Effect of cardiopulmonary bypass on tissue injury markers and endothelial activation during coronary artery bypass graft surgery.

BACKGROUND: Coronary artery bypass grafting (CABG) is done either using cardiopulmonary bypass (CPB) or without using CPB (OPCAB). But, recently, reports have shown that CPB is associated with increased postoperative morbidity because of the involvement of many systems. AIMS: The aim of this prospective study was to evaluate the influence of the technique of surgery on various tissue injury markers and the extent of endothelial activation in patients undergoing CABG and OPCAB coronary revascularization. SETTINGS AND DESIGN: This study was conducted at a tertiary healthcare center during the period May 2008 to December 2009. MATERIALS AND METHODS: This was a prospective nonrandomized blinded study. The activities of Creatine Phosphokinase (CK) and its isoenzyme CK-MB, Lactate dehydrogenase (LDH), levels of cardiac Troponin I, soluble vascular cell adhesion molecule-1 (sVCAM-I) and systemic nitric oxide production were assessed. STATISTICAL ANALYSIS: All the results were expressed as Mean ± SD. P value ≤ 0.05 was considered significant. The statistical analysis was carried out using SPSS Version 11.5-computer software (SPSS Inc., Chicago, IL, USA). RESULTS: The surgical trauma had elevated CK, CK-MB and Troponin I in both the groups and further elevation was seen in the CABG group in comparison to OPCAB (P<0.001). The Troponin I concentrations showed an increase from 0.11 ± 0.02 preoperatively to 6.59 ± 0.59 (ng/ml) at 24 h (P<0.001) compared to the OPCAB group. Mean serum levels of sVCAM-1 increased significantly after surgery in both the groups (P<0.02). To determine serum nitric oxide (NO) production, NO2- and NO3- (stable end products of NO oxidation) were analyzed which also increased significantly at 24 h in both the groups. But the increase was not significant at 48 h in both the groups compared to the preoperative value in our study. CONCLUSION: The present study indicates that, despite comparable surgical trauma, the OPCAB significantly reduces tissue injury. The overall pattern of endothelial activation after OPCAB is significantly lower than that after CABG. This may contribute to improved organ function, and improved postoperative recovery.

Physicians and communities knowledge and awareness about new vaccines in immunization program: a study to derive lesson for increasing uptake.

BACKGROUND: The knowledge, attitude of physicians about any interventions has effect on the practices while the perceptions about such intervention by caregivers have impact on the acceptance in community. OBJECTIVES: This study was conducted to assess the knowledge and attitude of physicians and perception of the caregivers about new vaccines, and to identify the solutions to address the knowledge gap, if any. MATERIALS AND METHODS: A cross sectional study was conducted a major city of India from Sept 2006-Jan 2007. 107 physicians and 298 caregivers were interviewed using a pre-tested semi structured interview schedule. The data so collected was analyzed using chi square test and proportions. P value of less than 0.05 was considered statistically significant. RESULTS: It was found that only 3/5th physicians were aware that typhoid vaccination was part of the immunisation program. The knowledge about all the aspects of typhoid was poor amongst physicians in comparison of other vaccine (Hepatitis B) in the immunisation program. Physicians at private health facilities had poor knowledge than those working at government health facilities. However, majority of the physicians had positive attitude towards typhoid vaccination. All the caregivers had heard about typhoid disease and 39.8% about the vaccine also. Almost 80% of them were ready to pay for typhoid vaccination. CONCLUSIONS: The study underlines the need for special efforts to increase the awareness about typhoid vaccination amongst these groups to increase the uptake of the vaccine.

Enhanced therapeutic efficacy of cisplatin by combination with diethyldithiocarbamate and hyperthermia in a mouse model.

A spontaneously metastasizing solid tumor model derived by transplanting the TA3Ha murine mammary carcinoma into the s.c. tail tissue of mice was used to develop a treatment strategy for enhancing the therapeutic efficacy of cisplatin (CDDP). This strategy was based on the findings that diethyldithiocarbamate (DDTC) reduces the toxicity of CDDP, and that localized hyperthermia (HT) augments the antitumor efficacy of CDDP. DDTC (500 mg/kg) reduced the CDDP-induced nephrotoxicity and gastrointestinal toxicity as well as increased the CDDP LD10 from 8 to 20 mg/kg in strain A mice. When CDDP and DDTC were used in multiple treatment schedules at 5-day intervals, DDTC protected the hosts but not the tumors against the toxicity of CDDP. HT administered locally to the tumor 1 h after the injection of CDDP (8 mg/kg) in 1 ml Hanks' balanced salt solution increased the antitumor effect but not the host toxicity. While administration of 8 mg/kg CDDP alone or with HT three times at 5-day intervals caused 100% host mortality, this dose of CDDP could be used with no mortality by combining it with DDTC. A combination of 8 mg/kg CDDP with DDTC (750 mg/kg) and HT (43 degree C for 60 min), administered three times at 5-day intervals, retarded the local tumor growth significantly compared to the untreated, CDDP plus DDTC plus HT control groups of mice. The frequency of lung metastasis in these groups on day 30 of tumor inoculation were 0, 90, 90, and 80%, respectively. The mean survival days of the mice treated with CDDP plus DDTC plus HT was 61 +/- 6 compared to 34 +/- 5 in the controls. The results presented here demonstrate that by combining CDDP with DDTC, high doses of CDDP can be safely administered. When localized HT is combined with high dose CDDP and DDTC, the tumor growth retardation and the host survival prolongation are significantly better than those obtained with the highest tolerable dose of CDDP alone or CDDP plus HT.

Combined effect of trans-diamminedichloroplatinum(II) and hyperthermia on murine and human tumor cells.

trans-Diamminedichloroplatinum(II), a paradigm of an inactive platinum compound, exhibited cytotoxic effect against HEP-2 human tumor cells, TA3Ha murine tumor cells, and freshly collected human ovarian carcinoma cells when combined with hyperthermia (43 degrees, 30 min). The heat treatment reduced the D0 of trans-platinum from 56 to 16.5 micrograms/ml in the HEP-2 system and from an undeterminable value at 37 degrees to 8.2 micrograms/ml in the TA3Ha system. Heat treatment before trans-platinum was more cytotoxic than that after trans-platinum in the TA3Ha system (P less than 0.001). TA3Ha cells treated in vitro with 40 micrograms/ml TDDP at 43 degrees failed to form tumors in mice upon subcutaneous implantation into the tails of mice. In contrast, these agents given singly did not alter the tumor-forming ability of TA3Ha cells. In vivo administration of trans-platinum after hyperthermia (43 degrees for 30 min) retarded the growth of TA3Ha tumors compared to either treatment alone. trans-Platinum did not form detectable DNA-interstrand cross-links in the HEP-2 cells treated at 37 degrees or 43 degrees. However, the DNA-protein cross-links were detectable under these conditions. The frequencies of DNA-protein cross-links were higher in the cells treated at 43 degrees than in those treated at 37 degrees, both immediately after and 12 h after the treatment with trans-platinum. Heat alone did not induce the formation of either DNA-interstrand or DNA-protein cross-links. Heat treatment did not appear to enhance the entry of trans-platinum into the cells.

Effect of localized hyperthermia on TA3Ha tumor transplanted subcutaneously in the tails of mice.

Localized hyperthermia (43 degrees) in single or multiple fractions was applied to mouse mammary adenocarcinoma TA3Ha implanted into the s.c. tail tissue of strain A mice. The effects of heat on the growth of local tumors, on the pattern of metastasis, and on the survival periods of the hosts were studied. Hyperthermia was administered by heating the tumor-bearing tails in a water bath. Multiple 30-min hyperthermia treatments at 5- or 7-day intervals controlled local tumor growth better than did a single 30-min treatment or multiple 30-min treatments at 3-day intervals or at intervals longer than 7 days. Heat treatments that produced cytostatic effects on tumors, sparing the normal tissue, had no effect on either the survival of the hosts or the extent of metastasis to the lungs and the lumbar lymph nodes. However, local treatments reduced the frequency of renal lymph node metastasis, indicating that concurrent metastases in different sites may exhibit differential heat sensitivities.

A randomized study of low and high doses of leukocyte alpha-interferon in metastatic renal cell carcinoma: the American Cancer Society collaborative trial.

A prospective randomized trial of low versus high doses of human leukocyte alpha-interferon (1 X 10(6) units/day for 28 days versus 10 X 10(6) units/day for 28 days) was carried out in 30 patients with metastatic renal cell carcinoma, to test the tolerance and relative antitumor effects of these interferon doses. Both doses were tolerated well, and responses to the human leukocyte alpha-interferon were observed overall in seven individuals, including complete, partial, and minimal tumor regressions. Six of the seven responses occurred in patients who received the high dosage, and three of these responses were major responses. While not statistically significant, this result suggested a dose-response relationship. One minimal response was observed in a patient treated at low dosage. Nine individuals who were stable after 1 month of therapy at low dosage were randomized to a further month of therapy at low or high dosage, during which one of four at high dosage had a partial response, and none of five at low dosage manifested response. Regression of pulmonary disease in one individual was delayed, occurring 3 months after therapy at the high dose and enduring for a period of 28 months. Major objective responses in other patients were of 4 and 15 months duration. Human leukocyte alpha-interferon is an active agent in renal cell carcinoma at the dosage of 10 million units daily. No relationship of toxicity to response was evident in this trial. Optimum dosage and duration of treatment have yet to be established.

Comparative activity and toxicity of cis-diamminedichloroplatinum (DDP) and a combination of doxorubicin, cyclophosphamide, and DDP in disseminated transitional cell carcinomas of the urinary tract.

From October 1978 to October 1981, 135 patients with disseminated transitional cell carcinomas of the urinary tract, with either measurable or evaluable disease, were randomized to receive either cis-diamminedichloroplatinum (DDP) or cyclophosphamide (CTX), Adriamycin (ADR) (Adria Laboratories, Columbus, Ohio), and DDP (CAD). DDP was given at a dose of 60 mg/m2, CTX at 400 mg/m2, and ADR at 40 mg/m2 intravenously every three weeks. Patients over the age of 65 and those with prior radiation received 75% of the dose initially. The dose was escalated if only mild toxicity developed. Of the patients on the CAD arm, 34% developed grade 3 or 4 hematologic toxicity, as compared to 3% in patients on the DDP therapy. Of the 93 patients with measurable disease, 48 received DDP. Seventeen percent had a partial or complete remission, as compared to 33% of the 45 patients on the CAD arm (P = .09). The crude median survival of patients on DDP was 6.0 months as compared to 7.3 months in patients receiving CAD (P = .17). We conclude that the CAD combination is more toxic than DDP with, at best, very marginal benefit in survival.

Phase II diaziquone-based chemotherapy trials in patients with anaplastic supratentorial astrocytic neoplasms.

We treated 103 patients with histologically confirmed anaplastic supratentorial astrocytic neoplasms with either diaziquone (AZQ) and carmustine (BCNU) or AZQ and procarbazine. There were 74 patients with glioblastoma multiforme (GBM) and 29 patients with anaplastic astrocytoma (AA). AZQ plus BCNU produced partial (PR) or unequivocal responses in seven of 32 (21.9%) patients with GBMs and three of ten (30%) patients with AAs. Two patients with GBMs (6.3%) and five patients with AAs (50%) showed stable disease (SD). AZQ plus procarbazine produced PRs or unequivocal responses in five of 42 (11.9%) patients with GBMs and nine of 19 (47.4%) patients with AAs. Eight patients with GBMs (19%) and one patient with an AA (5.2%) showed SD. In addition to histologic diagnosis, only the Karnofsky performance-status (KPS) rating independently influenced response and survival. Differences in response rates between the two regimens were not significant, although estimated median survival after adjusting for performance status was slightly better with AZQ plus BCNU than with AZQ plus procarbazine (P = .031). Neither age nor prior chemotherapy were significant independent risk factors. Toxicity was mild and primarily hematologic. We conclude that these AZQ-based regimens have activity in patients with recurrent anaplastic gliomas, but that they are not clearly superior to other agents in current use. The histologic diagnosis of GBM is associated with a significantly worse prognosis than AA, and we believe that this important distinction must be recognized in phase II as well as phase III trials.

Adherence to a dietary fat intake reduction program in postmenopausal women receiving therapy for early breast cancer. The Women's Intervention Nutrition Study.

PURPOSE: To evaluate the feasibility of integrating a program based on dietary fat intake reduction into adjuvant treatment strategies for postmenopausal women receiving therapy for early breast cancer. PATIENTS AND METHODS: Two hundred ninety postmenopausal women with localized (stage I to IIIa) breast cancer receiving conventional systemic therapy provided informed consent and were randomized in a multicenter trial to either a dietary intervention group receiving a program of individualized instruction for reducing total fat intake or a dietary control group with minimal dietary counseling. RESULTS: Significantly reduced (P < .001) fat intake (in terms of percent calories derived from fat) was observed in the intervention group versus the control group at 3 months (20.3% +/- 2.4% v 31.5% +/- 2.6%, mean +/- SD, respectively) and maintained throughout 24 months of observation. The 50% reduction in daily fat-gram intake (from 66 +/- 23 to 33 +/- 14 g, P < .001) seen at 6 months was associated with reduced saturated fat, monounsaturated fat, polyunsaturated fat, and linoleic acid (P < .001). Significantly lower body weight was also seen in intervention compared with control patients at all observation periods, resulting in a 3.3-kg weight difference 18 months after randomization (P < .001). CONCLUSION: Substantial and sustained dietary fat reduction with associated weight change can be achieved at relatively low cost within the context of conventional multimodality clinical management of postmenopausal women with localized breast cancer. This result supports the feasibility of conducting a full-scale evaluation of the influence of dietary fat intake reduction on the clinical outcome of breast cancer patients.

Endometrial carcinoma following estrogen therapy for breast cancer. Report of three cases.

Three patients with metastatic breast cancer responded to diethylstilbestrol (DES) therapy, but later they developed endometrial carcinoma. Evidence is presented to support the hypothesis that endometrial carcinoma can occur in breast cancer patients receiving diethylstilbestrol therapy.

Acute erythroleukemia complicating prolonged chemotherapy for ovarian carcinoma.

Two patients with ovarian carcinoma developed acute erythroleukemia following prolonged chemotherapy with an alkylating agent. An analysis of our patients, together with literature review of similar cases, suggests that the duration of chemotherapy may have been the most important factor in the leukemogenesis. We suggest that the duration of chemotherapy required to achieve a cure in patients with ovarian carcinoma in complete remission can be determined only by prospective controlled trials.

A phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain. CNS Cancer Consortium.

PURPOSE: This study was designed to evaluate strategies to overcome the resistance of anaplastic gliomas of the brain to external beam radiotherapy (ERT) plus carmustine (BCNU). Patients were > or = 15 years of age, had a histologic diagnosis of malignant glioma, and a Karnofsky performance status (KPS) > or = 60%. METHODS AND MATERIALS: In Randomization 1, patients were assigned to receive either ERT alone (61.2 Gy) or ERT plus mitomycin C (Mito, IV 12.5 mg/m(2)) during the first and fourth week of ERT. After this treatment, patients went on to Randomization 2, where they were assigned to receive either BCNU (i.v. 200 mg/m(2)) given at 6-week intervals or 6-mercaptopurine (6- MP, 750 mg/m(2) IV daily for 3 days every six weeks), with BCNU given on the third day of the 6-MP treatment. Three hundred twenty-seven patients underwent Randomization 1. One hundred sixty-four received ERT alone, and 163 received ERT + Mito [average 52.7 years; 63% male; 69% glioblastoma multiforme (GBM); 66% had a resection; 56% KPS > or = 90%]. Step-wise analysis of survival from Randomization 1 or 2 indicates that survival was significantly diminished by: (a) age > or = 45 years (b) KPS < 90%; (c) GBM/gliosarcoma histology; (d) stereotactic biopsy as opposed to open biopsy or resection. Median survival from Randomization 1 in both arms (ERT + Mito) was 10.8 months. Median survival from Randomization 2 was 9.3 months for BCNU/6MP vs. 11.4 months for the BCNU group (p = 0.35). Carmustine/6-MP showed a possible survival benefit for histologies other than GBM/GS. Two hundred and thirty-three patients underwent Randomization 2. The proportion of patients in the ERT group who terminated study prior to Randomization 2 was significantly less in the ERT group than in the ERT + Mito group (20 vs. 37%, p < 0.001). CONCLUSIONS: (a) The addition of Mito to ERT had no impact on survival; (b) patients treated with ERT + Mito were at greater risk of terminating therapy prior to Randomization 2; (c) there was not a significant survival benefit to the addition of 6-MP to BCNU.

A method for the quantitative analysis of human heat shock gene expression using a multiplex RT-PCR assay.

A quantitative multiplex RT-PCR assay is described to measure the levels of messenger RNAs for eight human genes encoding the heat shock proteins (HSP) and molecular chaperones hsp90alpha, hsp90beta, hsp70, hsc70, mtHsp75, Grp78 (BiP), hsp60 and hsp27. The basis of this assay is reverse transcription of total RNA isolated from human cells followed by amplification with PCR. By the careful selection of pairs of oligonucleotide primers corresponding to unique regions of each heat shock gene, selectivity can be attained such that messenger RNAs of multiple heat shock genes can be analyzed simultaneously in a single reaction. This method provides both the absolute and relative levels of each heat shock message by including in the reaction, reference control RNAs corresponding to in vitro transcripts of heat shock gene plasmids carrying small internal deletions.

Causes and evaluation of tumor-induced hypoglycemia.

We treated four patients who had hypoglycemia and nonpancreatic tumors. Two had pleural mesothelioma, one had primary fibrosarcoma of the liver, and one had pheochromocytoma metastatic to the liver. We propose four mechanisms for this syndrome: (1) insulin or insulin-like activity produced by the tumor, (2) decreased gluconeogenesis, (3) disruption of glucagon metabolism, and (4) increased utilization of glucose by the tumor. The local effects of the tumor in hepatic parenchyma may also play an important role. The important diagnostic tests are an insulin-glucose ratio, to rule out insulinoma, and fasting glucose levels. An assay of nonsuppressible insulin-like activity can be performed and is of investigative interest, but does not aid in individual patient therapy. Treatment consists of control of the tumor.

Thyroid disease following irradiation for benign conditions.

One hundred twenty-five patients with a history of prior irradiation to the head and neck region for benign disease underwent thyroidectomies between 1967 and 1976 at Evanston Hospital. One hundred twenty-four had a palpable abnormality. Forty-two had carcinoma, and nine of these had nodal metastases. Palpation was found to be more accurate than thyroid isotope scan in finding carcinoma within an abnormal gland. Some form of irradiation thyroiditis was found in one half of the resected specimens.

The spectrum of vascular lesions in the mammary skin, including angiosarcoma, after breast conservation treatment for breast cancer.

BACKGROUND: With the general acceptance of lumpectomy, axillary staging, and radiotherapy as local treatment for infiltrating breast cancer, an appreciation is evolving for the spectrum of vascular lesions that occur in the mammary skin after this treatment. Most of these lesions develop within the prior radiation field after breast conservation treatment. STUDY DESIGN: A retrospective chart and slide review was conducted, consisting of five patients with cutaneous vascular lesions after breast conservation treatment for infiltrating breast cancer. RESULTS: The latent time interval from definitive treatment of breast cancer to the clinical recognition of vascular lesions ranged from 5 to 11 years. Two patients did not have either arm or breast edema, two patients had breast edema, and the fifth patient had arm edema. Lesions arising in the irradiated mammary skin included extensive lymphangiectasia (one), atypical vascular lesions (two), and cutaneous angiosarcoma (four). CONCLUSIONS: Atypical vascular lesions at the skin margins of mastectomy may be predictive of recurrence after resection of angiosarcoma. Excision of skin from the entire radiation field may be necessary to secure local control of the chest wall in patients with cutaneous angiosarcoma after therapeutic breast radiotherapy.

Efficacy of vincristine and cyclophosphamide in the therapy of recurrent medulloblastoma.

We conducted a Phase II study of combination therapy with vincristine and cyclophosphamide in the treatment of patients with recurrent or metastatic medulloblastoma. Fourteen patients were treated with vincristine 2 mg/m2 (2.0-mg maximal dose) by intravenous bolus on Day 1 and cyclophosphamide 1 g/m2 by intravenous infusion on Days 1 and 2, with cycles repeated every 4 weeks. All 4 patients with extraneural disease (biopsy-proven bony metastases) responded (duration of responses 2+, 6+, 8, and 16+ months) and 4 of 8 evaluable patients with neuraxis disease responded (duration of response 2, 2+, 2+, and 21+ months). Toxicity was limited to neutropenia without any episodes of infection. These therapeutic results compare favorably with other reports of therapy for recurrent medulloblastoma and support the inclusion of vincristine and cyclophosphamide in randomized adjuvant therapy trials of patients with medulloblastoma.

Chemoimmunotherapy of head and neck cancer.

The present review aims at developing a perspective for surgeons of the role of chemoimmunotherapy in the management of head and neck cancer. The biochemical pharmacology of high dose methotrexate with leucovorin "rescue" is also discussed. The need for a combined modality approach in the treatment of patients with this cancer is emphasized.

Preoperative physical assessment of thyroid glands in previously irradiated patients.

The Evanston Hospital maintains an Irradiated Thyroid Evaluation Clinic that has evaluated 695 patients since 1975. One hundred fourteen patients were retrospectively analyzed, and an attempt was made to correlate the preoperative physical examination with the pathologic specimen after thyroidectomy. There was no statistically significant difference between the incidence of carcinoma in glands containing a single nodule (23 per cent) and in multinodular glands. Postirradiation thyroiditis complicated the physical description of glands preoperatively. The categorization of physical findings served only to identify persistent thyroid abnormalities, which must be explored surgically. The overall incidence of carcinoma in the 114 available cases was 34 per cent, with nodal metastases in 18 per cent of the patients with carcinoma.

Phase II study of cisplatin for metastatic prostatic carcinoma. An Eastern Cooperative Oncology Group study.

In a phase ii trial 18 previously treated patients with metastatic prostatic carcinoma with measurable or evaluable disease were treated with cisplatin 50 mg/m2 every 3 weeks. Treatment was well tolerated in this elderly group of patients except for GI toxicity seen in 75% of the patients. There were no objective responses. Changes in serum acid phosphatase were often transient and not accompanied by clinical improvement. Cisplatin does not appear to be an effective agent in metastatic prostatic carcinoma in the dose schedule employed.