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Biomedical subjects

G M Thomas

Publications and source records attributed to G M Thomas.

At least 37 records · Page 2Linked to original sources
PubMed1996

Does adjuvant chemotherapy change the prognosis of cervical cancer?

Although combination chemotherapy, which includes cisplatin, has a high response rate in cervical cancer, its usefulness as an adjunct to pelvic surgery or radiotherapy remains undefined. In most studies chemotherapy, either before, during, or after local treatment, has not been shown to improve outcome. Local treatment alone remains standard treatment, pending further randomized trials.

Chemotherapy, Adjuvant↗
PubMed1996

Is there a place for whole abdominal radiotherapy in the management of ovarian cancer?

Most patients with ovarian cancer require further therapy with chemotherapy or radiotherapy because of the high recurrence risk following surgery alone. Radiotherapy directed to the whole abdomen and pelvis is capable of producing survival rates of 70% in carefully selected patients. Such patients have no more than microscopic residual disease in the abdomen, and small volume residual disease in the pelvis. They are selected based on a prognostic matrix which considers grade, stage and the presence of pelvic residual disease. With optimal radiotherapy technique, long term serious toxicity occurs in less than 5% of patients. Patients with macroscopic residual disease are treated with chemotherapy. Patients who obtain a complete response have been treated with consolidative whole abdominal radiotherapy, although the benefit of such an approach is unclear.

Abdomen↗
PubMed1996

Adjuvant therapy after primary surgery for stage I-IIA carcinoma of the cervix.

Radical hysterectomy and bilateral pelvic lymph node dissection is commonly used as a primary management option for treatment of stage IB/IIA carcinoma of the cervix. Overall cure rates approach 85%. However, a spectrum of relapse risk exists, depending on the presence or absence of primary tumor and nodal-related prognostic factors. Known factors include number and location of lymph nodes; size of primary, deep invasion in the cervix; capillary lymphatic space involvement; occult parametrial involvement; and positive or close surgical margins. Biologic determinants have yet to be identified. No systematic analysis has examined various combinations of prognostic factors to precisely define associated levels of risk and to predict the sites of relapse. Decreased local control and survival rates in some high-risk subgroups, usually those with nodal positivity, has led to the exploration of adjuvant therapies. Compiled data from retrospective series have defined the overall patterns of failure. Seventy-two percent of those relapsing have a component of pelvic failure, while 42% experience relapse in the pelvis alone. Fifty-eight percent have a component of distant failure but only 28% have distant disease alone. Adjuvant treatment options include pelvic radiotherapy, extended-field radiotherapy, chemoradiotherapy, and chemotherapy. Trials of adjuvant chemotherapy are too few to evaluate the use of available agents. Pelvic radiotherapy has been shown to reduce the relapse risk when surgical margins are close or positive. It also reduces the risk of pelvic relapse and improves the relapse-free interval but has no apparent impact on overall survival in the groups that have been selected for treatment. The apparent lack of benefit may relate to the choice of patients with nodal involvement who, despite high risk of pelvic failure, most likely have a predominant pattern of distant failure. Maximization of the survival benefit of pelvic radiotherapy requires the identification and treatment of the subgroup with a predominant pattern of pelvic failure, such as that examined in Gynecologic Oncology Group protocol 92. These may be patients with primary tumor-related, high-risk factors but negative nodes. Extended-field irradiation for microscopically involved para-aortic nodes provides a cure in 25%-40% of the patients. Further studies of prognostic factors and their relationship to sites of failure after surgery are necessary to define the benefits of currently available adjuvant therapies with respect to local control, survival, and quality of life, and also to direct future studies. New, effective systemic agents are required for those at high risk of developing distant disease.

Chemotherapy, Adjuvant↗
PubMed1995

Carcinoma of the cervix: patterns of care studies: review of 1978, 1983, and 1988-1989 surveys.

PURPOSE: A review of the Patterns of Care Studies Process Survey data on carcinoma of the cervix conducted on patients in 1978, 1983, and 1988-89 was carried out to identify changes or trends in the demographics, evaluation, and treatment that might have occurred over this time period. METHODS AND MATERIALS: Patterns of Care Studies conducted surveys on patients treated by radiation therapy for cervical carcinoma in 1978, 1983, and 1988-89. These surveys have compiled demographic and treatment data on a total of 993 patients. There is outcome data for the 1978 and 1983 surveys, but not for the 1988-89 survey because follow-up has not been collected yet. The demographic and treatment delivery data on all three surveys has been reviewed and analyzed and is the subject of this study. RESULTS: There was no difference in the age distribution at the time of diagnosis of the patients in these surveys. The percentage of black patients remained constant in the three surveys, 19%, 17%, and 21%, respectively. The percentage of white patients was 76%, 78%, and 67%, but that of nonwhite/nonblack patients was 3%, 4%, and 12% (p < 0.001). The distribution of patients by stage was similar in the first two surveys. In the third survey, there was a decrease in the percentage of patients with Stage IA and IB (first = 35%; second = 38%; third = 29%) with a concurrent increase in Stage IIIA and IIIB patients (first = 20%; second = 18%; third = 26%). The surveys showed a major change in the pretreatment evaluation tests used. There was a progressive decrease in the use of intravenous pyelogram (IVP) (86 to 42%), barium enema (58 to 32%), cystoscopy for patients Stage IIB and higher (64 to 52%), and lymphangiography (18 to 14%). The use of abdominal or pelvic computed tomography dramatically increased from 6 to 70% between the first and third surveys. The use of 60Co units decreased from 35 to 2% from the first to the third survey [6 to 0% for short source-surface distance (SSD) 60Co units]. Point dose calculations for the intracavitary therapy increased from 78% in the 1978 survey to 95% in the third survey. As determined by the total dose delivered to the paracentral points, more patients (75.1%) were treated according to the Patterns of Care recommended guidelines in the 1988-89 survey than in the 1983 survey (63.6%). Chemotherapy was given to 12% of the patients undergoing radiation therapy during the period of the third survey, but these data are not available for the first and second surveys. CONCLUSION: Review of the Carcinoma of the Cervix Patterns of Care studies discloses significant changes in the demographics, patient evaluation, and radiation therapy techniques during the period of the studies. The potential impact of these changes on treatment outcome cannot be determined at this time until longterm follow-up for the 1988-89 survey is available, but improvements in the processes of care should lead to improvements in outcome.

Adult↗
PubMed1995

Phosphatidylinositol transfer protein dictates the rate of inositol trisphosphate production by promoting the synthesis of PIP2.

BACKGROUND: Phosphatidylinositol transfer protein (PI-TP), which has the ability to transfer phosphatidylinositol (PI) from one membrane compartment to another, is required in the inositol lipid signalling pathway through phospholipase C-beta (PLC-beta) that is regulated by GTP-binding protein(s) in response to extracellular signals. Here, we test the hypothesis that the principal role of PI-TP is to couple sites of lipid hydrolysis to sites of synthesis, and so to replenish depleted substrate for PLC-beta. RESULTS: We have designed an experimental protocol that takes advantage of the different rates of release of endogenous PI-TP and PLC-beta from HL60 cells permeabilized with streptolysin O. We have examined the kinetics of stimulated inositol lipid hydrolysis in cells depleted of PI-TP, but not of endogenous PLC-beta, in the presence and absence of exogenous PI-TP. Linear time-courses were observed in the absence of any added protein, and the rate was accelerated by PI-TP using either guanosine 5'[gamma-thio]-triphosphate (GTP gamma S) or the receptor-directed agonist fMetLeuPhe as activators. In addition, depletion from the cells of both PI-TP and PLC-beta isoforms by extended permeabilization (40 minutes) allowed us to control the levels of PLC-beta present in the cells. Once again, PI-TP increased the rates of reactions. To identify whether the role of PI-TP was to make available the substrate phosphatidylinositol bisphosphate (PIP2) for the PLC, we examined the synthesis of PIP2 in cells depleted of PI-TP. We found that PI-TP was essential for the synthesis of PIP2. CONCLUSIONS: The predicted function of PI-TP in inositol lipid signalling is the provision of substrate for PLC-beta from intracellular sites where PI is synthesized. We propose that PI-TP is in fact a co-factor in inositol lipid signalling and acts by interacting with the inositol lipid kinases. We hypothesize that the preferred substrate for PLC-beta is not the lipid that is resident in the membrane but that provided through PI-TP.

Animals↗
PubMed1995

Requirement for phosphatidylinositol transfer protein in epidermal growth factor signaling.

Stimulation of phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis is a widespread mechanism for receptor-mediated signaling in eukaryotes. Cytosolic phosphatidylinositol transfer protein (PITP) is necessary for guanosine triphosphate (GTP)-dependent hydrolysis of PIP2 by phospholipase C-beta (PLC-beta), but the role of PITP is unclear. Stimulation of phospholipase C-gamma (PLC-gamma) in A431 human epidermoid carcinoma cells treated with epidermal growth factor (EGF) required PITP. Stimulation of PI-4 kinase in cells treated with EGF also required PITP. Coprecipitation studies revealed an EGF-dependent association of PITP with the EGF receptor, with PI-4 kinase, and with PLC-gamma.

1-Phosphatidylinositol 4-Kinase↗
PubMed1995

Activation of the MAP kinase homologue RK requires the phosphorylation of Thr-180 and Tyr-182 and both residues are phosphorylated in chemically stressed KB cells.

A MAP kinase homologue, termed the reactivating kinase (RK), lies in a signalling pathway which mediates cellular responses to stress. Here we demonstrate that the stress-induced activation of the RK in human KB cells is accompanied by the phosphorylation of Thr-180 and Tyr-182, and that the phosphorylation of both residues is required for the activation of this enzyme.

Amino Acid Sequence↗
PubMed1995

Hydrochlorothiazide-induced pulmonary edema with severe acute myocardial dysfunction.

A 73-year-old woman presented with acute pulmonary edema and hypotension less than 1 h after taking hydrochlorothiazide 50 mg, a reaction which has been reported as a rare but classic adverse drug response. Though prior cases have supported a noncardiogenic pulmonary edema syndrome, hemodynamic monitoring in this patient demonstrated a refractory low cardiac output state for more than 24 h. In the absence of other etiologies, this represents a new finding.

Acute Disease↗
PubMed1995

The structure of rat ADP-ribosylation factor-1 (ARF-1) complexed to GDP determined from two different crystal forms.

The ARFs are a family of 21,000 M(r) proteins with biological roles in constitutive secretion and activation of phospholipase D. The structure of ARF-1 complexed to GDP determined from two crystal forms reveals a topology that is similar to that of the protein p21 ras with two differences: an additional amino-terminal helix and an extra beta-strand. The Mg2+ ion in ARF-1 displays a five-coordination sphere; this feature is not seen in p21 ras, due to a shift in the relative position of the DXXG motif between the two proteins. The occurrence of a dimer in one crystal form suggests that ARF-1 may dimerize during its biological function. The dimer interface involves a region of the ARF-1 molecule that is analogous to the effector domain in p21 ras and may mediate interactions with its effectors.

ADP-Ribosylation Factors↗
PubMed1995

Combined modality therapy for gynecologic cancer.

The use of combined modality therapy in the primary management of gynecologic cancer continues to be explored. Although early ovarian cancer is treated with postoperative adjuvant treatment, the data to support its value is lacking. In advanced disease, paclitaxel has emerged as the most optimal treatment after maximal cytoreduction. Although studies on consolidative therapy using radiotherapy, intraperitoneal therapy, or further chemotherapy are reported, there are no comparative data against a control arm. In those subsets of endometrial cancer patients who have a poor survival, adjuvant treatment strategies using chemotherapy or wide-field whole-abdominal therapy is being evaluated to improve outcome. Small phase II studies of either sequential or concurrent chemotherapy with radiation continue to be reported in advanced cervix cancer, yet large prospective randomized trials comparing standard radiotherapy to combined chemotherapy and radiotherapy are scarce. Alternative strategies to standard surgery to limit morbidity is being explored in the management of vulvar cancer with encouraging results. More properly conducted phase III trials are necessary to evaluate the efficacy of these newer treatment strategies.

Clinical Trials as Topic↗
PubMed1994

Crystallization and preliminary X-ray diffraction studies on ADP-ribosylation factor 1.

ADP-ribosylation factor 1 (ARF-1) is a member of a family of small G-proteins that regulate both intracellular vesicle transport and phospholipase D activity. Crystals of ARF-1 suitable for X-ray diffraction analysis have been grown in the presence of GDP by the hanging drop vapour diffusion method. Crystals grow in space group C2 with cell dimensions a = 122.36 A, b = 45.01 A, c = 91.96 A and beta = 133.62 degrees and diffract to at least 2.3 A resolution. A second crystal form has been characterized (space group C2, a = 69.70 A, b = 45.25 A, c = 60.45 A, beta = 109.6 degrees) but does not grow reproducibly.

ADP-Ribosylation Factors↗
PubMed1994

Phospholipase D: a downstream effector of ARF in granulocytes.

Activation of the phospholipase D (PLD) pathway is a widespread response when cells are activated by agonists that bind receptors on the cell surface. A 16-kD cytosolic component can reconstitute guanosine triphosphate (GTP)-mediated activation of phospholipase D in HL60 cells depleted of their cytosol by permeabilization. This factor was purified and identified as two small GTP-binding proteins, ARF1 and ARF3. Recombinant ARF1 substituted for purified ARF proteins in the reconstitution assay. These results indicate that phospholipase D is a downstream effector of ARF1 and ARF3. The well-established role of ARF in vesicular traffic would suggest that alterations in lipid content by PLD are an important determinant in vesicular dynamics.

ADP-Ribosylation Factor 1↗
PubMed1994

Radiotherapy in early ovarian cancer.

Radiation therapy is an effective curative treatment modality in early ovarian cancer. A combination of the independent prognostic factors of grade, stage, and residual disease defines an "intermediate" risk group whose probability of long-term disease-free survival from abdomino-pelvic radiation therapy (APRT) is between 62 and 91%. This group in which abdomino-pelvic radiotherapy is recommended as the sole postoperative treatment is mainly constituted from patients with Stage II disease of all grades with no residuum or less than 2 cm residuum in the pelvis and selected optimal Stage III patients with low grade tumors. No therapy has been shown to benefit patients with Stage I grade 2 or 3 tumors, although relapse risks of 30% justify postoperative treatment in this group. APRT significantly reduced relapse risk in patients with Stages I and II disease, where tumors were densely adherent. The late toxicity of APRT is acceptable. When the abdominal dose is restricted to a total of 25 Gy and the pelvic dose to 45 Gy serious complications occur in less than 4% of patients. 32P, widely utilized in early-stage disease, has not been shown to be beneficial compared to cisplatin in a study of the Norwegian Radium Hospital. Its dosimetry precludes effective dosing of tumor at a depth of more than 1 to 2 mm from the peritoneal surface and of the retroperitoneal nodes. Its use should be abandoned. APRT is an effective anti-tumor modality in ovarian cancer and cannot be discarded. Further studies of this modality are justified. Its future exploitation lies in manipulations to increase the therapeutic ratio by either altered radiotherapy fractionation schemes and/or potential combination with radiation sensitizers.

Combined Modality Therapy↗