Biomedical subjects
Publications and source records attributed to T S Ravikumar.
The use of semipermanent vascular access devices has become standard in the management of specific clinical populations. Recently, the use of peripherally inserted catheters has gained popularity owing to the relative ease of insertion and lower complication rates.
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Primary ciliary dyskinesia syndrome is characterised by chronic sinusitis, bronchiectasis, and, in 50% of cases, dextrocardia. It is generally believed to be inherited as an autosomal recessive disorder. In this report, we describe a family consisting of a mother and her five male children, the offspring of three different fathers, all of whom have this syndrome. This argues for either an X linked or autosomal dominant pattern of inheritance. Cytogenetic and FISH (fluorescent in situ hybridisation) analyses were done on the mother and one son and were found to be normal.
PURPOSE: This prospective, nonrandomized trial evaluated a percutaneous isolated chemotherapy perfusion approach for treating advanced primary and metastatic liver tumors. Chemotherapy was administered via hepatic artery catheter and hepatic venous blood isolated by a novel percutaneous double-balloon inferior vena cava (IVC) catheter was passed through a detoxification/filtration cartridge in a venovenous bypass circuit. PATIENTS AND METHODS: Among 23 patients enrolled onto the study, 58 procedures were performed on 21 patients. Twelve patients received dose escalations of fluorouracil (5-FU) (1,000 mg/m2 to 5,000 mg/m2), and nine received dose escalations of doxorubicin (50 mg/m2 to 120 mg/m2). Pharmacokinetic studies included drug accumulation in the liver, extraction by detoxification filters, systemic exposure, and alterations of half-life. Each patient received two treatments at 3-week intervals. Those showing stabilization or response received additional treatments. RESULTS: There was a direct relationship between dose and peak concentration of drug entering the hepatic veins. The system functioned efficiently throughout the dose range, with extraction efficiencies ranging from 64% to 91% (P < .001). The hepatic vein drug levels showed a sixfold increase in 5-FU with dose escalation from 1,000 to 5,000 mg/m2, and a twofold increase in dox with dose escalation from 50 to 120 mg/m2 (P < .001, filter-mediated drug extraction). The treatments were accomplished with only an overnight hospital stay and no mortality. The common procedure-related toxicity was transient hypotension (grade I to II), due to catecholamine depletion by the filter. Dose-limiting toxicity (leukopenia) was observed in patients receiving 5-FU at a dose of 5,000 mg/m2 and doxorubicin at a dose of 120 mg/m2. Significant tumor response (> 95% reduction) was obtained in two patients receiving doxorubicin at 90 mg/m2 and 120 mg/m2. CONCLUSION: The use of a double-balloon catheter to isolate and detoxify hepatic venous blood during intraarterial therapy is technically feasible, safe, and allows administration of large doses of intrahepatic chemotherapy at short intervals. This approach should allow new dose-intensification strategies to increase tumor responses in primary and metastatic liver tumors.
A prospective study of 110 patients undergoing liver surgery was undertaken to evaluate the usefulness of intraoperative ultrasonography (IOUS) and cryosurgery in treating primary and metastatic liver tumors. The diagnoses were colorectal cancer (n = 72), hepatocellular carcinoma (n = 15), ovarian cancer (n = 8), cholangiocarcinoma (n = 4), and other tumors (n = 11). IOUS results were compared with preoperative CT scan angioportography. IOUS detected 37 lesions not seen on CT in 21 patients (19%) and 13 lesions not detected by bimanual palpation in 6 patients (5%). IOUS-assisted cryosurgery was carried out to ablate unresectable liver tumors in 21 patients (19%). At median follow-up of 14 months, 5/21 patients (24%) achieved complete response; 24 and 52% of patients recurred in the liver and systematically, respectively. Thus, IOUS is useful in detecting occult liver tumors and in providing assistance in tumor ablative therapies. Cryosurgery is useful in controlling some of the unresectable liver tumors, but the 76% recurrence rate implies the need for an effective regional and systemic chemo/immunotherapy.
One of the extension proteins on the carboxy terminus of ubiquitin was reported as the ribosomal protein S27a. We have cloned a gene which encodes this ubiquitin hybrid protein from a complementary DNA library of a human colon carcinoma cell line. Northern blot analysis of surgical specimens from colon cancer patients showed that these messenger RNA levels were higher in tumor tissue than in adjacent normal mucosa. Furthermore, to investigate the role of this novel ubiquitin hybrid gene in cellular growth control, the responsiveness of this gene to serum growth factors was examined. Within 30 min after serum or 12-O-tetradecanoylphorbol-13-acetate stimulation, its messenger RNA expression in rat fibroblast cells (Rat 1) was increased. Nuclear runoff transcription studies showed that the kinetics of induction of this gene is almost identical to that of protooncogene c-jun or c-fos, the known early growth response genes. Thus, this ubiquitin hybrid gene appears to be a novel early growth response gene overexpressed in human colon cancer and warrants further studies in the pathogenesis of colorectal carcinoma.
Immunohistologic techniques were used to study the expression of colorectal carcinoma-associated antigens in colonic polyps and to compare this with expression in the normal colonic epithelium. Forty-nine polyps were studied using monoclonal antibodies to 16 different blood group and differentiation antigens and carcinoembryonic antigen epitopes. With the Lewis(a) antigen and the two epitopes of CEA recognized by 3D6 and COL-4 expression in polyp tissue was the same as that in the normal colon. Five types of alteration of antigen expression in polyps were seen. The blood group antigens A, B, and Lewis(b), which are expressed only on the right side of the normal adult colon, were detected in both neoplastic and nonneoplastic polyps from the distal colon. The Lewis(x) antigen and the antigen epitopes detected by the antibodies COL-12, CA19-9, ME491, and GA73.3 showed an increased frequency of expression in all types of polyps in comparison with the normal colonic epithelium, while H-type 2, ND4, and the antigen epitope detected by CO29.11 showed a slightly decreased frequency of expression in polyp tissue. The X-like antigen which was expressed in only 7% of normal colon specimens showed increased frequency of expression in polyp tissue with significantly greater expression in neoplastic than hyperplastic lesions (P = 0.003). The TAG-72 antigen was detected only in adenomas with severe dysplasia (P = 0.01), correlating well with premalignant histology. These findings have helped us clarify the variation of antigen expression in colonic polyps and allowed us to define which antigens are worthy of further investigation as markers of possible malignant transformation.
PURPOSE: A peripherally implanted central venous access device (P.A.S. Port; Pharmacia Deltec Inc, St Paul, MN) was evaluated for ease of insertion, functionality, acceptance, and complications in patients who required long-term venous access. A hand-held tracking system (Cath-Finder; Pharmacia Deltec Inc) used to determine catheter tip location was also evaluated. PATIENTS AND METHODS: A P.A.S. Port was placed in 47 patients who required long-term intravenous access. The median follow-up duration has been 32 weeks (range, 2 to 112). Total usage has been 2,028 catheter-weeks. The Cath-Finder was used to determine catheter tip location during insertion. Nursing staff and patient satisfaction were polled and functionality and complications were recorded. RESULTS: The device was found to be simple to insert, the procedure well tolerated, and, with one exception, the Cath-Finder accurately predicted catheter tip location. There was a 6.4% incidence of transient phlebitis and a 6.4% incidence of symptomatic axillary or subclavian vein thrombosis. There were no infectious complications. Access was simple in all but two obese patients. The device functioned well in all patients, except three in whom blood aspiration was difficult and two in whom fluid administration was slow. The device was well tolerated by all patients and nursing staff satisfaction was high. CONCLUSION: This device provides a highly acceptable, additional method of implantable, permanent central venous access for chemotherapy patients with a low complication rate. The successful use of the Cath-Finder and minor extent of the procedure may allow this device to be inserted in a clinic procedure room without sedation and fluoroscopy.
Statistics from the Connecticut Tumor Registry from 1979 to 1988 were examined, and individual medical records from 1979 to 1983 were also reviewed. Three hundred nineteen medical records were available for review, documenting 220 cases of ductal carcinoma in situ and 102 cases of lobular carcinoma in situ. In 1979, there were 33 new cases of ductal carcinoma in situ reported to the Connecticut Tumor Registry, representing 1.8% of all breast cancers. There has been a yearly increase in ductal carcinoma in situ, with 200 new cases, or 7.4% of all breast cancers, reported in 1988. Forty-eight (22%) of 217 patients with ductal carcinoma in situ had bilateral breast involvement with ductal carcinoma in situ or an invasive breast cancer. Ten (83%) of 12 mastectomy specimens from patients with ductal carcinoma in situ who presented with nipple discharge demonstrated residual tumor, suggesting a more diffuse involvement. Two of the three reported recurrences involved nipple discharge. Thirty-seven (16.8%) of the 220 patients with ductal carcinoma in situ and six (5.9%) of the 102 patients with lobular carcinoma in situ were diagnosed as having another unrelated cancer. Ongoing clinical trials will direct optimum therapy for patients increasingly diagnosed as having ductal carcinoma in situ.
Tumor invasion and metastasis involves the interaction between tumor cells and basement membrane, which is mediated in part by laminin receptors/laminin-binding proteins. We have reported that a 32-kDa laminin-binding protein (LBP-32) was overexpressed in colorectal cancer at the messenger RNA (mRNA) level and correlated with clinical staging. However, the function of this protein is not yet defined. In this study, we have analyzed the role of LBP-32 in tumor cell attachment and invasion through various basement membrane components. Blockade of LBP-32 synthesis with an anti-sense RNA was utilized in this study. The partial sequence (237 bp) of LBP-32 was inserted into the EMSV33 vector in the sense or antisense direction. Clone A, a poorly differentiated human colon carcinoma cell line, was transfected with EMSV33 alone (control), or EMSV33 with the insert in sense (LBP-S) or anti-sense (LBP-AS) direction using lipofectin. The cell adhesion assays (at 37 degrees C for 75 min) were performed using parental Clone A cells or the transfectants. Specific attachment to wells coated with laminin, fibronectin, or type IV collagen was evaluated. In vitro cell invasion assays were performed using the parental clone A cells and their transfectants to assess the passage through polycarbonate filters coated with matrigel, a reconstituted basement membrane. The results showed that (a) laminin and collagen IV (but not fibronectin) play a role in colon cancer cell attachment to substrata, and (b) anti-sense RNA of LBP-32 inhibits tumor cell attachment and invasiveness in vitro. These findings suggest a role for LBP-32 in colon cancer progression and metastasis.(ABSTRACT TRUNCATED AT 250 WORDS)
Chemotherapy for primary or metastatic hepatic malignancy is limited by poor tumor response and dose-related systemic toxicity. As an alternative to chemotherapy infusion by vein or by the hepatic artery, the authors have developed a percutaneous technique of isolated liver perfusion that allows the regional delivery of high-dose chemotherapy to the liver with little systemic toxicity. After placement of a hepatic artery infusion catheter, an 18-F double-balloon catheter is placed into the inferior vena cava through the opposite femoral vein. Balloons are inflated above and below the hepatic veins, thus isolating hepatic venous outflow. The effluent passes through fenestrations in the catheter and is pumped through charcoal hemoperfusion filters where the drug is removed. The filtered blood is returned to the patient through the internal jugular vein. Fifteen treatments have been conducted in eight patients in a phase I dose-escalation study with use of 5-fluorouracil (5-FU). While it is premature to assess tumor response to isolated liver perfusion, the data demonstrate that the procedure is safe and is tolerated by patients. Pharmacokinetic studies show a 5-FU extraction of up to 85%, with minimal drug leakage into the systemic circulation. This technique shows potential for improving liver tumor response while decreasing systemic toxicity.
Carcinoembryonic antigen (CEA) is the most widely used tumor marker for colorectal cancer. Plasma CEA levels have been variably associated with prognosis. Since plasma CEA level is multifactorial, CEA gene expression in tumors may provide one precise mechanism to evaluate its functional role. This study evaluated CEA expression at the messenger RNA (mRNA) level in 22 human colorectal carcinomas and their adjacent normal mucosae by Northern blot hybridization using a 32P-labeled CEA probe (a loop-domain specific cDNA, LV7). Both tumor and normal mucosa displayed three mRNA species of 4.0, 3.6, and 3.0 kb in length. The expression of 3.6-kb mRNA which encodes for CEA was dominant and it was correlated with another 4.0-kb CEA mRNA expression. The expression of 3.0-kb mRNA which encodes for nonspecific cross-reacting antigen was weak and not detectable in 8 of 22 colon tumors and 12 of 22 normal colon mucosae. In only one tumor, a 4.5-kb mRNA (which might encode for a new family member of CEA) was expressed. A two- to fourfold higher expression of CEA mRNA (3.6 kb) was observed in 11 of 22 colorectal tumors (2 of 9 proximal colon tumors and 9 of 14 rectosigmoid tumors) when compared with morphologically normal adjacent mucosae. Preoperative plasma CEA levels and Dukes' staging had no correlation with this CEA mRNA expression. CEA mRNA did not appear to correlate with metastasis because its expression in the primary colon cancers with metastases (Dukes' stage D tumor) was not always increased. These data also imply that factors other than mRNA expression in tumor might be important in regulating plasma CEA levels.
Tumor invasion and metastasis involve the interaction between tumor cells and basement membrane, which is mediated in part by laminin receptors. To search for tumor-associated-genes which can be used as new markers in colon cancers with known poor prognosis, cDNA libraries from a colon cancer cell line and colonic tissues were constructed and screened. We selected a cDNA clone which encodes 32-kD laminin-binding protein (LBP-32), and showed increased mRNA expression of LBP-32 in colon carcinoma. This mRNA expression was also correlated with clinical tumor staging. Furthermore, to investigate the role of LBP-32 in cancer invasion and metastasis, cell adhesion assays and in vitro invasion assays were performed, using anti-sense RNA of LBP-32 to block the synthesis of LBP-32. Results showed that anti-sense RNA of LBP-32 inhibits tumor cell attachment and invasiveness in vitro in transfectants of a colon cancer cell line. These data suggest that LBP-32 may play an important role in colon cancer progression, and that LBP-32 may be used as a marker of biological aggressiveness. These findings also imply that laminin receptors may provide a target for novel therapeutic strategies: modulating LBP-32 expression by anti-sense RNA or monoclonal antibodies may have clinical application in colorectal cancer therapy.
Cryosurgery, using liquid nitrogen at -196 degrees C, was explored for treating colorectal liver metastases in an experimental study of rat colon cancer and in a clinical investigation of patients with unresectable liver tumors. The viability of rat colon cancer isografts showed that while two or three freeze-thaw cycles were 100% effective in controlling established isografts and preventing isograft take, one freeze-thaw cycle was suboptimal. In these animals cryosurgery was as effective as surgical resection in controlling established experimental liver metastases. Cryosurgery by operative liver exposure and intraoperative ultrasound monitoring were used to treat liver metastases from colorectal cancer in 24 patients. At a median follow-up of 2 years (range, 5 months to 5 years), seven patients (29%) are disease free, eight (33.5%) are alive with recurrent tumors, and nine (37.5%) have died. The patterns of failure were: remaining liver and extrahepatic sites, ten patients (59%); remaining liver only, six patients (35%); and extrahepatic only, one patient (6%). These data demonstrate that cryosurgery is a useful modality for treating unresectable primary and metastatic liver cancers. Addition of systemic adjuvant therapy may improve the tertiary failure following the control of liver metastases.
Ubiquitin is involved in cell-cycle control and DNA replication through a specific proteolytic pathway. Our previous studies demonstrated selected higher expression of a gene encoding ubiquitin-ribosomal protein S27a in poorly differentiated colon carcinoma cell lines. In this study, we evaluated this ubiquitin hybrid protein gene expression in surgical specimens of colon cancers. Northern blot analysis showed that ubiquitin hybrid protein messenger RNA was overexpressed in primary colon cancers compared with adjacent normal colon mucosae in 17 of 20 patients. Dot blot analysis of RNA of 27 tumor samples revealed significantly greater expression in higher Dukes' stage primary colon tumors and liver metastases. These data imply that protein translation machinery is highly activated during progression and metastasis of colon tumors, and that ubiquitin hybrid protein may be useful as a marker of biological aggressiveness.
After analysis of 26 prospectively accrued patients with distal rectal adenocarcinomas who underwent sphincter preservation treatment, we have concluded that tumors that invade only the submucosa can safely be treated with surgery alone and that tumors that invade the muscularis or further can be safely treated with surgery combined with chemoradiotherapy. None of the patients had either local or distant recurrence, with a median follow-up of 21 months. All patients have been fully continent. The results, although preliminary, imply that resection of distal rectal adenocarcinoma with sphincter preservation, and adjuvant therapy when appropriate, have achieved local and distant control equal to the conventional Miles' abdominoperineal resection, but without the need for a permanent colostomy.
This report summarizes our 5-year experience with cryosurgery for in situ ablation of liver tumors. The liver was exposed with laparotomy, and the tumors were subjected to two freeze-thaw cycles using liquid nitrogen delivered by insulated probes; cryoablation was monitored with intraoperative ultrasonography. Tumor markers and computed tomography evaluated tumor response during long-term follow-up. From 1985 to 1990, 32 patients (19 men and 13 women) were entered into this study. The histologic characteristics of the tumors were as follows: colorectal, 24 patients; hepatoma, three patients; neuroendocrine, two patients; and others, three patients. After a follow-up period of 5 to 60 months (median follow-up, 24 months), nine patients (28%) remained disease free, 11 patients (34%) were alive with disease, and 12 patients (38%) died. The patterns of failure included liver and extrahepatic disease in 54% of cases, liver disease only in 32% of cases, and extrahepatic disease only in 14% of cases. In patients with "liver only" failure, recurrence at the treatment site occurred in three patients (9%). This study establishes the long-term effectiveness of cryosurgery in the treatment of primary and metastatic liver tumors.
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