Endoscopic transseptal transsphenoidal hypophysectomy with three-dimensional intraoperative localization technology.
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Adenoma↗
Biomedical subjects
R Goel
Publications and source records attributed to R Goel.
Concurrent use of multiple low dose chemotherapy agents with differing mechanisms of action as a strategy vs passive resistance: A pilot study.
Resistance may be classified as active (or competitive) (due to excess amount of a factor) vs passive (or non-competitive) (due to a deficiency of a factor). Passive resistance may be important in human solid tumors. In passive resistance, the dose-response curve may be shallow, or may flatten at a relatively low dose. We hypothesized that, if passive resistance were important, it might be advantageous to use low doses of multiple concurrent chemotherapy agents with differing mechanisms of action, rather than using high doses of 2 or 3 drugs. We combined single day cisplatin 60 mg/m2, cyclophosphamide 250 mg/m2, epirubicin 40 mg/m2, paclitaxel 60 mg/m2, and vinblastine 2.5 mg/m2, with 5 days of 5-fluorouracil 200 mg/m2, folinic acid 20 mg/m2 and dexamethasone 4 mg orally q.i.d. every 3 weeks. In later cohorts, doses were escalated, and tamoxifen and verapamil were added. Twenty-three patients were entered. ECOG performance status was 1 in 15 patients and 2 in 8. Number of prior chemotherapy regimens was 0 in 4 patients, 1 in 4, 2 in 8, 3 in 4, 4 in 2, and 7 in 1. Sixteen patients had prior radiotherapy, and 3 had no prior therapy. Myelosuppression and febrile neutropenia were frequent, and 4 heavily pretreated patients died of pneumonia contracted while neutropenic. Diarrhea, nausea and vomiting, and fatigue were also prominent. Among 9 patients with non-small cell lung cancer, one had a partial remission, 4 had stable disease (including 3 with minor objective responses). Two additional non-small cell lung cancer patients also had objective tumor regression, but were coded as failures, since one had tumor progression in <6 weeks and the other died of respiratory failure (thought to be due to severe mucous plugging) one week after his first course of treatment. Among 14 patients with other tumor types, there was one partial response (esophageal carcinoma), 6 patients with stable disease for >6 weeks (including minor responses in one patient each with adenocarcinomas of kidney and breast), and 7 failures (including one patient with adenocarcinoma unknown primary who had minor tumor regression lasting 4 weeks). Despite the unacceptably high toxic death rate, median survival time was 24 weeks (range, 1 week to >104 weeks). This regimen is toxic, but survival duration is longer than would be expected in this heavily pre-treated population. Doses recommended for further study are those used in the first treatment cohort (as described above). Since myelosuppression is the major toxic effect, hemopoietic growth factors might prove helpful with this regimen.
Adult↗
Molecular control of the LDL receptor gene in leukemic cells.
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Gene Expression Regulation, Neoplastic↗
A rapid reversed phase high performance liquid chromatographic method for the determination of docetaxel (Taxotere) in human plasma using a column switching technique.
A rapid, simple and sensitive isocratic high performance liquid chromatography (HPLC) method was developed to measure the concentration of docetaxel in plasma samples with UV detection at 227 nm. The method uses a column switching technique with an Ultrasphere C18 column (75 x 4.6 mm ID, 3 mu, Altex, USA) as clean-up column and a CSC-nucleosil C8 column (150 x 4.6 mm ID, 5 mu, CSC, Montreal, Canada) as the analytical column. The mobile phase consisted of Phosphate buffer (30 mM, pH = 3)-acetonitrile (47:53, v/v) with the flow rates of 1.1 and 1.3 ml min-1 for clean-up and analytical columns, respectively. Paclitaxel was used as an internal standard. The plasma samples were extracted using a solid phase extraction method with Ammonium acetate (30 mM, pH = 5)-acetonitrile (50:50, v/v) as final eluent. The extraction method showed a recovery of 92% for docetaxel. In this system, the retention times of docetaxel and Paclitaxel were 7.2 and 8.5 min, respectively. The detection limit of docetaxel in plasma is 2.5 ng ml-1. This analytical method has a very good reproducibility (7.2% between-day variability at a concentration of 10 ng ml-1). It is applicable in clinical and pharmacokinetic studies.
Antineoplastic Agents, Phytogenic↗
A multicentre phase II study of carboplatin and prolonged oral etoposide in the treatment of cancer of unknown primary site (CUPS).
Cisplatin-based combination chemotherapy is frequently used to treat patients with carcinoma of unknown primary site (CUPS). Response rates in the literature range from 12% to 26% and median survival from 5 to 7 months. The goal of this study was to evaluate the combination of carboplatin and prolonged oral etoposide in patients with CUPS, with the hope of minimizing toxicity but improving efficacy and convenience. Treatment consisted of carboplatin, 300 mg m(-2) on day 1, and oral etoposide 50 mg on days 1-20, every 4 weeks for up to nine cycles. A total of 33 patients were treated and all were evaluable for toxicity. Non-haematological toxicity was mild to moderate, with the exception of one case of grade 4 stomatitis. Grade 4 leucopenia was observed in eight (24%) patients and sepsis in four (12%), with two and possibly three treatment-related deaths. For the 26 patients evaluable for response, the response rate was 23% with responses lasting a median of 11 months (range 7-13 months), with one patient still responding at 12 months. An additional nine patients (35%) had stable disease. Median survival for all patients was 5.6 months (range 2 weeks to 33 months). The combination of carboplatin with prolonged oral etoposide has moderate activity similar to that of other platinum-based regimens and is a well tolerated, convenient, outpatient regimen. Dosing according to estimated creatinine clearance to achieve a carboplatin AUC of 6.0 mg ml(-1) min might have decreased the incidence of severe myelotoxicity without compromising the regimen's efficacy.
Adenocarcinoma↗
Acute and chronic effects of nicotine on anastomotic patency following ischemia/reperfusion.
The effect of nicotine on anastomotic patency was studied using an isogenic rat-knee transplantation model. Animals were divided into experimental and control groups, with experimental animals exposed to either 40 days of twice-daily nicotine injections (Group 1-chronic exposure) or acute nicotine exposure by graft perfusion (Group 2-acute exposure). Four and 6 hr warm ischemia times were studied. Syngeneic rat knees were transplanted from donor to recipient by microvascular anastomosis of the femoral vessels. There was a statistically significant difference (p < 0.05) in anastomotic patency after 4 hr of ischemia in Group 1 animals exposed to nicotine (33 percent patency) vs. controls (89 percent patency). In addition, there was a statistically significant difference in anastomotic patency after 4 hr of ischemia in Group 2 animals exposed to nicotine (11 percent patency) vs. controls (67 percent patency). No significant differences between controls and Group 1 animals were noted in anastomotic patency after 6 hr of ischemia. Both acute and chronic nicotine exposure reduces anastomotic patency after short intervals of warm ischemia in vascularized composite tissue grafts. This detrimental effect is lost when the ischemic interval is prolonged to periods with poor anastomotic patency rates related to the ischemia/reperfusion itself.
Anastomosis, Surgical↗
Phase I-II study of 5-fluorouracil, leucovorin, doxorubicin, methotrexate, and long-term oral etoposide (FLAME) in unresectable or metastatic gastric cancer.
The objective of this phase I-II study was to determine the efficacy and toxicity of combination chemotherapy with 5-fluorouracil, leucovorin, doxorubicin, methotrexate, and oral etoposide (FLAME) in patients with measurable unresectable or metastatic gastric cancer. Starting doses on the phase I study were as follows: methotrexate 50 mg/m2 intravenous bolus day 1; leucovorin 20 mg/m2 intravenous bolus days 2 through 4, starting 24 hours after the methotrexate dose; 5-fluorouracil 325 mg/m2 intravenous bolus 15 minutes after leucovorin days 2 through 4; doxorubicin 25 mg/m2 intravenous bolus day 8; and oral etoposide 50 mg/day for 14 days, starting on day 8. A new cycle started on day 28. A total of 42 patients were treated--10 patients in the phase I study and 32 patients in the phase II study. Dose-limiting toxicity was encountered in the phase I study on the second escalation step, when doxorubicin was escalated to 30 mg/m2 and 5-fluorouracil was escalated to 350 mg/m2. In the phase II study 28 patients (109 courses) were evaluable for toxicity. Neutropenia grade 3 or more was dose limiting and was documented in 12 patients (43%) during 22 treatment courses (20%). Neutropenia was associated with febrile neutropenia requiring hospitalization in four patients during five courses of therapy. Grade 3 stomatitis and grade 3 diarrhea was infrequent, documented in two patients (two courses) and three patients (four courses), respectively. All other toxicity was grade 1 and grade 2. The combined objective response rate in 38 evaluable patients entered in both studies was 23.3% (six partial responses and one complete response). Stable disease was documented in 15 patients (39.5%). The median survival for the 42 patients entered in both trials was 6.9 months (95% confidence interval, 5.9-8.5 months). The objective response rate and median survival for the combined group is comparable with that reported for the etoposide, leucovorin, and 5-fluorouracil (ELF), and 5-fluorouracil and methotrexate (FMTX) regimens in a recently reported, multicenter, phase III study.
Adenocarcinoma↗
Arterial occlusion in patients with peripheral vascular disease treated with platinum-based regimens for lung cancer.
BACKGROUND: Patients with cancer may be hypercoagulable, and smoking can cause both lung cancer and peripheral vascular disease. Cisplatin-based chemotherapy has been reported to cause a variety of vascular side effects. CASE REPORTS: Five patients with bronchogenic carcinoma and peripheral vascular disease developed acute arterial occlusion soon after receiving a combination of cisplatin or carboplatin plus etoposide. All these patients had risk factors for atherosclerosis and three of them had preexisting known peripheral vascular disease. CONCLUSIONS: The occurrence of acute arterial occlusion soon after initiation of chemotherapy suggests that it might have been a complication of this therapy. Hence, caution should be exercised when using platinum-based (and other?) chemotherapy in patients with known moderate or severe peripheral vascular disease.
Aged↗
Association of cisplatin nephrotoxicity with patient characteristics and cisplatin administration methods.
OBJECTIVE: To assess factors that affect cisplatin nephrotoxicity. METHODS: In 425 patients treated with cisplatin, we assessed the effect of pretreatment factors and treatment conditions on the rise in serum creatinine with the first course of cisplatin, on the maximum rise in serum creatinine over the entire course of the cisplatin therapy, and on residual nephrotoxicity after the last cisplatin treatment ended. (Because of the nature of the relationship between serum creatinine and creatinine clearance, rise in serum creatinine was divided by pretreatment creatinine squared.) Patients were dichotomized into the upper quartile versus the lower three quartiles of degree of nephrotoxicity. Multivariate analyses were based on logistic regression, controlling for cisplatin dose per course. RESULTS: Controlling for cisplatin dose per course, factors most closely associated with nephrotoxicity during the first course of cisplatin were: serum albumin and potassium, body surface area, and administration of cisplatin over 2-5 days per course vs 1 day (negative associations). Controlling for cisplatin dose per course, the single factor most closely associated with maximum life-time cisplatin nephrotoxicity was concurrent use of a vinca alkaloid (negative association). Controlling for cisplatin dose per course, factors most closely associated with residual nephrotoxicity after the end of cisplatin therapy were cumulative dose of cisplatin, concurrent use of metoclopramide (positive associations), uric acid and concurrent use of phenytoin and a vinca alkaloid (negative associations). The association of nephrotoxicity with uric acid and with body surface area was felt to be an artifact resulting from its positive association with pretreatment serum creatinine. Nephrotoxicity during the first course of cisplatin also correlated significantly with autopsy kidney cortex platinum concentrations in 77 evaluable patients. CONCLUSIONS: (1) While several factors correlated with cisplatin nephrotoxicity, most of the observed nephrotoxicity was not explained by the variables identified. (2) While most patients received intravenous hydration, patients receiving high hydration volumes did not have significantly less nephrotoxicity than patients receiving lower hydration volumes: (3) Of the variables identified, serum albumin, metoclopramide and phenytoin may have affected nephrotoxicity by altering cisplatin uptake into or distribution within the kidney.
Antineoplastic Agents↗
Pilot study of multiple chemotherapy resistance modulators plus epirubicin in the treatment of resistant malignancies.
We studied the toxicity and efficacy of adding to epirubicin five resistance modulators in the treatment of resistant solid tumors. Additional drugs were added in successive cohorts of patients, such that cohort 1 patients received two drugs along with their epirubicin, while cohort 4 patients received five modulators along with their epirubicin. Metronidazole, tamoxifen (cohort 1), dipyridamole (cohort 2), ketoconazole (cohort 3) and cyclosporin (cohort 4) were administered with epirubicin. A total of 22 patients were treated. Nausea and vomiting was usually mild to moderate. There was an unexpectedly high incidence of possible cardiac toxicity associated with treatment, although in some patients it was uncertain whether or not observed cardiac events were related to treatment. Granulocytopenia was significant in all four cohorts, but it was unclear whether it was increased by the modulators. There were two febrile neutropenic events in cohorts 1 and 2 successfully treated with antibiotics, and three septic deaths (one in each of cohorts 1, 2 and 4). It was elected to discontinue enrollment on the study prematurely in light of cardiac and other toxicity seen in the first two patients accrued in cohort 4. A single response was observed. While this approach is feasible, the observed toxicity and the difficulty patients experienced in ingesting the large number of prescribed pills will make further exploration of this approach difficult.
Adjuvants, Pharmaceutic↗
Phase II study of a one hour paclitaxel infusion in combination with carboplatin for advanced non-small cell lung cancer.
PURPOSE: To determine the activity, toxicity, and optimal dose of paclitaxel when given by one hour infusion combined with carboplatin in advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty-seven previously untreated patients with stage IIIB or IV NSCLC were enrolled. Paclitaxel was administered by one hour infusion at a dose of 175 mg/m2 for the first cycle, and was escalated up to 255 mg/m2 over successive cycles if tolerated. In the absence of toxicity, the carboplatin dose was kept constant at an area under the concentration-time curve (AUC) of 6. Cycles were repeated at 3-week intervals until progression or intolerable toxicity occurred. RESULTS: Thirty-six patients were evaluable for toxicity and survival, and thirty-five for responses. The partial response rate was 10 of 35 (29%) and there were no complete responses. The median duration of response was 4.8 months (range 0.5-11.7 months). The median survival duration was 6.5 months, and 1 year survival was 31%. The mean paclitaxel dose was 188 mg/m2. Treatment was generally well tolerated. Four patients (11%) had febrile neutropenia. Five patients (14%) had grade 3 neuropathy, and 4 (11%) had grade 3 nausea and vomiting. Minor toxicities included alopecia, myalgias, arthralgias and stomatitis. CONCLUSIONS: Paclitaxel and carboplatin is a well-tolerated regimen that can safely be given by a one hour paclitaxel infusion. The modest response rate observed in this study may be due to either the low dose-intensity of paclitaxel or the short infusion duration. Further trials to optimize the relative doses of paclitaxel and carboplatin are needed.
Adult↗
Multiple resistance modulators combined with carboplatin for resistant malignancies: a pilot study.
BACKGROUND: Chemotherapy resistance is probably multifactorial; hence, we assessed the feasibility of adding to carboplatin 6 concurrent resistance modulators in 53 patients with resistant cancers. METHODS: Pentoxifylline and dipyridamole were added to carboplatin 400 mg/m2 in cohort 1, and metronidazole was also given in cohort 2. Mannitol and saline were administered in each cohort with the theoretical objective of improving carboplatin delivery to tumors by reducing blood viscosity. Because of excessive toxicity in cohort 2, cohort 3 received the same modulators as in cohort 2 but with a reduced dose of carboplatin (200 mg/m2). Subsequent patients had the following drugs added to those in the previous cohort: novobiocin (cohort 4), tamoxifen (cohort 5), ketoconazole (cohort 6). Cohort 7 patients received the 6 cohort 6 modulators along with carboplatin 300 mg/m2. RESULTS: Thrombocytopenia was excessive in early cohorts with a carboplatin dose of 400 mg/m2, but was minimal at lower doses. Other toxicity was generally tolerable and reversible, particularly at carboplatin doses < or = 300 mg/m2, although gastrointestinal and neurological toxicity tended to worsen as additional modulators were added. No major responses (but 4 minor responses) were seen in this patient population with heavily pretreated or primarily resistant cancers. CONCLUSIONS: Acceptable doses for phase II studies are carboplatin 300 mg/m2, 20% mannitol 250 ml plus normal saline 500 ml over 1 hr prior to carboplatin, pentoxifylline 700 mg/m2/day p.o. from 3 days before carboplatin to cessation of therapy, dipyridamole 100 mg/m2 p.o. q6h x 6 days starting 24 hr before carboplatin, metronidazole (750 mg/m2 p.o. 12 hr and immediately before, and 24 hr after carboplatin; 250 mg/m2 suppository p.r. 12 hr and immediately before, and 6 and 24 hr after carboplatin; and 500 mg/m2 i.v. right after carboplatin), novobiocin 600 mg/m2 p.o. q12h x 6 days starting 24 hr before carboplatin, and tamoxifen 100 mg/m2/day plus ketoconazole 700 mg/m2/day x 3 days starting the day before carboplatin, with oral dexamethasone and ondansetron as antimetics.
Adult↗
Receptor-'Ck' dependent signalling regulates the LDL-receptor gene transcription.
Evidence of a novel receptor, having affinity for cholesterol in lipoproteins and intrinsic tyrosine kinase activity (designated as Receptor 'Ck') prompted us to explore its role in LDL-dependent transcriptional regulation of apoprotein-B specific LDL receptor gene in human lymphocytes. The results of this study revealed that LDL dependent activation of this Receptor 'Ck' was essential for the regulation of apoprotein-B specific LDL receptor gene transcription. Further, by using various blockers of as well as simulating the Receptor 'Ck'-dependent signalling in human lymphocytes, we were able to show that Receptor 'Ck'-dependent signalling was involved in the LDL-dependent transcriptional regulation of 160 kDa apoprotein B specific LDL receptor gene. Based upon these results, we conclude that cholesterol derived from LDL. catabolism within the cell does not have any role in the transcriptional regulation of apoprotein B specific LDL receptor gene.
Apolipoproteins B↗
Retrospective comparative analysis of 5FU + low-dose folinic acid vs. 5FU + high-dose folinic acid in the treatment of metastatic colorectal cancer. The Ottawa experience.
Two regimens of 5FU and folinic acid in the treatment of metastatic colorectal cancer were retrospectively analyzed. 33 patients received the high dose (HD) schedule (5FU 370 mg/m2 and Folinic Acid 200 mg/m2 i.v. on D1-5, every 4 weeks), 61 patients received the low dose (LD) schedule (5FU 400 mg/m2 and Folinic Acid 20 mg/m2 i.v. on D1-5, every 4 weeks). One patient in each group achieved a complete response, the overall response rate was 28% and 11% for the HD and LD groups, respectively. The median response duration was 183 days for the HD and 112 days for the LD group. The median survival duration was 387 days for the HD and 405 days for the LD group. The response rate and duration of response were higher in the HD group though this did not reach statistical significance. There was no difference in overall survival between the two patient groups. Neutropenia and gastro-intestinal symptoms were the most common toxicities, they were equal in both groups. One patient (3%) in the HD and 5 patients (9%) in LD group discontinued treatment due to toxicity. There were no treatment related deaths. It is concluded that low dose folinic acid in combination with 5FU is effective and produces similar toxicities as high dose folinic acid. It is concluded that low dose folinic acid in combination with 5FU is an effective alternative to high dose regimen in the palliative management of patients with metastatic colorectal cancer. However though it did not reach statistical significance the high dose regimen was associated with a higher response rate. This could have a significant effect when the combination is used in the adjuvant treatment of high risk patients.
Adult↗
Primary vaginal urinary calculus following abdominoperineal resection of rectum.
A rare case of primary vaginal calculus is presented. The case is unusual since it occurred after abdominoperineal resection for carcinoma rectum. The mechanism of stone formation in the patient has been discussed.
Adenocarcinoma↗
Tuberculosis of the pancreas: a clinical rarity.
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Antitubercular Agents↗
Sterol dependent LDL-receptor gene transcription in lymphocytes from normal and CML patients.
Sterol regulatory element (SRE) has been recognized to regulate various key genes coding for especially low density lipoprotein (LDL)-receptor, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and HMG-CoA synthase known to play a crucial role in the cholesterol feedback mechanism. The deranged cholesterol feedback mechanism has been widely recognised in initiation as well as progression of various types of cancers including chronic myeloid leukaemia (CML). Consequently, the present study was addressed to understand this phenomenon and revealed the existence of a unique 47 kDa protein factor having affinity for this SRE sequence in lymphocytes from normal subjects as well as its absence in lymphocytes from untreated CML patients. However, this factor appeared when the CML patients achieved complete haematological remission (CHR) through alpha-interferon therapy. Further, an inverse relationship was also observed between sterol modulated LDL-receptor gene transcription and the binding affinity of this 47 kDa factor to the SRE sequence. Based upon these results we propose that alpha-interferon through its receptor initiates phosphatidic acid dependent signalling which in turn regulates the affinity of 47 kDa sterol regulatory element binding factor as well as LDL-receptor gene transcription in lymphocytes from CML patients.
Bucladesine↗
Cytotoxicity, accumulation, and efflux of cisplatin and its metabolites in human ovarian carcinoma cells.
Cisplatin (CP) is one of the most useful antineoplastic drugs. When CP is dissolved in human plasma, different metabolites are formed. Using the OV 2008 human ovarian cancer cell line, we examined the relative cytotoxicities of CP and its metabolites (aquated CP [AP], monomethionine CP [MP], bismethionine CP [BP], and a mixture of CP metabolites in ultrafiltrated human plasma [UP]) in vitro. By clonogenic assay, cell survival (percent of mean +/- SE) of OV 2008 cells exposed for 1 hr to 6.7 microM of CP was 9.8 +/- 0.7 and for its equal platinum contents of AP, MP, BP, and UP solutions were 3.3 +/- 0.7, 9.8 +/- 0.9, 15.9 +/- 1.1, 76.8 +/- 2.1, and 13.1 +/- 0.7, respectively. AP was the most cytotoxic species, and BP was the least cytotoxic species. Cellular platinum uptake (ng/10(6) cells) after addition of 0.33, 1.6, and 2.5 mM of each species for 1 hr was measured and a strong correlation was found between cytotoxicity of each CP metabolite and its corresponding cellular platinum (Pt) uptake (r = 0.997). There was a strong correlation between cytotoxicity of the CP metabolites and their DNA binding. With fractionation of these cells into DNA, nucleoplasm and cytoplasm, the highest platinum content was found on DNA. The most important factor that seems to be responsible for the cytotoxicities of the different CP metabolites is the amount of their associated intracellular accumulation, and particularly the degree of their binding to DNA.
Carcinoma↗