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Biomedical subjects

W J John

Publications and source records attributed to W J John.

17 recordsLinked to original sources
PubMed2000

Preoperative chemoradiation in fixed distal rectal cancer: dose time factors for pathological complete response.

PURPOSE: Preoperative chemoradiation is being utilized extensively in the treatment of rectal cancer. However, a variety of dose time factors in both delivery of chemotherapy and irradiation remain to be established. This study was undertaken to examine the impact of dose time factors on pathological complete response (pCR) rates following preoperative chemoradiation for fixed rectal cancer. METHODS AND MATERIALS: Thirty-three patients with fixed rectal cancers were treated with combined 5-fluorouracil (5-FU) chemotherapy and pelvic radiation. Twenty-one patients received bolus 5-FU during the first 3-5 days of radiation and repeated on days 28-33 of their radiation treatment. Twelve patients were treated with continuous infusion (CI) 5-FU, 225 mg/m(2) for the duration of the pelvic radiation. Fifteen patients received a planned total radiation dose of 45 to 50 Gy and 18 patients received a dose of 55 to 60 Gy. Surgical resection was then carried out 6-8 weeks after completion of treatment. RESULTS: Diarrhea was the most frequent acute toxicity. Grade 3 diarrhea was observed in 6 patients requiring treatment interruption and was not related to the chemotherapy regimen. There was no Grade 4 or 5 toxicity. pCR was observed in 2 of 21 (10%) patients treated with bolus 5-FU as compared to 8 of 12 (67%) for patients treated with CI (p = 0.002). pCR were observed in 8 of 18 (44%) patients receiving radiation dose > or = 5500 cGy as compared to 2 of 15 (13%) patients treated to a dose < or = 5000 cGy (p = 0.05). In the high-dose radiation (> or = 5500 cGy) group, a significant difference in pCR rate was observed in patients treated with CI, 8 of 12 (67%) (p = 0.017) as compared with bolus 5-FU (0 of 6). There was no significant difference in operative morbidity or in wound healing between patients treated with bolus 5-FU or CI or within the groups treated with low or high doses of radiation. Three patients have developed local recurrence at 14 and 24 months, two in the low-dose group treated with bolus 5-FU and one patient in the CVI group. The overall 5-year survival for the whole group is 71%. CONCLUSION: Dose intensity of 5-FU and dose of radiation correlate significantly with the likelihood of achieving a pCR. Continuous infusion 5-FU (CI) and a preoperative radiation dose of 5500 cGy or higher can achieve pCR rates of approximately 50%, even in fixed cancers of the rectum.

Adult↗
PubMed2000

The feasibility of dose escalation using concurrent radiation and 5-fluorouracil therapy following pancreaticoduodenectomy for pancreatic carcinoma.

We evaluated the feasibility of dose escalation using external beam radiation therapy (RT) and 5-fluorouracil (5-FU) following pancreaticoduodenectomy for pancreatic carcinoma. Fourteen patients who underwent pancreaticoduodenectomy for stage I-III adenocarcinoma of the pancreas received postoperative high-dose chemoradiation. RT was given at 1.8-Gy daily fractions to total doses of 54 Gy for patients with negative surgical margins (n = 12), and 64.8 Gy for those with gross residual disease (n = 2). Concurrent 5-FU was given as a continuous infusion (CI) at 225 mg/m2 per day (n = 9) beginning or day 1 and continuing until the completion of RT, or by bolus injection at 500 mg/m2 per day (n = 5) during weeks 1 and 4 of RT. Follow-up ranged from 32 to 36 months (median, 35 months). All patients were able to complete the planned high-dose postoperative chemoradiation and none required a treatment break. No grade 4 acute toxicity was observed. Grade 3 acute toxicity was limited to 2 patients. Two patients developed grade 3 (n = 1) or 4 (n = 1) subacute toxicity, all gastrointestinal-related. There have been no fatal toxicities and no grade 3 or 4 late toxicity has been observed. The 3-year survival is 21%. Dose escalation of postoperative 5-FU chemoradiation following pancreaticoduodenectomy for pancreatic carcinoma is well tolerated. Further dose-intensification of postoperative adjuvant therapy in these patients appears feasible and is being evaluated in a recently activated national trial.

Adenocarcinoma↗
PubMed1999

Clinical and immune responses in resected colon cancer patients treated with anti-idiotype monoclonal antibody vaccine that mimics the carcinoembryonic antigen.

PURPOSE: We generated an anti-idiotype antibody, designated CeaVac, that is an internal image of the carcinoembryonic antigen (CEA). We previously demonstrated that the majority of patients with advanced colorectal cancer generate specific anti-CEA responses. The purpose of the current study was to treat patients with surgically resected colon cancer with CeaVac to determine the immune response and clinical outcome to treatment with vaccine. We also compared the immune responses between patients treated with fluorouracil (5-FU) chemotherapy regimens plus vaccine versus vaccine alone. PATIENTS AND METHODS: Thirty-two patients with resected Dukes' B, C, and D, and incompletely resected Dukes' D disease were treated with 2 mg of CeaVac every other week for four injections and then monthly until tumor recurrence or progression. Fourteen patients were treated concurrently with 5-FU chemotherapy regimens. RESULTS: All 32 patients entered onto this trial generated high-titer immunoglobulin G and T-cell proliferative immune responses against CEA. The 5-FU regimens did not have a qualitative or quantitative effect on the immune response. Three of 15 patients with Dukes' B and C disease progressed at 19, 24, and 35 months. Seven of eight patients with completely resected Dukes' D disease remained on study from 12 to 33 months; one patient with resected Dukes' D disease relapsed at 9 months. One patient with incompletely resected Dukes' D disease remained on study at 14 months without evidence of progression; eight experienced disease progression at 6 to 31 months. CONCLUSION: CeaVac consistently generated a potent anti-CEA humoral and cellular immune response in all 32 patients entered onto this trial. A number of very high-risk patients continue on study. 5-FU regimens, which are the standard of care for patients with Dukes' C disease, did not affect the immune response. These data warrant a phase III trial for patients with resected colon cancer.

Adjuvants, Immunologic↗
PubMed1998

Adjuvant therapy for pancreatic cancer: current status.

Only 5% to 15% of patients with pancreatic adenocarcinoma are candidates for a potentially curative resection. Evidence that postoperative adjuvant therapy improves outcome has been limited to a single randomized trial of a well tolerated split-course, 5-Fluorouracil (5-FU) based, chemoradiation regimen. More aggressive regimens have since been developed and are associated with, at best, a modest improvement in patient outcome. The potentially significant morbidity associated with pancreaticoduodenectomy, which can compromise the delivery of postoperative adjuvant chemoradiation, has led to the development of preoperative (adjuvant/neoadjuvant chemoradiation) regimens in these patients. Although experience suggests that such an approach is feasible, the ultimate impact warrants further evaluation. In addition, despite evolving experiences towards more dose intensive pre or postoperative adjuvant chemoradiation regimens, the problem of distant metastases remains significant. New chemotherapeutic agents, such as gemcitabine, appear to have the potential to produce better results than those achieved over the last quarter century with 5-FU. A cooperative group study has recently been activated and is evaluating its impact in an adjuvant setting when given in addition to 5-FU based chemoradiation. In the meantime, ongoing investigations into optimal integration of different therapeutic modalities, along with advances in surgery, radiation, and systemic therapy, should lead us towards further improvements in outcomes for these patients.

Adenocarcinoma↗
PubMed1998

Evolving trends in combined modality therapy for pancreatic cancer.

Only 5%-15% of patients with pancreatic adenocarcinoma undergo potentially curative resection. Evidence that postoperative adjuvant therapy improves outcome is limited to a single randomized trial utilizing split-course chemoradiation. More aggressive regimens have developed and are associated with, at best, a modest improvement in patient outcome. The potentially significant morbidity associated with pancreaticoduodenectomy, which can compromise the delivery of postoperative chemoradiation, has led to the investigations of preoperative regimens. Although such an approach is feasible, its ultimate impact warrants further evaluation. Among the 4% of patients who present with unresectable or locally advanced disease, combined modality therapy has produced the most promising results. However, only modest improvements in survival have so far been achieved. Combined modality therapy with radioisotope implantation appears to have the greatest potential for improving local control and survival in these patients. Intraoperative radiation therapy (IORT) may be associated with lower morbidity than radioisotope implantation, but its impact may be limited by radiobiological disadvantage associated with single-dose boost therapy. The problem of distant metastasis remains significant. New chemotherapeutic agents have the potential to produce better results than those achieved with 5-fluorouracil. Continued advances in surgery, radiation, and systemic therapy should lead to the increased use of modern combined modality interventions with an associated further improvement in patient outcome.

Adenocarcinoma↗
PubMed1998

Continuous venous infusion 5-fluorouracil and interferon-alpha in pancreatic carcinoma.

Chemotherapy treatment for advanced pancreatic cancer is universally disappointing. Evidence suggested the possibility of improved activity of 5-fluorouracil (5-FU) in this disease when administered by continuous infusion in combination with interferon-alpha. Thirteen patients who had histologically documented stage III and IV adenocarcinoma of the pancreas were treated with 5-FU, 250 mg/m2/day by continuous infusion, in combination with interferon-alpha, 3 million units subcutaneously 3 times per week. Treatment was adjusted for toxicity and was continued until disease progression, unacceptable toxicity, or 8 weeks after a complete response. Responses were documented on two separate occasions that were separated by 4 weeks. Eleven men and two women were treated an average of 48 days. There was one responder, for a response rate of 7.7% (95% confidence interval, 0.1%-36%). The duration of response was 90 days. The median survival of the entire group was 8.3 months. Toxicity was significant, with more than 50% of patients requiring treatment breaks and dosage reductions. The most common toxicities were mucositis, hand-foot syndrome, diarrhea, and nausea. There were no treatment-related deaths. Treatment of advanced adenocarcinoma of the pancreas with continuous-infusion 5-FU and interferon-alpha is associated with significant toxicity without significant evidence of response.

Adenocarcinoma↗
PubMed1997

Current and emerging treatments for pancreatic cancer.

The worldwide annual pancreatic cancer death rate equals its estimated annual incidence. Surgery has been considered the only curative modality for this disease, but only 5 to 15% of patients are candidates for potentially curative resection. Evidence that postoperative adjuvant treatment improves outcome has been limited to a single randomised trial of a well tolerated split-course chemoradiation regimen. More intensive regimens have since been developed and are associated with, at best, a modest improvement in patient outcome. The potentially significant morbidity associated with pancreaticoduodenectomy, which can compromise the delivery of postoperative adjuvant chemoradiation, has led to the development of preoperative adjuvant ('neoadjuvant') chemoradiation in these patients. Although experience suggests that such an approach is feasible, its ultimate impact awaits further evaluation. Combined modality therapy has produced the most promising results in patients with unresectable or locally advanced disease. However, only modest improvements in median survival and minimal increases in long term survival have so far been achieved. This observation has encouraged many investigators to devise innovative methods of delivering therapy, including radioisotope implantation and intraoperative radiation therapy (IORT). Combined modality therapy with radioisotope implantation appears to have the greatest potential for improving local control and survival in these patients. IORT may be associated with lower morbidity than radioisotope implantation, but its impact may be limited by the radiobiological disadvantage associated with single dose boost therapy. Although new radiosensitising drugs are being tested, the problem of distant metastasis remains significant. New chemotherapeutic agents such as gemcitabine appear to have the potential to produce better results than those achieved over the last 35 years with fluorouracil. Investigations into the optimal integration of different therapeutic modalities, along with continued advances in surgery, radiation and systemic therapy, should lead to the increased use of modern multimodality interventions. In turn, this will lead us towards further improvements in outcomes for patients with pancreatic carcinoma.

Antimetabolites, Antineoplastic↗
PubMed1997

Clinical and immune responses in advanced colorectal cancer patients treated with anti-idiotype monoclonal antibody vaccine that mimics the carcinoembryonic antigen.

Carcinoembryonic antigen (CEA) is expressed in a wide variety of adenocarcinomas, and it is well recognized that cancer patients are immunologically "tolerant" to CEA. The purpose of this study was to determine whether we could break immune tolerance to CEA by vaccinating patients with a monoclonal anti-idiotype antibody that is the internal image of CEA and to determine what impact this might have on patient survival. Twenty-four patients with advanced CEA-positive colorectal cancer who failed standard therapies except for two were entered into this Phase Ib trial. One patient was considered not assessable, because on the day of entering into the study, she was diagnosed with acute myelogenous leukemia. Patients were treated with 1, 2, or 4 mg of aluminum hydroxide-precipitated 3H1 anti-idiotype antibody every other week for four injections and then monthly until tumor progression was observed. Immunological monitoring included humoral and cellular idiotypic and CEA responses, and all patients were evaluated for toxicity, response, and survival. Hyperimmune sera from 17 of 23 patients demonstrated an anti-anti-idiotypic Ab3 response, and 13 of these responses were demonstrated to be true anti-CEA responses (Ab1'). The antibody response was polyclonal, and 11 mediated antibody-dependent cellular cytotoxicity. Ten patients had idiotypic T-cell responses, and five had specific T-cell responses to CEA. None of the patients had objective clinical responses, but overall median survival for the 23 evaluable patients was 11.3 months, with 44% 1-year survival (95% confidence interval, 23-64%). Toxicity was limited to local swelling and minimal pain. Anti-idiotype monoclonal antibody 3H1 that mimics CEA was able to break immune tolerance in the majority of treated patients. Overall survival of 11.3 months was comparable to other phase II data with advanced colorectal cancer patients treated with a variety of chemotherapy agents, including irinotecan, with considerably less toxicity. Although it is not clear that the vaccine itself had an impact on survival, this should be determined in a Phase III randomized trial.

Adult↗
PubMed1995

A phase I trial of 5-day continuous infusion cisplatin and interferon alpha.

Combination therapy of cisplatin with interferon alpha (IFN) has been shown in several in vitro as well as in vivo models to be synergistic. In order to decrease toxicity seen with cisplatin, 5-day continuous infusions, in place of bolus administration, have been introduced. This led us to investigate the combination of 5-day continuous infusion cisplatin with repeated IFN dosing in a phase I cisplatin dose escalation study. A group of 17 patients were enrolled in this trial. The maximum tolerated dose (MTD) of cisplatin was 20 mg/m2 per day when combined with 3 x 10(6) units IFN given three times a week. The dose-limiting toxicities seen included thrombocytopenia, leukopenia, and nausea and vomiting. Pharmacokinetic analyses of free (unbound or ultrafilterable) platinum revealed that the decay curve fitted a monoexponential model. Pharmacokinetic parameters of cisplatin were found to correlate with toxicity. Both increases in the maximum concentration of cisplatin achieved (Cpmax) as well as the area-under-the-curve (AUC) for free platinum, correlated with the incidence of nausea and vomiting (both acute and delayed) and hematological toxicities (leukopenia and thrombocytopenia). None of the patients exhibited significant changes in renal function while on this study. The free platinum levels were higher than found in similar studies evaluating comparable cisplatin infusions alone. The enhanced toxicities seen in this trial may be explained by the results of an in vitro study using human plasma spiked with cisplatin and IFN that revealed decreased protein binding of cisplatin by 2.5-3.0-fold. Of the 17 patients treated, two non-small cell lung cancer patients obtained a partial response and one malignant melanoma patient obtained complete resolution of a malignant pleural effusion. Considering the acceptable toxicity seen in this trial, we recommend phase II trials be conducted with continuous infusion cisplatin with IFN in the treatment of non-small cell lung cancer.

Adult↗
PubMed1995

Combination therapy with 5-fluorouracil and L-canavanine: in vitro and in vivo studies.

L-Canavanine (CAV) is a potent L-arginine antagonist, produced by legumes such as the jack bean, Canavalia ensiformis. CAV is cytotoxic to MIA PaCa-2 human pancreatic cancer cells. We sought to determine whether CAV's efficacy as an anticancer agent might be increased in combination with 5-fluorouracil (5-FU), a pyrimidine antimetabolite with activity against solid tumors. Using optimal conditions for the expression of CAV's cytotoxicity against MIA PaCa-2 cells, CAV was more cytotoxic to the cells than 5-FU. The combination of both drugs at a fixed molar ratio of 1:1 exhibited synergistic effects in the cells as determined by combination index analysis. The combination of 5-FU:CAV was tested at a ratio of 5:1 and exhibited antagonism at lower effect levels, additivity at 50% effect levels and slight synergism at higher effect levels. A 10:1 combination of both drugs (5-FU:CAV) exhibited antagonistic effects at all levels. When the drugs were combined at a molar ratio of 20:1, increased antagonism was observed. When CAV (1.0 or 2.0 g/kg daily) and/or 5-FU (35 mg/kg daily) was administered to colonic tumor-bearing rats for five consecutive days, the antitumor activity of the drug combination was significantly greater than the combined effects of either drug alone. However, the body weight loss experienced by CAV-treated rats was increased in those rats exposed to a combination of both drugs. These studies using different tumors provide in vitro and in vivo evidence that combination therapy offers a viable means of improving CAV's intrinsic efficacy while decreasing the concentration of 5-FU required to produce the same cytotoxic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Immune response to the carcinoembryonic antigen in patients treated with an anti-idiotype antibody vaccine.

We have generated an IgG1 murine monoclonal anti-idiotype antibody (Ab2) designated 3H1, which mimics a specific epitope on the carcinoembryonic antigen (CEA). Patients with CEA positive tumors are immunologically "tolerant" to CEA. We used 3H1 as a surrogate for CEA for vaccine therapy of 12 patients with advanced colorectal cancer. Each of the patients received a minimum of four intracutaneous injections of aluminum hydroxide precipitated 3H1 at either 1, 2, or 4 mg dosage per injection. 9 of 12 patients demonstrated anti-anti-idiotypic (Ab3) response to 3H1. All nine patients generated specific anti-CEA antibody demonstrated by reactivity with radiolabeled purified CEA; some cases were confirmed by immunoprecipitation of purified CEA. We also demonstrated Ab3 stained both autologous and allogeneic colonic tumors. 7 of 12 patients demonstrated idiotype specific T cell proliferative responses and four also showed T cell proliferation to CEA. Toxicity was limited to local reaction with mild fever and chills. All 12 patients eventually progressed after finishing 4-13 dosages. This is the first report demonstrating that a vaccine therapy is capable of breaking "immune tolerance" to CEA in patients with CEA positive tumors. Future studies will focus on treating patients with minimal residual disease.

Adult↗
PubMed1993

5-fluorouracil and interferon-alpha-2a in advanced colorectal cancer. Results of two treatment schedules.

BACKGROUND: Potential synergy between 5-fluorouracil (5-FU) and interferon alpha-2a (IFN-alpha-2a) has been demonstrated in the treatment of colorectal carcinoma. Continuous low-dose infusion of 5-FU may have superior response rates to bolus 5-FU in these malignancies. This report presents results of two Phase II trials using these principles in colorectal cancer. METHODS: Forty-eight patients were entered onto two protocols; 18 were treated with 5-FU by a bolus infusion schedule with concurrent IFN-alpha-2a (Group 1). Thirty patients were treated with continuous low-dose 5-FU and IFN-alpha-2a thrice weekly (Group 2). RESULTS: The overall response rates were 33% (95% confidence interval [CI], 16-68%) and 33% (95% CI, 17-53%), respectively, for Groups 1 and 2. In Group 2, in 16 previously untreated patients, there was a response rate of 56% (95% CI, 30-80%). The median survival was 11 months and 6 months for Groups 1 and 2, respectively. Toxicity in Group 1 was as expected, except the incidence of central nervous system toxicity was low, with only one patient requiring dose reduction because of cerebellar ataxia. The toxicity in Group 2 was substantial, with four patients being removed from study because of toxicity and all patients treated for more than 2 months requiring dose reductions. The most common (67%) toxicity was mucositis, with 33% of those patients classified as Grade III or IV (Southwest Oncology Group criteria). Other major toxicities were fatigue and hand/foot syndrome. CONCLUSIONS: The first trial confirms previous response rate data for bolus injection 5-FU and IFN-alpha-2a. The second trial of low-dose continuous infusion 5-FU with IFN-alpha-2a demonstrates similar efficacy with substantially greater toxicity.

Adenocarcinoma↗
PubMed1992

Fleroxacin pharmacokinetics in patients with liver cirrhosis.

In this open-label study, the disposition of fleroxacin in liver disease in 12 healthy male volunteers, 6 male cirrhotics without ascites (group A), and 6 male cirrhotics with ascites (group B) was evaluated. Fleroxacin (400 mg) was administered orally and intravenously to each subject in a random crossover fashion. Fleroxacin was completely absorbed and achieved similar peak concentrations in plasma in all three study groups (P greater than 0.05). The volume of distribution exceeded 1 liter/kg in healthy controls and was not affected by liver impairment (P greater than 0.05). Only group B demonstrated differences in the pharmacokinetic parameters evaluated: the systemic and renal clearances of fleroxacin and the renal clearances and clearances of the two major metabolites of fleroxacin formed, N-demethyl fleroxacin and fleroxacin N-oxide, were significantly lower and the half-lives of the parent drug and its metabolites were significantly longer in group B than in healthy controls and group A (P less than 0.05). The elimination of the two metabolites appeared to be formation rate limited in all three study groups. It was concluded from this study that a 50% reduction in the fleroxacin maintenance dose in patients with liver disease appears justified only in patients with ascites. However, no change in the fleroxacin loading dose is needed in patients with compromised liver function.

Administration, Oral↗
PubMed1990

Right ventricular thrombosis after peritoneovenous shunt: nonoperative treatment with successful outcome.

Complications of peritoneovenous shunt for intractable ascites include a high propensity to malfunction, facilitation of infection, and the induction of coagulopathies. Right heart thrombosis is a rarely encountered adverse effect, the management of which has not yet been defined. We report a patient with an extensive right heart thrombus in the setting of a blocked peritoneovenous shunt that was discovered incidentally and treated expectantly with subsequent complete resolution and satisfactory outcome.

Adult↗
PubMed1980

The in vivo glucocorticoid and antiglucocorticoid actions of medroxyprogesterone acetate.

The in vivo glucocorticoid actions of medroxyprogesterone acetate [6 alpha-methyl-17-acetoxy-pregn-4-ene-3,20-dione (MPA)] were assessed in intact prepubertal female Wistar rats using five simultaneous assays: plasma glucose, plasma corticosterone, hepatic glycogen content, hepatic tyrosine aminotransferase activity, and croton oil-induced ear inflammation. Antiglucocorticoid acitivity was measured through interference by MPA with the glucocorticoid effect of a standard 5-microgram dose of dexamethasone in these same assays. The glucocorticoid activity of MPA was evident from suppression of corticosterone and ear inflammation and stimulation of tyrosine aminotransferase activity. The antiglucocorticoid activity of MPA was detected through inhibition of basal and dexamethasone-stimulated hepatic glycogen and partial reversal of the suppression of ear inflammation by dexamethasone. The progestational steroid MPA was thus found to have assay-specific glucocorticoid and antiglucocorticoid actions and may have a potential use in the treatment of some states of glucocorticoid excess.

Animals↗
PubMedDate not supplied

Resting energy expenditure in patients with alcoholic hepatitis.

Patients with alcoholic hepatitis are typically malnourished. A hypermetabolic state would explain, at least in part, the muscle wasting observed in these patients. However, data on hypermetabolism in liver disease are limited and conflicting. In this study, we evaluated measured energy expenditure (MEE) vs predicted energy expenditure (PEE), and MEE in relation to urinary creatinine excretion in 20 patients with moderate and severe alcoholic hepatitis, and 20 controls. Patients with alcoholic hepatitis had depressed creatinine height index (moderate 66%, severe 78%) demonstrating muscle depletion. Patients with alcoholic hepatitis also had depressed mean serum albumin concentrations, the moderate group 2.6 g/dl and the severe group 2.0 g/dl. The mean values for measured energy expenditure in moderate alcoholic hepatitis patients, severe alcoholic hepatitis patients, and the control group were: 1556 kcal, 1878 kcal, and 1943 kcal, respectively. The mean measured energy expenditures per g of creatinine for the same groups were: 1520 kcal, 1813 kcal, and 1043 kcal, respectively. The mean measured energy expenditure/predicted energy expenditure ratio was not increased in alcoholic hepatitis patients compared to controls. However, when related to urinary creatinine excretion, the alcoholic hepatitis patients had a mean measured energy expenditure that was 55% higher than controls. In conclusion, whereas the measured energy expenditure to predicted energy expenditure ratio was not elevated in alcoholic hepatitis patients compared to controls, the measured energy expenditure per gram of creatinine was significantly increased in alcoholic hepatitis patients, supporting the concept of alcoholic hepatitis as a hypermetabolic state.

Creatinine↗