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Optimization of multidimensional high-performance liquid chromatography for the determination of drugs in plasma by direct injection, micellar cleanup and photodiode array detection.

Improvements in a multidimensional liquid chromatography system for the direct determination of drug substances in blood plasma are reported. The system employs an on-line micellar chromatographic cleanup followed by a reversed-phase analytical separation. The limit of detection of propranolol is improved by a factor 10 compared to previously reported work. The technique is applied towards the determination of a multicomponent mixture of tricyclic anti-depressants in blood plasma. A protocol for optimization is described.

Chromatography, High Pressure Liquid↗

Macrophage targeting with technetium-99m labelled J001 acylated poly-galactoside for scintigraphy of inflammation: optimization and assessment of imaging specificity in experimental arthritis.

J001, an acylated poly-(1,3)-galactoside purified from the membrane of Klebsiella pneumoniae, associates selectively with macrophages via the binding to CD11b and CD14 molecules. Inflammatory foci known to recruit macrophages could thus be imaged with technetium-99m labelled J001. This study aims to define the optimal scintigraphic protocol for 99mTc-J001 imaging and to evaluate the specificity of J001 scans. A dose range study was conducted in rabbits with immunological arthritis using six different specific activities ranging from 370 to 11840 MBq·mg-1 while the intravenously injected activity was constant (37 MBq) Radiochemical purity for each preparation was documented together with the in vivo stability of the 99mTc-J001 complex using exclusion-diffusion radioHPLC of serum collected 1 h after radiopharmaceutical administration. Scintigraphic images were recorded at 2, 3 and 4h and analysed using indexes calculated from regions of interest. Specificity of the macrophage imaging was assessed by comparison with scans obtained after administration of 99mTcO4(- )or 99mTc-albumin nanocolloids. A protocol of plasma transfusion was also used to inject 99mTc-J001 after complete removal of radioactive colloids likely to be generated during the labelling. For the higher specific activities (5920 and 11840 MBq.mg-1), radiochemical purity degradation and in vitro 99mTc transchelation were noted. To prevent transchelation and 99mTc bond hydrolysis likely to impair imaging specificity, 1480 MBq.mg-1 corresponding to 25microg injected J001 was found to be the optimal usable specific activity. Results obtained with the various tracers support the hypothesis that macrophage targeting is the main factor involved in the J001 imaging of arthritis.

Animals↗

Tailoring immunosuppressive therapy for renal transplant recipients.

During the past decade several new potent immunosuppressive agents with different modes of action and different side-effect profiles have become available. Nowadays immunosuppression after renal transplantation is no longer one single regimen applicable to all patients. In the selection of the optimal immunosuppressive protocol, individual drug-related toxicity, recipient-related risk factors as well as donor organ characteristics have to be taken into account. This article will give an overview of the most recently developed immunosuppressive agents available for clinical use. Their individual mode of action and their different efficacy and safety profile will be described as basis for selection of each of these drugs in an attempt to tailor the optimal therapeutic regimen for the individual patient both in terms of short-term and long-term outcome.

Antibodies, Monoclonal↗

Clinical implications of thromboprophylaxis in the management of total hip and knee arthroplasty.

Thrombosis is the most common cause of mortality in the United States, resulting in more than 2 million deaths per year. Almost an equal number of individuals are affected each year by nonfatal thrombosis, including deep vein thrombosis and nonfatal pulmonary embolism. A large proportion of thrombotic episodes can be prevented by the appropriate selection of prophylactic therapy--a clinical decision that figures greatly in numerous clinical conditions associated with an increased risk of thrombosis, including major orthopedic surgery. Orthopedic surgeons are well aware of the risks for complications inherent in total hip arthroplasty and total knee arthroplasty in particular. However, determining which protocols are optimal for thromboprophylaxis remains a matter of contention, and the choice of prophylactic therapy is a critical factor in the successful completion of any major orthopedic surgical procedure. Although there are key differences between total hip and knee arthroplasty in terms of the measures available for thromboprophylaxis and the data documenting their relative degree of effectiveness, the two procedures share many similarities in these respects as well as in their surgical protocols. By reviewing the data and practice guidelines on thromboprophylaxis in total hip and knee arthroplasty together, orthopedic surgeons can more clearly see the implications for clinical success that the choice of prophylactic therapy has on their management of these two vitally important procedures.

Anticoagulants↗

Childhood non-Hodgkin's lymphoma--results of treatment with ALL high-risk protocol.

Between August 1984 and September 1990, 13 children with non-Hodgkin's lymphoma (NHL) were treated with ALL high-risk protocol (5 with TCLSG 842 regimen and 8 with TPOG 882B protocol) at Taichung Veterans General Hospital. Diagnosis of NHL was confirmed by histology. Nine had lymphoblastic lymphoma, three had histiocytic lymphoma and one had small non-cleaved cell lymphoma, according to the Rappaport classification. After thorough clinical evaluation eight children were NHL stage IV; four were stage III; and one was stage II. All these children had received chemotherapy as acute lymphocytic leukemia (ALL) high-risk protocol for a total of three years, including central nervous system (CNS) prophylaxis. Of the 13 patients, 9 (69.2%) gained complete remission. Over-all survival rate was 46.2%, with a median interval of 36 months. The complete remission rate and survival rate for the nine children with lymphoblastic lymphoma was better at 77.7% & 66.6% respectively. Within the nonresponsive group, two failed to remit because of early withdrawal from the protocol; the other two patients were refractory to treatment. Relapse was noted in one patient. As to the side effects, neutropenic fever was the most common problem encountered (9 occurrences in 13 patients). Other major complications included severe mucositis, massive GI bleeding, intracranial thrombosis induced by l-asparaginase and tumor lysis syndrome. Childhood NHL is often of diffuse types in pathology, and most affected children have advanced diseases at diagnosis. Choosing an optimal treatment protocol is important for good treatment results.

Adolescent↗

Extending the applicability of carboxyfluorescein in solid-phase synthesis.

Optimized coupling protocols are presented for the efficient and automated generation of carboxyfluorescein-labeled peptides. Side products, generated when applying earlier protocols for the in situ activation of carboxyfluorescein, were eliminated by a simple procedure, yielding highly pure fluorescent peptides and minimizing postsynthesis workup. For the cost-efficient labeling of large compound collections, coupling protocols were developed reducing the amount of coupling reagent and fluorophore. To enable further chemical derivatization of carboxyfluorescein-labeled peptides in solid-phase synthesis, the on-resin introduction of the trityl group was devised as a protecting group strategy for carboxyfluorescein. This protecting group strategy was exploited for the synthesis of peptides labeled with two different fluorescent dyes, essential tools for bioanalytical applications based on fluorescence resonance energy transfer (FRET). Tritylation and optimized labeling conditions led to the development of a fluorescein-preloaded resin for the automated synthesis of fluorescein-labeled compound collections with uniform labeling yields.

Fluoresceins↗

Light and electron microscopic immunohistochemical detection of bromodeoxyuridine-labeled cells in the brain: different fixation and processing protocols.

Bromodeoxyuridine (BrdU) immunohistochemistry is the method of choice for labeling newly generated cells in the brain. Most BrdU studies utilize paraformaldehyde-fixed brain tissue because of its compatibility with both BrdU and other immunohistochemical methods. However, stronger fixation is required for electron microscopic studies, and unfixed tissue is needed for biochemical and molecular studies. Because there are no systematic studies comparing the effects of different fixatives on BrdU immunohistochemistry in brain tissue, we compared BrdU immunohistochemical methods in brain tissue fixed with 4% paraformaldehyde, a mixed glutaraldehyde-paraformaldehyde fixative for electron microscopy, and unfixed tissue from brains perfused only with buffer and flash frozen. After optimizing immunostaining protocols, qualitative assessments of light microscopic diaminobenzidine labeling and of double-label immunofluorescence with confocal microscopy demonstrated excellent BrdU labeling in each of the three groups. Quantitative stereological assessment of the number of BrdU-labeled cells in rat dentate gyrus showed no significant difference in the number of labeled cells detected with each perfusion protocol. Additionally, we developed a protocol to visualize BrdU-labeled cells in the electron microscope with adequate preservation of fine structure in both rat and monkey brain.

Animals↗

NLCQ-1 (NSC 709257) in combination with radiation against human glioma U251 xenografts.

BACKGROUND: The efficacy of the weak DNA-intercalative hypoxia-selective cytotoxin NLCQ-1 (NSC 709257) was investigated in combination with single or fractionated doses of radiation against human glioma U251 xenografts. Two "advanced stage" experiments were performed in female athymic nude mice. MATERIALS AND METHODS: Tumor-bearing mice were allocated in groups of 8-10 (treated) or 10-20 (control) and irradiated in the presence or absence of NLCQ-1. Fractionated radiation was administered either qd x 4 or qd x 2, followed by a 9-day rest and repeated dosing. NLCQ-1 was administered i.p. 45 min before each radiation dose. RESULTS: NLCQ-1 alone did not show antitumor activity or toxicity. Radiation at the highest single dose used (5.0 Gy) showed antitumor activity without weight loss (optimal T/C = -45). Lower single radiation doses (2.0 or 3.0 Gy) were marginally effective (optimal T/C of 34 and 40, respectively). The addition of NLCQ-1 to the treatment with each single radiation dose provided better optimal T/C values (e.g., -64 with 5.0 Gy). Fractionated radiation at 1.0 Gy qd x 4 showed minimal effectiveness (T/C = 27) but, in combination with NLCQ-1, the T/C value was improved to 19. Radiation alone, given on a 3.0 Gy qd x 2, 9-day rest and repeat schedule was very effective (T/C = -57) without toxicity and resulted in 5 out of 10 complete regressions up to 42 days. When NLCQ-1 was added to the above protocol an optimal TIC value of -100 and 9 out of 10 complete regressions were obtained with a follow-up of 52 days. CONCLUSION: The above results suggest a significant advantage in combining radiation with NLCQ-1 against glioma tumors.

Animals↗

Critical pathways for acute myocardial infarction.

Critical pathways are standardized protocols for optimizing and streamlining patient care. They are important in the management of patients with acute myocardial infarction, many of whom do not receive evidence-based therapies. Several studies have demonstrated that the development and implementation of critical pathways that follow published guidelines and are tailored to the needs and resources of each institution result in increased use of evidence-based therapies, such as aspirin and beta-blockers, and is associated with decreased mortality. Use of these protocols has also been shown to reduce unnecessary therapy and under- or overutilization of certain procedures, thereby resulting in more cost-effective treatment.

Adrenergic beta-Antagonists↗

A positron emission tomography/computed tomography (PET/CT) acquisition protocol for CT radiation dose optimization.

BACKGROUND: In current combined positron emission tomography/computed tomography (PET/CT) systems, high-quality CT images not only increase diagnostic value by providing anatomic delineation of hyper- and hypometabolic tissues, but also shorten the acquisition time for attenuation correction compared with standard PET imaging. However, this technique potentially introduces more radiation burden to patients as a result of the higher radiation exposure from CT. METHODS: In this study, the radiation doses delivered from typical germanium-based and CT-based transmission scans were measured and compared using an anthropomorphic Rando Alderson phantom with insertions of thermoluminescent dosimeters. Image geometric distortion and quantified uptake values in PET images with different manipulating CT acquisition protocols for attenuation correction were also evaluated. RESULTS: It was found that radiation doses during germanium-based transmission scans were almost negligible, while doses from CT-based transmission scans were significantly higher. Using a lower radiation dose, the CT acquisition protocol did not significantly affect attenuation correction and anatomic delineation in PET. CONCLUSIONS: This study revealed the relation between image information and dose. The current PET/CT imaging acquisition protocol was improved by decreasing the radiation risks without sacrificing the diagnostic values.

Body Burden↗

Kidney morcellation in laparoscopic nephrectomy for tumor: recommendations for specimen sampling and pathologic tumor staging.

Laparoscopic nephrectomy is a novel approach for small renal tumors in selected patients; however, removal of the kidney through the small laparoscopic abdominal wall incision site requires the kidney to be morcellated into small fragments while still in situ. Morcellation presents two problems for the pathologist. First, guidelines for optimal sampling of morcellated fragments have not been described. Second, morcellation precludes complete pTNM tumor staging, in particular, tumor size, margins, and renal vein involvement. Based on our initial experience with 23 laparoscopic nephrectomies/nephroureterectomies (13 clinically suspected neoplasms, confirmed pathologically as renal cell carcinoma [RCC, n = 7], urothelial carcinoma of the renal pelvis [n = 3], angiomyolipoma [n = 1], and cystic nephroma [n = 1], and 10 clinically benign entities) and a conservative statistical model, we present a decision analysis model of various specimen sampling protocols that optimize cost, labor, or time to diagnosis (single vs sequential sampling). Using the tumor-to-kidney volume ratio (TKR), calculated from preoperative radiologic imaging and specimen gross weight, several specimen sampling algorithms were compared. For the average situation in which TKR is > or =0.15, the algorithm that most significantly optimizes cost and labor is one that initially samples 5% of the morcellated specimen. However, additional sampling may be required in one fourth of the cases. The optimal amount of sampled tissue may indeed be less than 5% because this assumes no suspicious tissue is grossly visible and in all our cases of RCC grossly visible tumor was identified. Additional nomograms for a spectrum of TKR, sampling success, and cost are presented to allow pathologists their own discretion in determining optimal sampling of the morcellated kidney. Tumor staging is severely limited by morcellation. Tumor size, renal capsule involvement, and renal vein involvement cannot be fully pathologically evaluated for RCC, whereas invasion cannot be definitively assessed for urothelial carcinoma of the renal pelvis. Knowledge of the radiologic features (lesion size, capsule, and vein involvement) is important in sampling and staging morcellated kidneys removed laparoscopically.

Algorithms↗

[Evaluation of time resolution in cardiac synchronized image reconstruction using multi-slice CT].

One of the newest CT application technologies is cardiac synchronized image reconstruction. In this technology, evaluation of time-resolution is very important. We developed a method of measuring time-resolution in cardiac synchronized reconstruction, and evaluated various scanning protocols. In our experiment, ECG-gated scanning was done by multi-slice CT (Aquilion16 Super Heart Edition, Toshiba Medical Systems Co., Ltd., Japan). The nominal slice thickness was 0.5 mm, and rotation time was 0.5 sec. Input heart rate was set at 40, 45, 50, 55, 60, 70, 75, 80, and 90 bpm, and helical pitch at 3.2, 4.0, and 4.8 (beam-pitch: 0.200, 0.250 and 0.300). We measured FWTM of the obtained sensitivity distribution and compared at each scanning protocol. Time resolution improved as helical pitch decreased and heart rate increased. However, phase-time resolution deteriorated as heart rate increased. The results of our experiment indicated that a segment center was determined by X-ray tube rotation time and heart rate, and the number of segments was determined by heart rate, helical pitch, and reconstruction position. Time resolution changed with X-ray tube rotation time, heart rate, helical pitch, and reconstruction position. In this report, we provide a reference for an optimal scanning protocol in cardiac synchronized image reconstruction.

Electrocardiography↗

An optimized PCR leads to rapid and highly sensitive detection of Borrelia burgdorferi in patients with Lyme borreliosis.

The present study aimed at developing an optimized PCR protocol fro the sensitive and specific detection of all three Borrelia burgdorferi genospecies pathogenic to humans in Lyme borreliosis patients. A rapid DNA extraction method using alkaline lysis was introduced and was found to be superior to other DNA extraction methods. Nested PCR was performed with primer sets targeting the plasmid-located ospA gene and a chromosomal gene segment encoding a 66-kDa protein (p66). In spiked synovial fluid (SF) fewer than three borreliae/sample were detected. The specificities of the amplicons were confirmed by Southern blot analysis with PCR-derived probes. Urine, cerebrospinal fluid (CSF), and SF specimens from 57 patients with Lyme borreliosis and from 58 controls were examined. In clinical samples the diagnostic sensitivity of PCR was 85% with SF samples, 79% with urine samples, and 91% with paired SF-urine samples from patients with Lyme arthritis and was 79% with CSF samples, 45% with urine samples, and 87% with paired CSF-urine specimens from neuroborreliosis patients. One patient each with neuroborreliosis and with Lyme arthritis had PCR-positive urine samples only. In 17% of all cases both primer sets yielded positive results, while the other patients were positive with only one primer set. Among these, more positive results were obtained with the p66 gene primer than with the ospA primer. The specificity exceeded 99%. We conclude that DNA from B. burgdorferi sensu lato species can sensitively and specifically be detected with the optimized PCR method described. At least two different primer sets should be used, and whenever possible, urine and CSF or SF should be analyzed in parallel to achieve maximum sensitivity of the test. This protocol, therefore, considerably enhances the diagnostic power of PCR in patients with B. burgdorferi infection.

Adolescent↗

A novel laboratory screening bioassay for crop seedling allelopathy.

Crops that control weeds by root exudation of allelochemicals are receiving increased attention, and there are efforts to breed allelopathic cultivars in several crops. The genetic improvement of allelopathic traits is based upon parental germ plasm with high allelopathic activity. Identification of allelopathic germplasm is done in laboratory screening bioassays, but experimental protocols are limited. We developed a fast and reliable laboratory screening bioassay for grain crops that includes dose-response considerations as an integral part of the experimental design. The bioassay was conducted in hydroponic culture, and a range of experiments with 2-(3H)-benzoxazolinone (BOA), an allelochemical of several grain crops, was carried out to define the basic protocol. Because of its sensitivity to BOA, Sinapis alba L. was selected as the receiver species. BOA affected growth (fresh weight and length of shoot and root), enzyme activities (ascorbate peroxidase, catalase, glutathione S-transferase, peroxidase, phenylalanine ammonia-lyase), and chlorophyll fluorescence, whereby root length was the most reliable response parameter. BOA sensitivity was dependent on nutrients for all parameters measured, and, thus, no nutrients were added. A set of experiments with Secale cereale L. and Triticum aestivum L. as donor species was carried out to optimize the protocol. Light and pH were eliminated as primary causes for the observed inhibition. The proposed bioassay has several methodological advantages over current bioassays.

Benzoxazoles↗

Monolayers of diphenyldiacetylene derivatives: Tuning molecular tilt angles and photopolymerization efficiency via electrodeposited Ag interlayer on Au.

An electrodeposited Ag adlayer (upd, underpotential deposition) is utilized to improve monolayer photopolymerization of diphenyldiacetylene derivatives (DPDAs) that would otherwise exhibit no polymerization in solid state. Topochemical reaction of diacetylene derivatives via solid-state 1,4-addition yields polydiacetylenes which are of great importance due to properties associated with their ene-yne conjugated backbones. The polymerization efficiency heavily depends on the molecular arrangement in the crystals. For example, crystals of most DPDA derivatives show no activity for topochemical reaction because the bulky phenyl end groups space out the triple bonds and thus DPDAs require relatively large translation and rotation angles for polymerization. In principle, topochemical reaction is viable if molecules are in optimal arrangement. The upd interlayer can be applied to tune the adsorbate-substrate interactions, intermolecular spacing, and the molecular tilt angle by controlling the coverage of the Ag adlayer. It is thus possible to manipulate the molecular arrangement of DPDAs for the subsequent polymerization. Successful photopolymerization of DPDA monolayers is realized from the decrease in nu(C[triple bond]C) intensity by infrared reflectance absorbance spectroscopy, growth of ene-yne pi-pi* transition by UV-vis measurements, and enhanced electrochemical stability by the cathodic desorption protocol. The optimal efficiency of polymerization takes place on upd-modified substrates that can generate approximately 45 degrees tilt angle for DPDA derivatives.

Journal Article↗

The use of rapid assessment of enteric ICC and neuronal morphology may improve patient management in pediatric surgery: a new clinical pathological protocol.

Alterations in interstitial cells of Cajal (ICC) distribution and density may seriously influence gut motility. We and others have documented a disturbance of ICC and neurons in Hirschsprung's disease (HD), intestinal ischemia, and inflammation. The ability to remove intestine with permanent dysmotility improves significantly the prognosis. This may be important in the developing intestine especially in HD. More complete pathological information increases the accuracy of surgical decisions. Therefore we sought to develop a rapid, intraoperative immunohistochemical protocol for ICC and neurons in surgical specimens for routine diagnostic and therapeutic assessment of pediatric patients. To date, cKit is the only reliable immunohistochemistry for ICC identification. There are multiple antibodies in use for neuronal identification. A comparison of fixation methods and immunostaining using cKit and multiple intestinal neuronal antibodies was done. Fresh segments of surgically resected intestine were sectioned and stained using antibodies for ICC cell identification (anti-cKit) and for neuronal characterization. By carefully changing tissue fixation methods, different neuronal antibodies were tested to determine an optimal rapid protocol. Each suggested protocol was tested on normal and pathological intestinal tissue and compared to the previous overnight immunostaining of the same tissue. A new rapid tissue fixation and immunostaining protocol using cKit for ICC identification and NF 68 was developed. By employing this protocol, we could obtain ICC and neuro-immunohistochemistry in unfixed frozen sections within 1 h with tissue vibration to diminish the time for immunostaining. Without vibration the protocol takes 3 h. ICC and enteric neuronal changes could be readily observed and the quality of staining was comparable to standard immunohistochemistry. Each gut pathology displayed characteristic changes in ICC and neuronal density/distribution in the affected bowel. The time-scale of the 1-h immunoprocessing is still longer than the standard clinical pathological "quick" sections using H&E staining; however, the protocol duration is within the surgery timescale. Standard H&E stain used in combination with our rapid neuronal and ICC immunohistochemistry protocol enables a fast, comprehensive, and accurate assessment of the pathophysiology of signaling networks controlling gut motility while the patient is still in the operating room. We propose that the addition of this simple and rapid immunohistochemical assessment in the pathologist evaluation of surgical specimens would result in a more complete characterization for diagnosis and prognosis of the pediatric patient. Specifically, we propose that this test will differentiate good versus poor prognosis HD patients based on their neuron/ICC ratio and present a rapid, standardized method for use in general pathology.

Colon↗

A reliable and sensitive method for non-radioactive northern blot analysis of nerve growth factor mRNA from brain tissues.

This report describes a sensitive, rapid and reproducible protocol for non-isotopic Northern blotting analysis. Church buffer and probes labeled with digoxigenin (DIG) were used for studying the expression of nerve growth factor (NGF) in the rat brain. Using the described method, NGF cRNA probe was hybridized to blotted RNA and the results were compared to Northern blot obtained using the method recommended by the manufacturer (Boehringer Mannheim). Comparison revealed that the blot treated with Church buffer detected at least 10-fold more NGF mRNA as compared to blot hybridized with formamide buffer. In summary, we have developed an optimal hybridization protocol to perform non-radioactive Northern blot analysis using antisense RNA as a probe. This method allowed us to detect the specific low-abundant mRNA and analyze the expression of neurotrophic factors in the rat brain.

Animals↗

Regional chemotherapy of non-resectable liver metastases from colorectal cancer - literature and institutional review.

BACKGROUND: Cure is possible by resecting colorectal isolated liver metastases. In non-resectable isolated colorectal liver metastases (CRLM), regional chemotherapy has been advocated to optimize the disease control in the liver in order to improve the results of the alternative, systemic chemotherapy. The drugs are delivered by means of hepatic artery infusion (HAI) via ports or pumps; pharmacological modifications of the hepatic arterial blood-flow-like HAI with starch microspheres or stop-flow and perfusion techniques were applied to improve HAI. METHODS: We reviewed the literature and report our progress, up to May 1999, in analyzing the validity of HAI for CRLM therapy. RESULTS: In the majority of phase-II and -III trials, the response rates to HAI were significantly higher than those from systemic chemotherapy, and local disease control could be achieved even when HAI was used second line to systemic chemotherapy. The meta-analysis of randomized trials comparing HAI with either systemic chemotherapy (five trials) or, optionally, either 5-fluorouracil (FU) or symptomatic treatment (two trials) showed a significant advantage of HAI in response (41% vs 14%, P<10(-10)) and median survival time (15 months vs 11 months, P<0.0009). The active anabolite of 5-FU, 5-fluordeoxyuridine (5-FUDR), the drug of choice for HAI in those trials, may cause severe hepatotoxicity. To avoid this toxicity, we developed a HAI protocol using mitoxantrone, 5-FU plus folinic acid (FA) and mitomycin C (MFFM). The response rates of HAI with 5-FU plus FA or MFFM were 45% and 66%, the interim median survival times 19.8 months and 27.4 months. 5-Year survivors were observed in all our protocols. Since no severe hepatotoxicity occurred, 9 of 74 patients were resected after response to HAI with 5-FU plus FA or MFFM, without surgical mortality and with survival times from 2+ months to 58+ months. CONCLUSION: The high response rates, the long survival times, the possibility of achieving 5-year-survival either by HAI alone or by resection after down staging with HAI all sum up to the evidence that HAI could be the primary choice of treatment for CRLM. Phase-III trials are conducted to compare the protocols with optimal regional versus systemic chemotherapy.

Adenocarcinoma↗