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Biomedical subjects

H Brem

Publications and source records attributed to H Brem.

At least 37 records · Page 2Linked to original sources

Evaluation of the effectiveness of portable low-bandwidth telemedical applications for postoperative followup: initial results.

BACKGROUND: The idea of using telemedical applications to evaluate patients remotely is several decades old. It has already been established that x-ray images (and magnetic resonance images) can be transferred using a personal computer and a modem, and many other such applications have been implemented. Over the past 50 years the expense and technical demands of the equipment involved in telemedicine have hindered its widespread deployment. The purpose of this study is to evaluate the ability of a mobile, low-bandwidth telemedicine platform to achieve real-time postoperative visits in the home. STUDY DESIGN: This evaluation was designed to evaluate the feasibility of performing a real-time clinical visit with computer and telecommunications hardware and software. A nurse and medical student (for information gathering only) made postoperative visits at patients' homes while the physician stayed at the office. Clinical evaluations were performed by using low-resolution and frame-rate video, high-resolution still images, and simultaneous telephony over a standard telephone line. These remote visits were followed by a standard visit in the office. Eleven patients were included, all of whom had undergone various laparoscopic procedures. They lived 5 to 240 miles from their surgeon. Efficiency was measured by recording the time required to capture and send data required by the physician to make a clinical decision. The time expense was measured at both the patients' and physician's locations. Technical issues were evaluated and patient satisfaction was assessed by standardized objective questionnaires. The accuracy of the evaluation at the remote visit was determined with a standard office visit. RESULTS: No technical problems were observed. The mean total time of the housecall at the remote site was 86 minutes (range 60 to 160 minutes) and at the base station site was 41 minutes (range 21 to 71 minutes). After personnel became familiar with the system, the last three visits averaged 61 and 25 minutes at the two sites, respectively. This corresponds favorablywith current time requirements for visiting nurses and office visits. The patients were highly satisfied with the home visit and, on average, rated the experience as 4.8 out of a maximum of 5. CONCLUSIONS: Followup visits in patients' homes after laparoscopic procedures can be accomplished by transmitting simultaneous voice, low-resolution video, and high-resolution still images to accurately perform postoperative evaluations over standard telephone lines, with time requirements and clinical accuracy similar to those of standard visits.

Adult↗

Local drug delivery.

Intensive research efforts are now focused on the development of new strategies for more effective delivery of drugs to the central nervous system. These strategies include chemical modification of drugs, disruption of the blood-brain barrier, and utilization of alternative routes for drug delivery. This paper focuses on local drug delivery for the treatment of brain tumors. It reviews papers published in the past year on local chemotherapy and immunotherapy. Other aspects of local drug delivery are discussed, including convection-enhanced delivery and drug delivery via a controlled-release microchip.

Antineoplastic Agents↗

Paracrine delivery of IL-12 against intracranial 9L gliosarcoma in rats.

OBJECT: Interleukin-12 (IL- 12) has potential for the treatment of tumors because it can stimulate an antitumor immune response and possesses antiangiogenic properties. In the study reported here, the authors investigated the therapeutic role of locally delivered IL-12 in a malignant brain tumor model. METHODS: After genetically engineering 9L gliosarcoma cells to express IL-12 (9L-IL12 cells), the authors used these cells as a source of locally delivered cytokine. First, they investigated the behavior of these cells, which were implanted with the aid of stereotactic guidance into the rat brain, by using serial magnetic resonance imaging and histopathological examination. Second, they assessed the antitumor efficacy of proliferating, as well as nonproliferating (irradiated), 9L-IL12 cells by implanting these cells in animals challenged by wild-type 9L gliosarcoma (9Lwt) cells. The IL-12 expression in brain regions injected with 9L-IL12 was confirmed by reverse transcription-polymerase chain reaction. Last, the authors explored whether animals treated with 9L-IL12 cells developed an antitumor immunological memory by rechallenging the survivors with a second injection of 9Lwt cells. The authors demonstrated that local delivery of IL-12 into the rat brain by genetically engineered cells significantly prolongs survival time in animals challenged intracranially with a malignant glioma. CONCLUSIONS: These findings support continued efforts to refine local delivery systems of IL-12 in an attempt to bring this therapy to clinical trials.

Animals↗

The Hunterian Neurosurgical Laboratory: the first 100 years of neurosurgical research.

Modern neurosurgery has long had a strong laboratory foundation, and much of this tradition can be traced to the Hunterian Neurosurgical Laboratory of the Johns Hopkins Hospital. Founded with the basic goals of investigating the causes and symptoms of disease and establishing the crucial role that surgeons may play in the treatment of disease, the Hunterian laboratory has adhered to these tenets, despite the dramatic changes in neurosurgery that have occurred in the last 100 years. Named for the famous English surgeon John Hunter (1728-1793), the Hunterian laboratory was conceived by William Welch and William Halsted as a special laboratory for experimental work in surgery and pathology. In 1904, Harvey Cushing was appointed by Halsted to direct the laboratory. With the three primary goals of student education, veterinary surgery that stressed surgical techniques, and meticulous surgical and laboratory record-keeping, the laboratory was quite productive, introducing the use of physiological saline solutions, describing the anatomic features and function of the pituitary gland, and establishing the field of endocrinology. In addition, the original development of hanging drop tissue culture, fundamental investigations into cerebrospinal fluid, and countless contributions to otolaryngology by Samuel Crowe all occurred during this "crucible" period. In 1912, Cushing was succeeded by Walter Dandy, whose work on experimental hydrocephalus and cerebrospinal fluid circulation led to the development of pneumoencephalography. The early days of neurosurgery evolved with close ties to general surgery, and so did the Hunterian laboratory. After Dandy began devoting his time to clinical work, general surgeons (first Jay McLean and then, in 1922, Ferdinand Lee) became the directors of the laboratory. Between 1928 and 1942, more than 150 original articles were issued from the Hunterian laboratory; these articles described significant advances in surgery, including pioneering research on calcium metabolism by William MacCallum and Carl Voegtlin and seminal preclinical work by Alfred Blalock and Vivian Thomas that led to the famous "blue baby" operation in 1944. With the introduction of the operating microscope in the 1950s, much of the focus in neurosurgical science shifted from the laboratory to the operating room. The old Hunterian building was demolished in 1956. The Hunterian laboratory for surgical and pathological research was rebuilt on its original site in 1987, and the Hunterian Neurosurgical Laboratory was reestablished in 1991, with a focus on novel treatments for brain tumors. The strong tradition of performing basic research with clinical relevance has continued.

Baltimore↗

Long-term visual outcome after nonradical microsurgery patients with parasellar and cavernous sinus meningiomas.

OBJECTIVE: To determine the long-term visual outcome in patients with parasellar and cavernous sinus meningiomas treated with nonradical surgery. METHODS: Retrospective clinical review of 29 patients with parasellar or cavernous sinus meningiomas and visual sensory or ocular motor dysfunction at presentation, all of whom had at least 10 years of follow-up after initial diagnosis and treatment with nonradical surgery. RESULTS: Nineteen of 29 patients had a unilateral or bilateral optic neuropathy at presentation, and 7 patients developed a unilateral or bilateral optic neuropathy during a mean follow-up period of 13.6 years. However, 27 (93%) of 29 patients retained vision of 20/40 or better in at least one eye, and 14 patients (48%) retained vision of 20/40 or better in both eyes. New ocular motility deficits developed in 3 (10%) of 29 patients during the follow-up period. CONCLUSION: Radical surgery is not required to achieve long-term useful visual function for patients with parasellar or cavernous sinus meningiomas.

Adolescent↗

Conceptually new sulfone analogues of the hormone 1alpha, 25-dihydroxyvitamin D(3): synthesis and preliminary biological evaluation.

A conceptually new series of vitamin D(3)-like nonfluorinated and fluorinated 16-ene side chain tert-butyl sulfones 3-7 has been synthesized. Even though these novel C,D-ring side chain analogues of the hormone 1alpha,25-dihydroxyvitamin D(3) (1,1,25D(3)) lack a terminal OH group, thought previously to be essential for high biological activity, they are highly antiproliferative and, in several cases, transcriptionally active in vitro but desirably noncalcemic in vivo. The side chain sulfone group may be binding to the nVDR as a hydrogen-bond acceptor, in contrast to the hydrogen-bond donor function of the 25-OH group of natural 1,25D(3).

Animals↗

Paracrine immunotherapy with interleukin-2 and local chemotherapy is synergistic in the treatment of experimental brain tumors.

Potent immune responses against malignant brain tumors can be elicited by paracrine intracranial (i.c.) immunotherapy with interleukin (IL)-2. Additionally, i.c. delivery of carmustine via biodegradable polymers has been shown to significantly prolong survival in both animal models and clinical trials. In this study, we show that the combination of paracrine immunotherapy, with nonreplicating genetically engineered tumor cells that produce IL-2, and local delivery of chemotherapy by biodegradable polymers prolongs survival in a synergistic manner in mice challenged intracranially with a lethal murine brain tumor. Animals receiving IL-2-transduced cells and polymers containing 10% 1,3-bis(2-chloroethyl)-1-nitrosourea had significantly improved survival compared with animals receiving IL-2-transduced cells or 10% 1,3-bis(2-chloroethyl)-1-nitrosourea alone. Median survival for the control group was 19 days. Survival in animals receiving IL-2-transduced cells and 1% carboplatin-containing polymers was also significantly improved compared with either therapy alone. Histopathological examination on day 14 of animals receiving combination treatment showed rare degenerating tumor cells. In addition to tissue necrosis surrounding the polymer, a marked inflammatory reaction was observed. In long-term survivors (all animals receiving combination treatment), no tumor was observed and the inflammatory reaction was completely resolved. The brains of animals receiving combination therapy showed both tissue necrosis due to local chemotherapy and strong inflammation due to paracrine immunotherapy. The demonstration of synergy between paracrine IL-2 and local i.c. delivery of antineoplastic drugs is novel and may provide a combined treatment strategy for use against both primary and metastatic i.c. tumors.

Adjuvants, Immunologic↗

Treatment of liver metastases from colon carcinoma with autologous tumor vaccine expressing granulocyte-macrophage colony-stimulating factor.

BACKGROUND AND OBJECTIVES: In preclinical studies, tumor cells genetically altered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) can generate systemic antitumor immunity. Clinically relevant immunotherapeutic approaches for the treatment of colorectal cancer should address efficacy within the liver, a common site of metastatic disease. We investigated the effect of irradiated colon cancer cells engineered to produce GM-CSF on protecting from and treating established liver metastases. METHODS: Using a model of liver metastasis by intrahepatic injection of CT-26 murine colon carcinoma cells in syngeneic BALB/c mice, GM-CSF-producing irradiated cells were given as an intradermal vaccine either 14 days prior to hepatic challenge or in animals with early established tumor (days 5 and 10). The presence of tumor, tumor volume, and survival were endpoint determinants. RESULTS: Animals receiving GM-CSF-producing vaccination demonstrated significant protection from subsequent hepatic challenge of viable tumor cells, even at the highest challenge doses. In animals with early established tumors, a significant response was seen with prolongation in survival. CONCLUSIONS: We conclude that GM-CSF autologous tumor vaccination was effective for the treatment of hepatic colorectal metastases in this murine model. These findings provide support for immunotherapeutic approaches for metastatic liver cancer.

Animals↗

Synthetic, implantable polymers for local delivery of IUdR to experimental human malignant glioma.

PURPOSE: Recently, polymeric controlled delivery of chemotherapy has been shown to improve survival of patients with malignant glioma. We evaluated whether we could similarly deliver halogenated pyrimidines to experimental intracranial human malignant glioma. To address this issue we studied the in vitro release from polymers and the in vivo drug delivery of IUdR to experimental human U251 glioblastoma xenografts. METHODS AND MATERIALS: In vitro: To measure release, increasing (10%, 30%, 50%) proportions of IUdR in synthetic [(poly(bis(p-carboxyphenoxy)-propane) (PCPP):sebacic acid (SA) polymer discs were serially incubated in buffered saline and the supernatant fractions were assayed. In vivo: To compare local versus systemic delivery, mice bearing flank xenografts had intratumoral or contralateral flank IUdR polymer (50% loading) treatments. Mice bearing intracranial (i.c.) xenografts had i.c. versus flank IUdR polymer treatments. Four or 8 days after implantation of polymers, mice were sacrificed and the percentage tumor cells that were labeled with IUdR was measured using quantitative microscopic immunohistochemistry. RESULTS: In vitro: Increasing percentage loadings of IUdR resulted in higher percentages of release: 43.7 + 0.1, 70.0 + 0.2, and 90.2 + 0.2 (p < 0.001 ANOVA) for the 10%, 30%, and 50% loadings, respectively. In vivo: For the flank tumors, both the ipsilateral and contralateral IUdR polymers resulted in similarly high percentages labeling of the tumors versus time. For the ipsilateral IUdR polymers, the percentage of tumor cellular labeling after 4 days versus 8 days was 45.8 +/- 7.0 versus 40.6 +/- 3.9 (p = NS). For the contralateral polymer implants, the percentage of tumor cellular labeling were 43.9 +/- 10.1 versus 35.9 +/- 5.2 (p = NS) measured 4 days versus 8 days after implantation. For the i.c. tumors treated with extracranial IUdR polymers, the percentage of tumor cellular labeling was low: 13.9 +/- 8.8 and 11.2 +/- 5.7 measured 4 and 8 days after implantation. For the i.c. tumors having the i.c. IUdR polymers, however, the percentage labeling was comparatively much higher: 34.3 +/- 4.9 and 35.3 +/- 4.0 on days 4 and 8, respectively. For the i.c. tumors, examination of the percentage cellular labeling versus distance from the implanted IUdR polymer showed that labeling was highest closest to the polymer disc. CONCLUSION: Synthetic, implantable biodegradable polymers provide the local, controlled release of IUdR and result in the high, local delivery of IUdR to experimental intracranial human malignant glioma. This technique holds promise for the local delivery of IUdR for radiosensitization of human brain tumors.

Animals↗

Hemorrhagic vestibular schwannoma: an unusual clinical entity. Case report.

Hemorrhagic vestibular schwannomas are rare entities, with only a few case reports in the literature during the last 25 years. The authors review the literature on vestibular schwannoma hemorrhage and the presenting symptoms of this entity, which include headache, nausea, vomiting, sudden cranial nerve dysfunction, and ataxia. A very unusual case is presented of a 36-year-old man, who unlike most of the patients reported in the literature, had clinically silent vestibular schwannoma hemorrhage. The authors also discuss the management issues involved in more than 1000 vestibular schwannomas treated at their institution during a 25-year period.

Journal Article↗

Late-onset facial nerve degeneration after vestibular schwannoma surgery: incidence, putative mechanisms, and prevention.

Delayed facial nerve dysfunction after vestibular schwannoma surgery is a poorly understood phenomenon that has been reported to occur in 15 to 29% of patients undergoing microsurgery. It is a condition characterized by spontaneous deterioration of facial nerve function in a patient who has otherwise normal or near-normal facial function in the immediate postoperative period. This delayed paralysis is generally reported to occur in the first few days postsurgery, with the majority of patients eventually recovering their immediate postoperative facial function. However, infrequently, it can also occur more than 1 week after surgery (so-called late-onset facial nerve palsy). The authors reviewed facial nerve outcome in 611 patients who underwent microsurgery between 1973 and 1994. The facial nerve was anatomically preserved in 596 patients (97.5%), and 90% of patients had House-Brackmann[6] Grade 1 or 2 function 1 year after surgery. Late-onset facial dysfunction was seen in 13 patients (2.1%). All of these had significant deterioration in facial nerve function between 1 and 4 weeks postoperatively, and all showed improvement by 1 year. In this study, the focus on these patients who developed late-onset facial palsy. The incidence, treatment strategies, and outcomes will be discussed with emphasis on possible pathophysiological mechanisms that contribute to this relatively rare condition.

Journal Article↗

Noncalcemic, antiproliferative, transcriptionally active, 24-fluorinated hybrid analogues of the hormone 1alpha, 25-dihydroxyvitamin D3. Synthesis and preliminary biological evaluation.

Four new hybrid analogues of 1alpha,25-dihydroxyvitamin D3 (1) have been synthesized in a convergent manner by joining A-ring and C, D-ring fragments. Each hybrid analogue, having a noncalcemic 1-hydroxymethyl group and a potentiating 16-ene 24,24-difluorinated C,D-ring side chain, was designed to be lipophilic and inert toward 24-hydroxylase enzyme catabolism. Each hybrid analogue with 1beta, 3alpha-substituent stereochemistry (i.e., analogues 3b and 4b) showed a pharmacologically desirable combination of in vitro high antiproliferative activity in two different cell lines and high transcriptional activity with also low calcemic activity in vivo.

Administration, Oral↗

Squalamine inhibits angiogenesis and solid tumor growth in vivo and perturbs embryonic vasculature.

The novel aminosterol, squalamine, inhibits angiogenesis and tumor growth in multiple animal models. This effect is mediated, at least in part, by blocking mitogen-induced proliferation and migration of endothelial cells, thus preventing neovascularization of the tumor. Squalamine has no observable effect on unstimulated endothelial cells, is not directly cytotoxic to tumor cells, does not alter mitogen production by tumor cells, and has no obvious effects on the growth of newborn vertebrates. Squalamine was also found to have remarkable effects on the primitive vascular bed of the chick chorioallantoic membrane, which has striking similarities to tumor capillaries. Squalamine may thus be well suited for treatment of tumors and other diseases characterized by neovascularization in humans.

Animals↗

Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain.

Polymeric interstitial chemotherapy increases survival of humans with recurrent gliomas and animals with transplanted tumors in the brain, but the relationship between rates of drug release from polymer implants and drug concentration in brain tissue is unknown. This work presents a pharmacokinetic framework for application of this new modality of chemotherapy delivery in primates. Either [3H]carmustine, 4-hydroperoxycyclophosphamide (4-HC), or paclitaxel was encapsulated in a polyanhydride pellet (28-41 microCi/animal, 40 mg/animal), which was implanted intracranially in cynomolgus monkeys (Macaca fascicularis); (n = 17) for up to 30 days. Drug concentrations in the brain, blood, and cerebrospinal fluid were measured by quantitative autoradiography, TLC, and scintillation counting. High drug concentrations (0.5-3.5 mM for carmustine, 0.3-0.4 mM for 4-HC, and 0.2-1.0 mM for paclitaxel) were measured within the first 3 mm from the polymer implant; significant (0.4 microM for carmustine, 3 microM for 4-HC, and 0.6 microM for paclitaxel) concentrations were measured up to approximately 5 cm from the implant as long as 30 days after implantation. Pharmacokinetic analysis indicated that tissue exposure to carmustine area under concentration-time curve achieved by polymeric delivery was 4-1200 times higher than that produced by i.v. administration of a higher dose.

Animals↗

Effect of interstitial and/or systemic delivery of tirapazamine on the radiosensitivity of human glioblastoma multiforme in nude mice.

The purpose of this study was to investigate the feasibility and the efficacy of administering tirapazamine by a slow-releasing polymer disc that was implanted interstitially into a U251 (human glioblastoma multiforme) tumor grown in nude mice. Tumor-bearing animals, with a tumor nodule 0.8 cm3 in size, were distributed to groups receiving combinations of empty or drug-containing polymer implants in the tumor or contralateral leg, intraperitoneal (i.p.) drug, and/or irradiation. The drug (i.p.) alone (14 mg/kg x6) or in combination with tumor drug implant (2 mg) did not significantly increase the tumor volume doubling time compared to that of control animals. Given with 12 Gy of irradiation in twice a day 2-Gy fractions, combined i.p. drug and tumor drug implant significantly delayed tumor growth compared to irradiation alone, which was not achieved with either drug treatment alone added to irradiation. Toxicity, as manifested by transient weight loss, was primarily seen in animals receiving radiation and i.p. tirapazamine. These results indicated that a slow-releasing tirapazamine disc can be produced and the addition of an interstitially implanted tirapazamine disc further increased the effectiveness of i.p. tirapazamine.

Animals↗

Stereotactic radiosurgery for brain metastases: comparison of lung carcinoma vs. non-lung tumors.

In the medical literature, stereotactic radiosurgery (SRS) for brain metastases results in rates of local control of 65 to 85 %. To define patient selection criteria, we measured the survival in a population with a high proportion of non-small cell lung carcinoma (NCS lung) metastases that occurred soon after primary diagnosis. Between 9/89 and 10/93 30 adults (21 M, 9 F) had SRS for metastatic NSC lung carcinoma (14 patients) vs. non-lung carcinomas (16 patients having breast (3), renal (3), melanoma (3), GI (2, thyroid (1) or carcinoma of unknown origin (4)). The metastases were solitary for 22 patients and multiple for 8 patients. Average ages (y) (+/-SD) were 58.6+/-10.4 for NSC lung patients and 53.4+/-12.5 (p = 0.32) for non-lung patients. The average interval (months) from diagnosis of the primary to metastasis was 23.8+/-41.4 for all patients. This interval was shorter for NSC lung patients: 3.1+/-6.0 vs. 48.0+/-51.7 (p < 0.001) for non-lung patients. Twenty seven patients had conventional radiotherapy (XRT) before (24 patients) or after (3 patients) SRS. Doses (cGy) were 3303+/-841 for 13 NSC lung patients and 4256+/-992 for 14 non-lung patients (p = 0.034). The median time from primary diagnosis to SRS was shorter for the NSC lung patients (11 mo) compared to the non-lung patients (35 mo). SRS was given for recurrence of metastases after XRT for 11/14 NSC lung patients and 13/16 non-lung patients. The doses (cGy) of SRS were 1579+/-484 vs. 1682+/-476 (p=0.45) for the NSC lung and non-lung groups, respectively. After SRS a decrease in metastasis diameter was observed in 10 of 14 NSC lung patients vs. 12 of 16 non-lung patients (p=0.85 Chi-square). Twenty-seven of the 30 patients have died. For all patients, the median survival after diagnosis of the primary and after radiosurgery was 31.3 and 8.4 months, respectively. The median survival (95% CI) from primary diagnosis was 24.3 months (13.2-27.3) for NSC lung patients and 46.5 months (39.2-65.5) for non-lung patients (p=0.005 logrank test). The median survival (95% CI) after SRS was 7.9 months (3.0-14.3) for the NSC lung patients and 8.4 (2.9-11.9) months for the non-lung patients (p=0.98 logrank test). Within the two groups, no difference in survival was observed for patients who had SRS sooner (< 1 yr for NSC lung; < 3 yr for non-lung) after primary diagnosis: 9.3 vs. 6.5 mo for NSC lung (p=0.21) and 10.5 vs. 7.2 mo for non-lung (p=0.87). In this series, the shortened intervals from primary diagnosis to SRS for NSC lung metastases was associated with post-SRS survivorship that was equivalent to the more favorable non-lung group.

Adult↗

Interferon-containing controlled-release polymers for localized cerebral immunotherapy.

Controlled-release ethylene-vinyl acetate copolymers (EVAc), which were used previously for the in vivo intracerebral delivery of chemotherapeutics, were evaluated as a possible route of localized intracerebral delivery of interferon (IFN). Natural mouse IFN-alpha/beta (Mu-IFN-alpha/beta) was incorporated into polymers at 5% or 10% by weight with 2 x 10(4) U or 4 x 10(4) U, respectively. In vitro and in vivo studies of the release of Mu-IFN-alpha/beta from EVAc polymers showed the released IFN to be biologically active, as determined by the inhibition assay of viral cytopathic effect (CPE). Evaluation of the in vitro kinetics of release showed that most of the IFN activity was released in the first 4 days, with the rest being released thereafter. The in vivo kinetic release of Mu-IFN-alpha/beta from intracerebrally implanted polymers showed that most of the IFN activity was released within 24 h after polymer implantation in the hemisphere ipsilateral to the polymer. This IFN activity gradually decreased over the next 72 h, with a significant linear trend (p < 0.0001). The hemisphere contralateral to the implanted polymer showed no significant levels of IFN activity throughout the 4 days of evaluation. By contrast, blood levels of IFN increased from day 1 to day 4, showing a significant linear trend (p = 0.0125), with IFN levels on day 4 being significantly higher (p < 0.05) than on day 1 after polymer implant. This study demonstrates the feasibility of intracranial controlled local delivery of IFN using a polymer delivery device.

Animals↗