Calculating drug doses. Teaching of undergraduates must be improved.
Explore the source record for details and available documents.
Education, Medical, Undergraduate↗
Biomedical subjects
A M Cohen
Publications and source records attributed to A M Cohen.
Long-term outcomes of deep-vein thrombosis.
OBJECTIVE: To assess the long-term outcomes of patients with acute deep-vein thrombosis. METHODS: We followed up 124 patients with deep-vein thrombosis 6 to 8 years after the index thrombosis to determine the frequency of death, recurrent venous thromboembolism, postphlebitic symptoms, and their relationship to three domains of health-related quality of life. RESULTS: Fifty-two (42%) of the 124 patients died. The cumulative incidence of death was 17% at 1 year and 39% at 5 years. Death was especially common among patients older than 75 years and those with cancer or stroke (5-year cumulative incidence, 66%, compared with 12% among other patients; P < .0001). Most deaths were attributable to cancer or cardiovascular disease. Venous thromboembolism recurred in 18 patients (15%); the cumulative incidence was 6% at 1 year and 13% at 5 years. Recurrence was more common, however, among patients younger than 65 years with a history of recurrent venous thromboembolism (5-year cumulative incidence, 34%, compared with 10% among other patients; P < .01). In interviews with 52 patients 6 to 8 years after the index deep-vein thrombosis, 42% reported pain, swelling, or discoloration in the leg affected by the index thrombosis. Perceptions of health, physical functioning, and role limitations attributed to physical health were worse (P < .01 for each domain) in symptomatic patients than in asymptomatic patients. CONCLUSIONS: Six to 8 years after deep-vein thrombosis, many patients had died of preexisting cancer or cardiovascular disease. Recurrent venous thromboembolism was uncommon. Symptoms in the leg affected by the index thrombosis were common, however, and were associated with worse health-related quality of life.
Adolescent↗
The antiproliferative activity of c-myb and c-myc antisense oligonucleotides in smooth muscle cells is caused by a nonantisense mechanism.
Smooth muscle cell (SMC) proliferation is thought to play a major role in vascular restenosis after angioplasty and is a serious complication of the procedure. Developing antisense (AS) oligonucleotides as therapeutics is attractive because of the potentially high specificity of binding to their targets, and several investigators have reported inhibition of SMC proliferation in vitro and in vivo by using AS strategies. We report here the results of our experiments on vascular SMCs using AS oligonucleotides directed toward c-myb and c-myc. We found that significant inhibition of SMC proliferation occurred with these specific AS sequences but that this inhibition was clearly not via a hybridization-dependent AS mechanism. Rather, inhibition was due to the presence of four contiguous guanosine residues in the oligonucleotide sequence. This was demonstrated in vitro in primary cultures of SMCs and in arteries ex vivo. The ex vivo model developed here provides a rapid and effective system in which to screen potential oligonucleotide drugs for restenosis. We have further explored the sequence requirements of this non-AS effect and determined that phosphorothioate oligonucleotides containing at least two sets of three or four consecutive guanosine residues inhibit SMC proliferation in vitro and ex vivo. These results suggest that previous AS data obtained using these and similar, contiguous guanosine-containing AS sequences be reevaluated and that there may be an additional class of nucleic acid compounds that have potential as antirestenosis therapeutics.
Animals↗
Sphincter preservation with preoperative radiation therapy and coloanal anastomosis.
PURPOSE: To determine if preoperative radiation therapy allows sphincter preservation in the treatment of rectal cancer. METHODS AND MATERIALS: Thirty patients with the diagnosis of invasive, resectable, primary adenocarcinoma of the rectum limited to the pelvis were enrolled on a Phase I/II trial of preoperative radiation therapy plus low anterior resection/coloanal anastomosis. By preoperative assessment, all patients had invasive tumors (2: T2 28:T3) involving the distal half of the rectum and required an abdominoperineal resection. The median tumor size was 4 cm (range: 1.5-6 cm) and the median distance from the anal verge was 4 cm (range: 3-7 cm). The whole pelvis received 46.8 Gy followed by a 3.60 Gy boost to the primary tumor bed. The median follow-up was 43 months (range: 6-82 months). RESULTS: Of the 29 patients who underwent resection, 3 (10%) had a complete pathologic response and 24 (83%) were able to successfully undergo a low anterior resection/colonanal anastomosis. The incidence of local failure was crude: 17% and 4-year actuarial: 23%. The 4-year actuarial survival was 75%. One patient developed a partial disruption of the anastomosis and two developed rectal stenosis. Analysis of sphincter function using a previously published scale was performed at the time of last follow-up in 22 of the 24 patients who underwent a low anterior resection/coloanal anastomosis. Function was good or excellent in 77%. The median number of bowel movements/day was two (range: 1-6). CONCLUSIONS: This technique may be an alternative to an abdominoperineal resection in selected patients. Continued follow-up is needed to determine if this approach ultimately has similar local control and survival rates as an abdominoperineal resection.
Adenocarcinoma↗
Differential expression of protein kinase C isoforms in human colorectal cancers.
Protein kinase C (PKC), a serine/threonine kinase central to signal transduction, is implicated in tumor promotion. At present, 10 PKC isoforms have been cloned but their precise tissue-specific role has yet to be defined. In order to determine if PKC is reduced in colorectal cancers (CRC) and if specific PKC isoforms are altered in different stages of human CRC progression, total RNA was extracted from human primary CRC, liver metastases, paired normal mucosa, and liver as well as CRC cell lines and examined for specific PKC isoform mRNA expression. PKC-alpha, beta II, delta, epsilon, eta(L), theta, and zeta were expressed in all tissues examined, while PKC-beta I was not detected. PKC-alpha, beta II, delta, epsilon, and zeta were decreased in most primary CRC. However, the reduction in PKC-beta II was greatest in advanced primary CRC (P < 0.05). Although PKC-gamma was detected in about 29.6% of primary CRC and liver metastases, it was absent from all corresponding normal tissue. In addition, a second band hybridizing to our PKC-gamma probe was uniquely present only in cancerous tissue and not in brain control, suggestive of alternative splicing. PKC-alpha, delta, epsilon, and zeta were present in all cell lines. PKC-beta I/II were both uniformly absent from all cell lines. Since mRNA expression for most PKC isoforms is decreased in CRC, the previously reported decreases in overall PKC activity in CRC are not solely due to a post-translational enzyme modification.(ABSTRACT TRUNCATED AT 250 WORDS)
Cloning, Molecular↗
Effect of myo-inositol supplementation on the development of renal pathological changes in the Cohen diabetic (type 2) rat.
A lower concentration of intracellular myo-inositol has been implicated in the development of diabetic nephropathy. This was based on short-term studies showing that early administration of aldose reductase inhibitors or myo-inositol supplementation reduces increased glomerular filtration rate and partly reduces increased urinary albumin excretion in streptozotocin diabetic rats. We studied the effect of long-term (4 months) administration of 1% myo-inositol supplement to the Cohen diabetic (type 2) rat on the development of nephropathy and renal Na(+)-K(+)-ATPase. This treatment reduced the increased renal Na(+)-K(+)-ATPase activity but had no effect on blood glucose levels, body weight, increased kidney weight, or creatinine clearance and did not prevent or reduce the development of renal glomerular pathology. There was no correlation between the level of Na(+)-K(+)-ATPase activity and the degree of nephropathy. It is possible that the renal pathological changes are due to metabolic and humoral factors resulting from hyperglycaemia, other than myo-inositol depletion. The fact that myo-inositol treatment had no effect on the development of renal pathological changes but was shown to have a beneficial effect on restoring impaired conduction velocity and on the disruption of structural elements in the nerve indicates that the effect of the biological changes ensuing from hyperglycaemia vary in different tissues depending on local conditions.
Animals↗
p53 nuclear overexpression may not be an independent prognostic marker in early colorectal cancer.
PURPOSE: This study was designed to determine if p53 nuclear overexpression, as detected by immunohistochemistry, is a marker of prognostic significance in early (Stage I) colorectal cancer (CRC). METHODS: Tissue sections obtained from archival blocks of 66 patients with surgically treated Stage 1 CRC were stained immunohistochemically for p53 using a monoclonal antibody (PAB 1801-Ab2). Differences in survival between p53 positive (p53+) and p53 negative (p53-) groups were compared using Kaplan-Meier survival curves and the log-rank test. RESULTS: Thirty-four patients (51.5 percent) were p53+ and 32 (48.5 percent) were p53-. There were significantly more p53+ tumors in females (23 of 34) compared with males (11 of 34) (P = 0.01). Follow-up ranged from 1 to 128.5 (mean, 44.7; median, 38.2) months. Thirteen patients (19.7 percent) developed recurrence, of whom five died of disease. Univariate analysis of clinical and pathologic variables did not reveal my statistically significant differences between p53+ and p53- tumors. Mean actuarial survival was longer (48.2 months) in the p53- group compared with the p53+ group (41.5 months). However, comparison of survival curves using the log-rank test did not show a statistically significant difference in survival (log-rank chi-squared = 0.2; P = 0.6). CONCLUSION: p53 nuclear overexpression does not appear to be an independent marker of prognostic significance in surgically treated early CRC. Females were more likely to have p53+ tumors. The biologic significance of this findings is unknown.
Biomarkers, Tumor↗
Analyses of protein kinase C isoform expression in a colorectal cancer liver metastasis model.
BACKGROUND: Protein kinase C (PKC), centrally involved in signal transduction, has been implicated in colorectal carcinogenesis. The purpose of this study was to identify specific PKC isoform alterations associated with colorectal cancer metastases to the liver in an orthotopic transplantation nude mouse model. MATERIALS AND METHODS: Solid subcutaneous tumors from colorectal cancer cell lines were established in dorsal sites of nude mice (3 mice per cell line) by subcutaneous injection of 10(7) cells (> 90% viable). Orthotopic transplantation cecal tumors, representative of each passage (S1-5) were examined for specific PKC isoform messenger ribonucleic acid (mRNA) expression. In addition, a cell line representative of passage S5 was established, characterized by light and electron microscopy, karyotype, clonogenicity, doubling time, and assayed for total PKC activity and PKC isoform mRNA expression. RESULTS: After the fifth (S5) sequential orthotopic transplantation passage of the human colorectal cancer cell line, SW620, a highly metastatic clone was obtained. Relative to parental cells, metastatic SW620-S5 cells were less differentiated and demonstrated many more chromosomal abnormalities and lower clonogenicity. Total PKC activity was elevated in metastatic cells. In addition, specific PKC isoform mRNA alterations were noted: PKC-n (L) was abundantly expressed in the metastatic clone but absent from the parental cell line; PKC-alpha, delta and theta expression increased with serial orthotopic transplantation passages; PKC-delta remained unchanged, while PKC-beta was absent. CONCLUSIONS: Metastases-specific PKC isoform alterations may serve as novel markers of metastases and treatment targets via specific PKC isoform modulation.
Animals↗
Convective warming after hypothermic cardiopulmonary bypass.
Explore the source record for details and available documents.
Cardiopulmonary Bypass↗
Interferon-alpha for induction and maintenance in multiple myeloma: results of two multicenter randomized trials and summary of other studies.
BACKGROUND: Interferon (IFN) treatment trials in multiple myeloma have yielded discordant results regarding response rates, maintenance duration, and survival times. Further randomized trials and global evaluations of available data are urgently needed for clarification. PATIENTS AND METHODS: 256 patients participated in a randomized trial, 125 on IFN + VMCP, and 131 on VMCP alone. 100 patients were randomized to IFN maintenance (n = 46) or were untreated controls (n = 54). Global evaluations are based on 1,518 patients in induction and 924 in maintenance trials. RESULTS: The induction trial demonstrated a significantly (p < 0.05) lower rate of progressive disease under IFN + VMCP (10.6%) than under VMCP (22.9%), but this benefit was limited to stage I or II patients. Median progression-free survival was longer in the IFN + VMCP arm (23.2 months vs. 15.8 months); median overall survival did not differ significantly (38.9 vs. 30.2 months). The IFN maintenance treatment trial showed significantly superior results in the IFN arm versus controls (median maintenance duration: 17.8 months and 8.2 months (p < 0.01), survival: 50.6 and 34.4 months (p < 0.05), respectively). Previous IFN treatment increased the benefits of IFN maintenance therapy. Adverse effects of IFN during induction were hematologic toxicity, fever, and infections, requiring dose reductions. Toxic effects of IFN maintenance treatment were mild. Global evaluations of randomized trials showed small but significant benefits of combined IFN induction therapy and significantly prolonged maintenance duration and survival under IFN maintenance. CONCLUSIONS: Presently available data support the use of IFN maintenance treatment because it significantly prolongs maintenance duration and survival. IFN added to induction chemotherapy resulted in minor improvements at the expense of increased toxicity, highlighting the need for better induction regimens.
Adult↗
Efficacy of postoperative 5-FU, high-dose leucovorin, and sequential radiation therapy for clinically resectable rectal cancer.
We report the local control and survival in a previously reported phase I dose escalation trial of combined postoperative 5-FU, high dose leucovorin (LV), and sequential radiation therapy followed by maintenance LV/5-FU for the treatment of patients with clinically resectable rectal cancer. Following surgery for stages T3-4N0-2M0 primary (21) or recurrent (4) rectal cancer, 25 patients received 5-FU/LV x 1 cycle. Radiation therapy (5040 cGy) began on day 8. A second cycle of 5-FU/LV was given concurrent with the fourth week of radiation. Patients received an additional 10 cycles of LV/5-FU. The median follow-up was 40 months (range 18-52). The incidence of grade 3+ acute toxicity in the 9 patients who received the recommended dose of 5-FU was 44%. The local failure rate was 28%. Abdominal and distant failure rates were 24%. The 3-year actuarial disease-free survival was 74% and the overall survival was 80%. Our preliminary data reveal reasonable local control and survival rates. However, further follow-up is needed to assess our results at 5 years. Postoperative combined modality therapy with high-dose LV may be an option for the adjuvant treatment of patients with resectable rectal cancer.
Adenocarcinoma↗
Report of the Eighth International Symposium of the Foundation for Promotion of Cancer Research: basic and clinical research in colorectal cancer.
Explore the source record for details and available documents.
Chemotherapy, Adjuvant↗
Interferon-alpha-2b with VMCP for induction in multiple myeloma: the Israel Myeloma Cooperative Group experience.
In 1988, a prospective, randomized multicenter study was initiated to determine the efficacy of a combined induction regimen with recombinant interferon-alpha-2b (IFN-alpha) and maintenance with IFN-alpha on the response and survival rates in multiple myeloma (MM) patients. Induction therapy consisted of VMCP (vincristine, melphalan, cyclophosphamide, prednisone), randomized to combine IFN-alpha at a dose of 2 x 10(6) U, 5 days per week throughout the induction period of 12 months. Patients who achieved plateau phase were subsequently randomized again between IFN alpha maintenance (2 x 10(6) U, 3 days a week) for 12 months and no maintenance therapy. Of the previously untreated patients, 84 were initially randomized for induction therapy, and 31 for the maintenance phase with IFN-alpha. Results of the cohort median survival, based on the intention to treat, have shown that those on the VMCP/IFN-alpha arm had a median survival of 53 months, compared with patients on the VMCP induction arm who a median survival of 26 months (P = 0.052). The median survival of stage 3 evaluable patients who were on the VMCP/IFN induction arm was 43 months, and 13 months for patients treated by VMCP alone (P = 0.008). No significant difference in survival was detected among patients in partial remission (after induction) who had a second IFN-alpha randomization at the plateau phase. Hematologic toxicity, mild to moderate fever, and fatigue were more common in the VMCP/IFN induction arm. The results show that VMCP/IFN is a well-tolerated treatment regimen, and is superior to VMCP for patients with stage 3 myeloma.
Adult↗
Keratinocyte growth factor causes proliferation of urothelium in vivo.
PURPOSE: To determine the effect of keratinocyte growth factor (KGF), a mesenchymally derived epithelial growth factor that can cause proliferation of pulmonary, gastrointestinal and mammary epithelia, on urothelium. MATERIALS AND METHODS: Recombinant human KGF was systemically administered to rats and Rhesus monkeys, and the proliferative effects on the bladder were evaluated. RESULTS: Keratinocyte growth factor causes proliferation of transitional epithelial cells. Proliferating cell nuclear antigen (PCNA) expression in rat bladder is dramatically increased along the basal layer of urothelium 1, 3, 7 and 14 days after daily injections of KGF. Incorporation of 5-bromodeoxyuridine (BrdU) at 7 and 14 days in the urothelium of KGF-treated rats parallels PCNA immunoreactivity and confirms that KGF increases DNA synthesis in urothelial cells. Urothelial cell proliferation is accompanied histologically by an increase in mitotic activity. Keratinocyte growth factor-induced PCNA expression is reversible upon cessation of KGF administration. Keratinocyte growth factor mRNA and receptor mRNA are detected by whole organ RNAase protection assays of the urinary bladder and the kidney of normal rats. Rhesus monkeys receiving KGF for 7 days demonstrate a dramatic incorporation of BrdU in the urothelium of the bladder and renal pelvis as well as in the collecting ducts of the kidney. CONCLUSION: Systemic administration of KGF causes rapid and striking proliferation of urothelium.
Animals↗
A phase I trial of immediate postoperative intraperitoneal floxuridine and leucovorin plus systemic 5-fluorouracil and levamisole after resection of high risk colon cancer.
BACKGROUND: The purpose of this study was to evaluate the toxicity of immediate postoperative intraperitoneal (IP) floxuridine (FUdR) and leucovorin (LV) after resection of high risk colon cancer, and to determine the appropriate dose of intravenous fluorouracil (FU) plus levamisole during concurrent intraperitoneal therapy. METHODS: The authors conducted a tertiary referral Comprehensive Cancer Center Phase I Trial in patients with resected colon cancer at high risk for recurrence. After resection of all gross disease, intraperitoneal treatment was administered twice daily for 3 days every 2 weeks for three cycles (Days 1-3, 15-17, 29-31). Intravenous FU daily for 5 days was administered on days 29-33 concurrently with the third cycle of intraperitoneal therapy. Fluorouracil doses during the last cycle of intraperitoneal therapy were escalated; intraperitoneal FUdR and LV doses and weekly intravenous FU doses (starting on Day 58) were fixed. RESULTS: Twenty-six patients with resected high risk colon cancer were treated. Three had Dukes' B2, 16 Dukes' C, and 7 Dukes' D (M1) resected tumors. Intraperitoneal therapy was well tolerated with no increase in operative morbidity and no operative mortality. Two patients had > or = Grade 3+ toxicity during IP therapy alone. There were no treatment related deaths. During concurrent intraperitoneal and intravenous chemotherapy, the maximum tolerated dose of FU was 300 mg/m2/day for 5 days. The recommended dose for Phase II or III trials is 200 mg/m2/day for 5 consecutive days. Pharmacokinetic analysis indicated that using the doses used in this trial, measurable systemic concentrations of FUdR and LV were obtained during IP therapy. This may have contributed to observed toxicity with intravenous FU doses of 300-400 mg/m2. With a median duration of follow-up of 18 months, four patients had recurrence of disease. No peritoneal recurrences have been noted to date. CONCLUSIONS: Immediate postoperative IP FUdR and LV are well tolerated after resection of high risk colon cancer. The recommended dose of intravenous FU beginning on Day 29 (concurrent with the last dose of IP therapy) is 5FU 200 mg/m2 for 5 consecutive days. The remaining year of adjuvant fluorouracil and levamisole can be administered with standard dose attenuation. Although follow-up is short, the lack of recurrent peritoneal metastases is encouraging. Additional trials with this approach are warranted in patients with high risk colorectal cancer.
Adult↗
Anorectal disease in neutropenic leukemic patients. Operative vs. nonoperative management.
PURPOSE: This study was designed to evaluate the spectrum, clinical presentation, management, and outcome of anorectal disease in neutropenic leukemic patients and to compare operative and nonoperative management in neutropenic leukemic patients. METHODS: A retrospective review of hospital records was performed. RESULTS: One hundred fifty-one of 2,618 (5.8 percent) patients hospitalized with leukemia had concomitant symptomatic anorectal disease. Data from 81 patients were available for analysis. Fifty-two (64 percent) were treated nonoperatively and 29 (36 percent) underwent operative treatment. Fifty-seven (70.4 percent) had absolute neutrophil counts < 1,000/mm3, and 54 (66.7 percent) were severely neutropenic (absolute neutrophil count < 500/mm3). Management and outcomes of 54 severely neutropenic patients were analyzed. In 20 patients who underwent surgery there were 4 deaths (20 percent) and 4 recurrences (20 percent), whereas in 34 patients managed nonoperatively there were 6 deaths (18 percent) and 4 recurrences (12 percent) (P > 0.05). CONCLUSIONS: Symptomatic anorectal disease afflicted 5.8 percent of hospitalized leukemic patients. In these patients, anorectal sepsis was a major source of mortality. Our data suggest that anorectal abscesses in neutropenic leukemic patients may be safely drained. Because we did not observe excessive morbidity or mortality (20 percent vs. 18 percent) in the operated neutropenic leukemics as compared with the nonoperated patients, selected neutropenic leukemic patients should not be denied anorectal surgery when otherwise indicated.
Adolescent↗
High level of Nm23-H1 gene expression is associated with local colorectal cancer progression not with metastases.
This study aimed to determine the expression of Nm23-H1 in colorectal cancer and liver metastases and to correlate Nm23-H1 expression with clinicopathological variables. Specimens from 59 primary colorectal cancers and five liver metastases were studied using Northern blot hybridisation. The mean +/- s.e. of tumour/normal (T/N) ratio of Nm23-H1 RNA expression was 4.3 +/- 0.4 (P < 0.001) and 5.1 +/- 0.90 (P < 0.01) for colorectal cancer and liver metastases respectively. No significant relationship was observed between the level of Nm23-H1 RNA and the patient's age, sex, tumour location, differentiation, presence of lymph node involvement or distant metastases. Nm23-H1 RNA level was 2.6 +/- 0.5 for tumour size less than 3.0 cm and 4.6 +/- 0.5 for those > or = 3.0 cm (P = 0.05). There appeared to be a trend between increasing relative Nm23-H1 RNA and bowel wall invasion, irrespective of metastatic status (T1 = 1.9 +/- 0.3, T2 = 4.1 +/- 0.6, T3 = 4.1 +/- 0.5 and T4 = 6.4 +/- 1.6). This difference was statistically significant when T1 was compared against > or = T2 lesions (P = 0.01). Western blot analysis reveals two Nm23H-1 bands (17.0 kDa and 18.5 kDa). In 16 colorectal patients, the T/N fold-increase in protein expression was 2.66 +/- 0.46 (P < 0.001) and 2.40 +/- 0.32 (P < 0.001) for the 17.0 and 18.5 kDa band respectively. Both Nm23-H1 RNA and protein levels in primary colorectal cancers do not appear to correlate with synchronous regional or distant metastases. Since Nm23-H1 RNA expression is associated with increasing tumour size and tumour local invasion, Nm23-H1 RNA expression may be associated with local disease progression.
Adult↗
Obstetric anaesthetic management in a patient with the Fontan circulation.
We describe the pregnancy and obstetric anaesthetic management of a patient with congenital tricuspid atresia who had undergone the Fontan procedure in childhood. The unique arrangement of the Fontan circulation combined with the haemodynamic alterations during pregnancy presents special anaesthetic considerations for both analgesia during labour and anaesthesia for Caesarean section.
Adult↗