and in short-term follow-up. RESULTS: HRPC comprises a range of disease states with varying responsiveness to therapy and length of survival. Patients with progression as evaluated by increasing prostate-specific antigen (PSA) values alone have a more favorable prognosis than those presenting with increasing tumor spread. In the assessment of these patients, the modes of previous therapy and the kind of tumor progression must be taken into account. The benefit of treatment of HRPC is often modest. While duration of survival remains the main and ultimate endpoint, the means of measuring short-term responsiveness to therapy are limited. A minority of patients have measurable tumor lesions. Decrease of PSA or other biochemical tumor markers may indicate depression of the tumor activity, but is not always associated with prolongation of survival. A variety of new treatments in HRPC are being investigated. They affect measurable tumor parameters in different ways. CONCLUSIONS: When a new agent is to be tested, it is important to measure all possible parameters before deciding which particular ones are appropriate for future investigations of this agent. In symptomatic patients, evaluation of subjective parameters, for example, relief of pain or improvement of performance status, is often the most reliable measure of treatment effect. However, these parameters should be clearly defined.

Antineoplastic Agents, Hormonal↗
PubMed1997

Editorial.

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Journal Article↗