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M E Randall

Publications and source records attributed to M E Randall.

At least 19 recordsLinked to original sources
PubMed2003

Neurons in the periaqueductal gray are critically involved in the neuronal network for audiogenic seizures during ethanol withdrawal.

The periaqueductal gray (PAG) is implicated in the network subserving audiogenic seizures (AGS). AGS are seen during ethanol withdrawal (ETX), and the present study examined effects of focal NMDA receptor blockade in PAG during ETX and PAG neuronal firing changes associated with ETX. Bilateral cannulae or microwire electrodes were chronically implanted into PAG. Ethanol was administered intragastrically at 8-h intervals for 4 days, resulting in AGS susceptibility during ETX. Microinjection of a competitive NMDA receptor antagonist, DL-2-amino-7-phosphonoheptanoic acid (AP7) (2 and 5 but not 1 nmol/side), into the PAG suppressed AGS, in part, reversibly. In microwire experiments spontaneous and acoustically evoked PAG neuronal responses in behaving rats were reduced significantly 1 h after initial administration of ethanol. During ETX, when the animals were susceptible to AGS, significant increases in spontaneous and acoustically evoked PAG neuronal firing occurred. PAG neurons exhibited burst firing 2-4 s prior to the tonic-clonic phase of AGS and tonic repetitive firing during this seizure phase, which ceased during post-ictal depression. Increased NMDA receptor function in PAG may be important to the aberrant PAG neuronal firing in AGS, since previous studies observed upregulation of NMDA receptors during ETX, and the present study observed that focal microinjection of a NMDA antagonist into PAG blocked AGS.

2-Amino-5-phosphonovalerate↗
PubMed2001

Modulation of audiogenically kindled seizures by gamma-aminobutyric acid-related mechanisms in the amygdala.

Repetitive induction of audiogenic seizures (AGSs) ("AGS kindling") results in expansion of the AGS neuronal network from the brainstem to forebrain structures. AGSs in kindled genetically epilepsy-prone rats (GEPR-9s) exhibit a significant increase in the duration of posttonic clonus (PTC). The amygdala (AMG) does not appear to be a required network component before AGS kindling, but this structure is implicated in the seizure network after AGS kindling. gamma-Aminobutyric acid (GABA) is a major neurotransmitter in AMG, and histamine receptor activation is also reported to stimulate GABA release. The present study examined the effect on audiogenically kindled seizures of focal microinjections into the AMG of GEPR-9s. AGS kindling involved induction of 14 AGSs in GEPR-9s. Bilateral microinjection of a GABA(A) agonist, muscimol (0.3 nmol/side), into the AMG significantly reduced the duration of PTC, starting 0.5 h after drug infusion, with recovery by 24 h. Microinjection of histamine (60 nmol/side) suppressed PTC at 0.5 h, with total blockade at 24 h, but the seizure pattern did not revert to that observed before kindling until 120 h. This long duration suggests that mechanisms in addition to modulation of GABA function may be involved in the effect of histamine. The wild running and tonic components of AGS were never affected by microinjection of these agents into the AMG. These findings confirm previous work suggesting that the AMG is not a required nucleus in the AGS neuronal network before kindling. However, the AMG becomes critical in expansion of the seizure network during AGS kindling, and audiogenically kindled seizures are negatively modulated by increased GABA function.

Acoustic Stimulation↗
PubMed2001

A technique for inguinal node boost using photon fields defined by asymmetric collimator jaws.

A technique is described for treating inguinal nodes when using radiotherapy in the control of pelvic malignancies. A posterior photon field treats the pelvis. A wider anterior photon field treats pelvis and inguinal nodes. An anterior photon boost to nodes is delivered using asymmetric collimator jaws moved across center line. Advantages of this technique include simplicity of setup and treatment (a single isocenter is retained, and no transmission block is needed), minimal dose inhomogeneity, reduced dose to femoral necks reducing the risk of femoral fracture, low risk of nodal underdose, and elimination of dosimetric difficulties inherent in electron beam boosts.

Dose-Response Relationship, Radiation↗
PubMed2000

Integrating radiation therapy in the curative management of ovarian cancer: current issues and future directions.

Although important advances in surgery, chemotherapy (CT), and radiation therapy (RT) have been made, overall survival for patients with ovarian cancer (OC) has not changed significantly. Despite its long history in the treatment of OC and its proven curative role in patients with microscopic or minimal residual disease, the proper role of RT in the management of OC is not clearly established. Although the use of primary adjuvant RT (whole abdominal irradiation) has declined in the last 15 years, there has been a resurgence of interest in RT as part of a combined modality approach and as salvage therapy for patients with small-volume persistent disease after primary cytoreductive surgery and platinum-based CT. This article reviews the evidence supporting the use of RT alone or combined with chemotherapy as primary adjuvant therapy or in the salvage setting. Current issues in the radiotherapeutic management are discussed along with ideas for future clinical research directions.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Neurons in the deep layers of superior colliculus play a critical role in the neuronal network for audiogenic seizures: mechanisms for production of wild running behavior.

Recent investigations suggest that the deep layers of superior colliculus (DLSC) play a role in the neuronal network for audiogenic seizures (AGS). The present study examined DLSC neuronal firing and convulsive behavior simultaneously in freely-moving genetically epilepsy-prone rats (GEPR-9s) using chronically implanted microwire electrodes. An abrupt onset of acoustically-evoked firing at approximately 80-90 dB was observed in DLSC neurons of GEPR-9s, which was significantly above the normal threshold. DLSC neurons began to exhibit rapid tonic burst firing 1-2 s prior to the onset of the wild running behavior at the beginning of AGS. As the tonic phase of the seizure began, DLSC firing ceased, and only returned towards normal following post-ictal depression. These neuronal mechanisms may be relevant to other seizure models in which the DLSC is implicated. The temporal pattern of neuronal firing during AGS is specific to DLSC and differs markedly from those observed elsewhere in the AGS neuronal network. The temporal firing pattern suggests that the DLSC plays a primary role in the generation of the wild running phase of AGS. Previous studies indicate that the inferior colliculus is dominant during AGS initiation, and the pontine reticular formation is dominant during the tonic extension phase of AGS. Taken together these data suggest that the neurons in the neuronal network undergo a dominance shift as each specific convulsive behavior of AGS is elaborated.

Acoustic Stimulation↗
PubMed1998

Adenocarcinoma of the fallopian tube: results of a multi-institutional retrospective analysis of 72 patients.

PURPOSE/OBJECTIVE: To determine the prognostic factors for predicting outcome of patients with adenocarcinoma of the fallopian tube and to evaluate the impact of treatment modalities in managing this uncommon disease. MATERIALS AND METHODS: A retrospective analysis of the tumor registries from 6 major medical centers from January 1, 1960 up to March 31, 1995 yielded 72 patients with primary adenocarcinoma of the fallopian tube. The Dodson modification of the FIGO surgical staging as it applies to carcinoma of the fallopian tube was utilized. Endpoints for outcome included overall and disease-free survival. Univariate analysis of host, tumor, and treatment factors was performed to determine prognostic significance, and patterns of failure were reviewed. RESULTS: The median age of the study cohort was 61 years (range 30-79 years). Stage distribution was 24 (33%) Stage I; 20 (28%) Stage II; 24 (33%) Stage III; and 4 (6%) Stage IV. Adjuvant chemotherapy was administered to 54 (75%) patients, and postoperative radiotherapy was employed in 22 (31%). In the latter treatment group, 14 (64%) had whole pelvic external beam irradiation, 5 (23%) whole abdominal radiotherapy, 2 (9%) P-32 instillation, and 1 (4%) vaginal brachytherapy alone. Chemotherapy was used in 67% of Stage I and in 79% of Stages II/III/IV disease (not significant); radiotherapy was more commonly employed in Stage I than in Stages II/III/IV (46% vs. 23%, p = 0.05). The 5-, 8-, 15-year overall and disease-free survival for the study patients were 44.7%, 23.8%, 18.8% and 27.3%, 17%, 14%, respectively. Significant prognostic factors of overall survival included Stage I vs. II/III/IV (p = 0.04) and age < or = 60 years vs. > 60 years at diagnosis (p = 0.03). Only Stage I vs. II/III/IV (p = 0.05) was predictive of disease-free survival. Patterns of failure included 18% pelvic, 36% upper abdominal, and 19% distant. For all patients, upper abdominal failures were more frequently found in Stages II/III/IV (29%) than in Stage I (7%) (p = 0.03). Relapses solely outside of what would be included in standard whole abdominal radiotherapy portals occurred for only 15% of patients (6 of 40) with failures. Furthermore, patients having any recurrence, including the upper abdomen, were more likely (p = 0.001) to die (45%) than those without any type of relapse (18%). CONCLUSION: This retrospective, multi-institutional study demonstrated the importance of FIGO stage in predicting the overall and disease-free survival of patients with carcinoma of the fallopian tube. Future investigations should consider exploring whole abdominal irradiation as adjunctive therapy, particularly in Stage II and higher.

Adenocarcinoma↗
PubMed1998

New techniques in the radiotherapeutic treatment of gynecological malignancies.

The management of patients with gynecological malignancies serves as a prominent example of the importance of multi-modality oncologic therapy. Optimal treatment of these patients requires the skillful implementation of surgery, radiation therapy and chemotherapy. The decision to use simple versus combined modality therapy is crucial and best carried out in centers in which an experienced and coordinated multidisciplinary team is available. In this article, we have reviewed the most recent data regarding the role of radiation therapy in gynecological malignancies and have pointed out those areas where additional confirmatory studies are needed.

Antineoplastic Agents↗
PubMed1997

Advances in gynecologic radiation oncology.

Radiation therapy is an important modality in the curative and palliative management of patients with gynecologic malignancies. However, the specific roles of radiation therapy continue to evolve in terms of specific indications, volumes treated, techniques, and integration with other modalities. Retrospective assessments of outcome and prospective clinical trials are necessary to answer questions, generate additional hypotheses, and guide further refinements in the application of radiation therapy. This article focuses on recent literature and ongoing clinical trials in this disease group.

Antineoplastic Agents↗
PubMed1996

Chemotherapy, early surgical reassessment, and hyperfractionated abdominal radiotherapy in stage III ovarian cancer: results of a gynecologic oncology group study.

PURPOSE: To determine outcomes and treatment toxicities in patients with optimal (< or = 1 cm residual) Stage III ovarian carcinoma treated with three courses of cisplatin-cyclophosphamide, surgical reassessment (SRA), and hyperfractionated whole abdominal irradiation (WAI). METHODS AND MATERIALS: Forty-two eligible patients entered this prospective Phase II study conducted by the Gynecologic Oncology Group (GOG). Disease characteristics were as follows: age range, 32-76 years (median 58); Stage IIIA (n = 1, 2%), IIIB (n = 2, 5%), IIIC (n = 39, 93%); histology-serous papillary (n = 21, 50%); other (n = 21, 50%); Grade 1 (n = 1, 2%); 2 (n = 14, 33%); 3 (n = 27, 54%); residual disease after initial surgery (present: n = 23, 55%; absent: n = 19, 45%). Five patients progressed while on chemotherapy, could not be effectively cytoreduced, and were not eligible for WAI. Of the remaining 37 patients, 35 received WAI. Surgical reassessment was not performed in five patients. RESULTS: Of 37 patients with known SRA status after chemotherapy, 21 (57%) were grossly positive, 4 (11%) were microscopically positive, and 12 (32%) were negative. Based on measurements recorded following initial laparotomy and surgical reassessment, progression during chemotherapy was noted in 40%, stage disease in 37%, and objective response in 23%. Toxicity during hyperfractionated WAI was limited and reversible. No patient beginning WAI failed to complete or required a significant treatment break. Following WAI, six patients underwent laparotomies for abdominal symptoms; five had recurrent disease. Five additional patients were managed conservatively for small bowel obstruction (SBO) or malabsorption, of whom three subsequently developed recurrence. Twenty-two patients having pelvic boosts were significantly more likely to require management for gastrointestinal morbidity (p = 0.0021). Considering all eligible patients, median disease-free and overall survivals were 18.5 and 39 months, respectively. Considering patients completing chemotherapy and WAI, median disease-free and overall survivals were 24 and 46 months, respectively. CONCLUSIONS: (a) Disease progression occurred within three cycles of cisplatin and cyclophosphamide chemotherapy in 40% of patients with optimal (< or = 1 cm residual) Stage III ovarian carcinoma. (b) Following limited chemotherapy, hyper-fractionated WAI was acutely well tolerated. (c) Late radiation-related toxicity was observed in only three patients (8.6%) in the absence of recurrent disease. Late gastrointestinal morbidity was significantly associated with the administration of a pelvic radiotherapy (RT) boost. (d) Short duration chemotherapy followed by SRA and hyperfractionated WAI without a pelvic boost is a promising management option for patients with optimal Stage III ovarian cancer. A Phase III trial will be necessary to determine how this treatment strategy compares with chemotherapy or RT alone in this patient population.

Abdomen↗
PubMed1995

Pontine reticular formation neurons exhibit a premature and precipitous increase in acoustic responses prior to audiogenic seizures in genetically epilepsy-prone rats.

The genetically epilepsy-prone rat (GEPR-9) exhibits elevated seizure sensitivity and audiogenic seizures (AGS). The pontine reticular formation (PRF) is implicated in the neuronal network for AGS in the GEPR-9. The present study examined PRF neuronal firing and convulsive behavior simultaneously in the GEPR-9. Chronically implanted microwire electrodes in PRF allowed single neuronal responses and behavior to be examined in freely-moving rats. PRF neurons in the GEPR-9 exhibit precipitous intensity-evoked increases at a significantly lower (approx. 15 dB SPL) intensity than normal Sprague-Dawley rats. PRF neurons in the GEPR-9 also exhibit increased auditory response latencies. At the onset of AGS (wild running) the firing rate of PRF neurons increased, and the rate of PRF firing increased dramatically as the tonic phase of the seizure began. During post-ictal depression the rate of PRF neuronal firing slowed, gradually returning to normal. This pattern of PRF periseizural neuronal firing changes differ dramatically in pattern and temporal characteristics from those previously observed in inferior colliculus (IC). The IC serves as the AGS initiation site. IC neurons show extensive firing increases prior to and during the initial wild running, silence during the tonic and post-ictal phases, and gradual recovery of responses thereafter. The changes in PRF neuronal firing pattern suggest that the PRF may play a major role in the generation of the tonic phase of AGS. The premature onset of the precipitous rise in PRF neuronal firing suggests that the influence of the IC on PRF neurons may be magnified in association with AGS susceptibility. The PRF neuronal firing increases observed in the present study coupled with previous observation of AGS blockade by PRF microinjections in the GEPR-9 further support an important role of the PRF in the propagation of AGS in the GEPR-9. The mechanisms of PRF firing elevation may also be relevant in other seizure models in which the brain-stem reticular formation is implicated.

Acoustic Stimulation↗
PubMed1995

The efficacy of cranial irradiation in ovarian cancer metastatic to the brain: analysis of 32 cases.

OBJECTIVE: To determine the role of irradiation in the management of brain metastases from epithelial ovarian cancer. METHODS: Tumor registries from five university cancer centers were searched to identify ovarian cancer patients with brain metastases. During a 30-year period (1965-1994), 4027 ovarian cancer patients were evaluated, 32 of whom were found to have cerebral metastases. Each received fractionated whole-brain irradiation (median dose 30 Gy, range 20-52.5). Five patients received concomitant chemotherapy with whole-brain irradiation. RESULTS: The median survival time for the whole population was 4 months. For the entire series, symptomatic response (complete response and partial response) was achieved in 23, 16 of whom were palliated until death. Patients with higher Karnofsky performance status (70 or above versus below 70) were more likely to derive a palliative response and attained a statistically significant survival advantage. No other factor predicted the likelihood of deriving a palliative response or a survival advantage after treatment. CONCLUSIONS: In this large review of patients with cerebral metastases from ovarian cancer, we found that most of those treated with whole-brain irradiation achieved palliation until death. Nearly all women with high performance status derived durable palliation from cerebral irradiation. Whole-brain irradiation was an effective means of palliating ovarian cancer metastatic to the brain and provided a favorable alternative to other means of management.

Adult↗
PubMed1995

Brachytherapy: criteria for case selection.

Brachytherapy has an established role in the management of a number of malignancies. Contributing to successful application of brachytherapy techniques are proper planning, technical sophistication, and meticulous execution. Equally important, presumably, is proper case selection although conditions favoring brachytherapy utilization are not well described. To facilitate discussion of this topic, a semiquantitative system of brachytherapy case selection is proposed. Variables considered include the natural history of the malignancy, risks involved in the procedure, accessibility of implant site, and results obtainable with other treatment modalities. Brachytherapy Case Selection Scores (0-8) were generated for a number of malignancies. Higher scores were found for sites in which the use of brachytherapy is generally accepted and practiced, implying that the clinical factors considered in this system are clinically relevant, and that such a system could be useful when considering the use of brachytherapy in individual cases. Additional critical analysis regarding brachytherapy case selection is desirable.

Brachytherapy↗
PubMed1995

Whole abdominal radiotherapy versus combination chemotherapy with doxorubicin and cisplatin in advanced endometrial carcinoma (phase III): Gynecologic Oncology Group Study No. 122.

Although localized endometrial cancer is effectively treated with surgery and radiation therapy, the treatment of advanced disease remains problematic. With increasing utilization of primary surgical staging and therapy, the early identification of patients with tumor spread beyond the uterus is becoming routine. The impact of adjuvant radiotherapy and/or chemotherapy in these patients remains to be demonstrated. In several institutions, whole abdominal radiation therapy has been used with some success as adjuvant treatment in selected patients with advanced disease. The Gynecologic Oncology Group (GOG) has completed a phase II trial of the whole abdominal radiotherapy in this patient population. Although data analysis is not complete, the regimen employed appears to be tolerable and shows some evidence of efficacy. In previous GOG trials, cisplatin and doxorubicin have shown single-agent activity in patients with measurable, advanced endometrial cancer. Subsequently, the response rate with the combination of cisplatin and doxorubicin was found to be superior to that with doxorubicin alone. Because approximately 30%-50% of patients with extrauterine disease have systemic failure, the evaluation of combination chemotherapy with doxorubicin and cisplatin in the adjuvant setting seemed warranted. The current ongoing prospective, randomized trial (GOG No. 122) compares the survival and the progression-free interval and treatment failure patterns in patients with endometrial carcinoma of stage III or IV with up to 2 cm of residual disease when treated with either whole abdominal radiotherapy or a combination of doxorubicin and cisplatin. The incidence and type of acute and late adverse events observed with the two treatment regimens were determined and compared.

Abdomen↗
PubMed1994

Prognostic factors and treatment outcome for patients with locally recurrent endometrial cancer.

BACKGROUND: Women who do not receive adjuvant irradiation after hysterectomy for endometrial carcinoma (EC) are at risk for developing a pelvic recurrence. Disease- and treatment-related factors were examined for their impact on disease-specific survival (DSS) and pelvic control (PC) in patients with locoregional recurrences to whom salvage radiotherapy was administered. METHODS: Forty-five patients with pelvic/vaginal recurrences of EC were treated at a single institution between 1973 and 1991. The median follow-up period was 89 months. Multiple patient-, disease-, and treatment-related factors were examined with univariate and multivariate analysis for their impact on DSS and PC. Kaplan-Meier methods were used to estimate outcomes. RESULTS: Overall DSS and PC was 51 and 54% at 5 years, respectively. Univariate analysis revealed the following factors to impact on outcome (P < or = 0.05): age (DSS, PC), vaginal stage of recurrence (DSS, PC), size of recurrence (DSS, PC), time interval from hysterectomy (DSS, PC), initial grade (DSS), location of recurrence (PC), and radiation boost technique (PC). CONCLUSION: Women in whom endometrial cancer recurrences develop can be salvaged with aggressive radiotherapy consisting of external beam therapy followed by a radiation boost. Close follow-up after the initial hysterectomy is important because patients with low-volume recurrence limited to the vagina have the best outcome.

Adenocarcinoma↗
PubMed1994

Positron emission tomography of patients with head and neck carcinoma before and after high dose irradiation.

BACKGROUND: Positron emission tomography (PET) with labeled fluorodeoxyglucose (FDG) demonstrates increased tracer uptake in many neoplasms. This study was undertaken to define the patterns of FDG uptake in head and neck neoplasms before and after high dose irradiation. METHODS: Twenty-five patients were evaluated prospectively with PET and standard clinical and radiographic techniques before and after irradiation. RESULTS: Twenty-seven primary sites were confirmed pathologically in 23 patients and included the nasopharynx (four lesions), oropharynx (14 lesions), larynx (five lesions), oral cavity (two lesions), and paranasal sinuses (two lesions). Two patients had unknown primary sites. Twenty-four of 27 primary sites correlated with areas of increased tracer uptake on PET scans. Five patients had increased uptake in cervical lymph nodes that were uninvolved by radiographic or clinical criteria. Positron emission tomography seemed to be able to differentiate tumor activity from fluid-filled sinuses in two patients with paranasal sinus tumors. In two patients with unknown primary sites, increased uptake in the base of tongue after PET suggested occult primary sites. Positron emission tomography scans obtained 1 month after high dose irradiation (RT) indicated decreased levels of FDG uptake in all patients' tumors. However, these scans did not accurately reflect the status of disease in these patients. Scans obtained 4 months after RT were believed to assess more accurately the presence of malignancy. CONCLUSIONS: Positron emission tomography is a new modality that may be useful in defining tumor activity in clinically negative areas. Appropriately timed posttreatment PET may be useful in predicting outcome after definitive RT and in distinguishing viable tumors from normal tissue changes after RT in patients with head and neck carcinomas.

Carcinoma↗
PubMed1994

GABA in the inferior colliculus plays a critical role in control of audiogenic seizures.

Previous studies have implicated a decreased efficacy of GABA as an important defect subserving the audiogenic seizures of the genetically epilepsy-prone rat (GEPR-9). The inferior colliculus (IC) is a critical site for audiogenic seizure (AGS) initiation, and the pontine reticular formation (PRF) is implicated in the propagation of AGS and in other generalized seizure models. The present study observed that microinjection of baclofen, a GABA-B receptor agonist, into IC protects against AGS, and blockade of the breakdown of endogenous GABA by gabaculine, a GABA transaminase inhibitor, increased GABA levels and blocked AGS susceptibility in the GEPR-9. Microinjection of baclofen or gabaculine into the PRF reduced AGS severity, but the doses required were considerably greater and the degree of anticonvulsant effect was less. Uptake of [3H]GABA into GEPR-9 synaptosomes from the IC is significantly increased as compared to normal, which could contribute to the diminished effectiveness of GABA in the GEPR-9. Previous studies indicate that GABA-A receptor agonists block AGS with IC microinjection, and recent data indicate that blockade of GABA uptake in this nucleus significantly reduced AGS severity. These data taken together strongly support the critical importance of the defect in GABA function in the IC in modulating susceptibility to audiogenic seizure initiation in the GEPR-9.

Acoustic Stimulation↗
PubMed1994

Increased chronic bowel complications with split-course pelvic irradiation.

PURPOSE: To assess the possible impact of various treatment factors including split-course versus continuous course treatment on the incidence of chronic bowel complications in patients receiving adjuvant pelvic radiotherapy. METHODS AND MATERIALS: A retrospective review was performed of records of 153 patients treated with adjuvant external beam pelvic radiation therapy without brachytherapy for endometrial and colorectal carcinomas. Continuous course radiotherapy was administered in 91 patients (59%) and 62 patients (41%) received split course treatment with a planned 2 week mid-treatment break. Mean pelvic dose and daily fraction size were 51.4 and 1.71 Gray, respectively. Multiple patient and treatment variables were assessed for their possible relationship to chronic bowel complications. Univariate and multivariate statistical analyses were carried out. RESULTS: Twenty-seven patients (18%) developed chronic bowel complications at a median interval of 12 months after radiotherapy. Of all factors analyzed, only the use of split course technique was associated with a significantly higher rate of chronic bowel injury and decreased complication-free survival (p = 0.009). CONCLUSION: This study supports earlier suggestions that the use of split course rather than continuous course pelvic radiotherapy can increase late intestinal complication rates. Possible pathophysiologic mechanisms are discussed.

Adult↗