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1.
Ann Surg Oncol ; 22(8): 2578-84, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25582740

ABSTRACT

BACKGROUND: Currently, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are accepted treatments for surgically resectable appendiceal epithelial neoplasms. However, for nonsurgical candidates, systemic treatment may be considered. The purpose of this analysis was to determine the benefit of biologic therapy (anti-vascular endothelial growth factor and anti-epidermal growth factor receptor) in addition to systemic chemotherapy in this select patient population. METHODS: The MD Anderson Cancer Center tumor registry was retrospectively reviewed for systemic treatment-naive appendiceal epithelial neoplasm patients registered between January 2000 to July 2007 for prior cytoreductive surgery and hyperthermic intraperitoneal chemotherapy status, histologic grade, signet ring pathology, systemic chemotherapy, biologic therapy, tumor markers (carcinoembryonic antigen, carbohydrate antigen [CA] 125, and/or CA19-9), progression-free survival (PFS), overall survival (OS), and disease control rate. Kaplan-Meier method, log-rank, and Cox proportional hazard regression models were used for statistical analysis. RESULTS: A total of 353 patients were identified; 130 patients met the inclusion criteria. Fifty-nine patients received biologic therapy. The use of the anti-vascular endothelial growth factor (VEGF) agent bevacizumab improved both OS (42 months vs. 76 months, hazard ratio 0.49 [95 % confidence interval 0.25-0.94] P = 0.03) and PFS (4 months vs. 9 months, hazard ratio 0.69 [95 % confidence interval 0.47-0.995], P = 0.047) for all histologic subtypes. Moderately differentiated tumors had an improved PFS relative to well-differentiated tumors, 9 months versus 3 months (P = 0.05). CONCLUSIONS: Bevacizumab in combination with chemotherapy appears to play a role in surgically unresectable appendiceal epithelial neoplasm patients, with an improvement in PFS and OS. Anti-VEGF agents should be strongly considered in the management of patients with higher-grade appendiceal epithelial neoplasms who are suboptimal candidates for surgical resection.


Subject(s)
Adenocarcinoma, Mucinous/drug therapy , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Appendiceal Neoplasms/drug therapy , Appendiceal Neoplasms/pathology , Carcinoma, Signet Ring Cell/drug therapy , Peritoneal Neoplasms/drug therapy , Pseudomyxoma Peritonei/drug therapy , Adenocarcinoma, Mucinous/secondary , Adenocarcinoma, Mucinous/surgery , Adult , Aged , Bevacizumab/administration & dosage , CA-19-9 Antigen/blood , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Capecitabine/administration & dosage , Carcinoembryonic Antigen/blood , Carcinoma, Signet Ring Cell/secondary , Carcinoma, Signet Ring Cell/surgery , Cetuximab/administration & dosage , Cisplatin/administration & dosage , Cytoreduction Surgical Procedures , Disease-Free Survival , ErbB Receptors/antagonists & inhibitors , Female , Fluorouracil/administration & dosage , Humans , Irinotecan , Leucovorin/administration & dosage , Male , Middle Aged , Neoplasm Grading , Organoplatinum Compounds/administration & dosage , Peritoneal Neoplasms/secondary , Peritoneal Neoplasms/surgery , Pseudomyxoma Peritonei/surgery , Retrospective Studies , Survival Rate , Tumor Burden , Vascular Endothelial Growth Factor A/antagonists & inhibitors
2.
Ann Surg Oncol ; 21(5): 1501-5, 2014 May.
Article in English | MEDLINE | ID: mdl-23793364

ABSTRACT

BACKGROUND: The American Society of Peritoneal Surface Malignancies (ASPSM) is a consortium of cancer centers performing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). This is a position paper from the ASPSM on the standardization of the delivery of HIPEC. METHODS: A survey was conducted of all cancer centers performing HIPEC in the United States. We attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters: (1) method, (2) inflow temperature, (3) perfusate volume, (4) drug, (5) dosage, (6) timing of drug delivery, and (7) total perfusion time. Statistical analysis was performed using nonparametric tests. RESULTS: Response rates for ASPSM members (n = 45) and non-ASPSM members (n = 24) were 89 and 33 %, respectively. Of the responders from ASPSM members, 95 % agreed with implementing the proposal. Majority of the surgical oncologists favored the closed method of delivery with a standardized dual dose of mitomycin for a 90-min chemoperfusion for patients undergoing cytoreductive surgery for peritoneal carcinomatosis of colorectal origin. CONCLUSIONS: This recommendation on a standardized delivery of HIPEC in patients with colorectal cancer represents an important first step in enhancing research in this field. Studies directed at maximizing the efficacy of each of the seven key elements will need to follow.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/therapy , Consensus , Hyperthermia, Induced , Peritoneal Neoplasms/therapy , Practice Guidelines as Topic/standards , Chemotherapy, Cancer, Regional Perfusion , Combined Modality Therapy , Humans , Societies, Scientific
3.
Ann Oncol ; 23(3): 652-658, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21653683

ABSTRACT

BACKGROUND: Poorly differentiated and signet ring cell adenocarcinomas of the appendix represent a subset with aggressive tumor biology and poor outcomes with few studies evaluating the impact of systemic chemotherapy and cytoreductive surgery (CRS). PATIENTS AND METHODS: A retrospective chart review of patients with either poorly differentiated and signet ring cell appendiceal adenocarcinomas was completed from 1992 to 2010. RESULTS: One hundred forty-two patients were identified. Seventy-eight patients with metastatic disease received chemotherapy. Radiographic response was 44%, median progression-free survival (PFS) was 6.9 months, and median overall survival (OS) was 1.7 years. In multivariate analysis, response to chemotherapy [hazard ratio (HR) 0.5; P = 0.02] predicted improved PFS, and complete CRS (HR 0.3; P = 0.004) predicted improved OS. Patients who underwent complete CRS (n = 26) had a median relapse-free survival (RFS) of 1.2 years and a median OS of 4.2 years. In multivariate analysis for this subset, complete cytoreduction score of 0 was significantly correlated with improved RFS (HR 0.07; P = 0.01) and OS (HR 0.02; P = 0.01). CONCLUSIONS: Systemic chemotherapy appears to be a viable treatment option for patients with metastatic poorly differentiated and signet ring cell appendiceal adenocarcinomas. Complete CRS is associated with improved RFS and OS, though part of this benefit likely reflects the selection of good tumor biology.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Appendiceal Neoplasms/drug therapy , Appendiceal Neoplasms/surgery , Carcinoma, Signet Ring Cell/drug therapy , Carcinoma, Signet Ring Cell/surgery , Adult , Aged , Aged, 80 and over , Appendiceal Neoplasms/pathology , Carcinoma, Signet Ring Cell/pathology , Combined Modality Therapy , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Retrospective Studies
5.
Br J Cancer ; 99(5): 734-40, 2008 Sep 02.
Article in English | MEDLINE | ID: mdl-18728664

ABSTRACT

Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.


Subject(s)
Antineoplastic Agents/therapeutic use , Melanoma/drug therapy , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Skin Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Base Sequence , Benzamides , DNA Primers , Disease Progression , Female , Humans , Imatinib Mesylate , Male , Melanoma/blood supply , Melanoma/diagnostic imaging , Melanoma/secondary , Middle Aged , Piperazines/adverse effects , Positron-Emission Tomography , Pyrimidines/adverse effects , Skin Neoplasms/blood supply , Skin Neoplasms/diagnostic imaging , Skin Neoplasms/pathology , Treatment Outcome
6.
Phys Med Biol ; 53(7): 1811-27, 2008 Apr 07.
Article in English | MEDLINE | ID: mdl-18364540

ABSTRACT

Peripheral neural stimulation is a major problem in current gradient coil designs. Induced current problems in patients relate directly to gradient strength and modulation frequency. Present designs of gradient coil tend to limit ultra-high-speed imaging methods such as echo-planar imaging (EPI) and echo-volumar imaging (EVI) because of the effect of induced currents in the patient which produce neural stimulation resulting in tingling sensations and involuntary muscle twitch. Neural stimulation could also trigger epileptic fits and/or cardiac fibrillation. For reduction of induced currents, an important aspect is the coil geometry. It is desirable to design the gradient coil in such a way as to prevent closed loop circulating currents within the body. Preliminary results using a four-sector gradient coil with a rectangular geometry, operating in a low mutual coupling mode and using passive E-field control, indicate significant reduction of the E-field within the subject volume of the coil, leading to a reduction of induced currents in a patient. Such a reduction allows safer operation using higher magnetic gradient strengths together with faster scans. Currently very fast scans are prohibited by virtue of the neural stimulation effects produced in present standard coil geometries.


Subject(s)
Echo-Planar Imaging/methods , Magnetic Resonance Imaging/instrumentation , Magnetic Resonance Imaging/methods , Neurons/pathology , Algorithms , Animals , Computer Simulation , Electromagnetic Fields , Electronics, Medical/instrumentation , Equipment Design , Humans , Magnetics , Models, Statistical , Oscillometry/instrumentation , Software
8.
MAGMA ; 20(5-6): 223-31, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18004601

ABSTRACT

Results are presented for a model three-axis gradient coil incorporating active acoustic control which is applied to the switched read gradient during a single-shot rapid echo-planar imaging (EPI) sequence at a field strength of 3.0 T. The total imaging acquisition time was 10.6 ms. Substantial noise reduction is achieved both within the magnet bore and outside the magnet. Typical internal noise reduction over the specimen area is 40 dB(A) whereas outside the acoustic chamber the noise level is reduced by 60-67 dB(A). However these results are relative to a control winding which is switched in phase, adding 6 dB(A) in its non-optimized mode, which is included in the quoted figures.


Subject(s)
Magnetic Resonance Imaging/instrumentation , Acoustics , Biomedical Engineering , Echo-Planar Imaging/instrumentation , Equipment Design , Humans , Models, Theoretical , Noise/prevention & control , Phantoms, Imaging , Vibration/adverse effects
9.
Hum Reprod ; 21(6): 1442-52, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16439502

ABSTRACT

BACKGROUND: We evaluate the performance of ovulation detection methods and present new approaches, including evaluation of methods for precision, combining multiple markers into a hierarchical system and using ovulation markers in intermittent sampling designs. METHODS: With serum LH peak day as the 'gold standard' of ovulation, we estimated accuracy and precision of ovulation day algorithms using 30 ovulatory menstrual cycles with daily urinary and serum hormones and transvaginal ultrasound. Sensitivity and specificity for estimating the presence of ovulation were tested using visually assessed ovulatory (30) and anovulatory (22) cycles. RESULTS: Sensitivity and specificity ranged from 70 to 100% for estimating presence of ovulation with twice-per-cycle, weekly, twice weekly, every-other-day and daily specimens. A combined hierarchical method estimated ovulation day using daily specimens within +/-2 days of the gold standard in 93% of cases. Accuracy of estimating ovulation day within +/-2 days using intermittent sampling ranged from 40% (weekly sampling) to 97% (every-other-day). CONCLUSIONS: A combined hierarchical algorithm using precise and accurate markers allows maximal use of available data for efficient and objective identification of ovulation using daily specimens. In intermittent sampling designs, the presence and the timing of ovulation can be estimated with good sensitivity, specificity and accuracy.


Subject(s)
Chemistry, Clinical/methods , Hormones/urine , Ovulation/urine , Adult , Estrone/analogs & derivatives , Estrone/blood , Female , Follicle Stimulating Hormone/blood , Humans , Luteinizing Hormone/analysis , Luteinizing Hormone/blood , Middle Aged , Pregnanediol/analogs & derivatives , Pregnanediol/blood , Reproducibility of Results , Sensitivity and Specificity
10.
J Clin Oncol ; 23(6): 1237-44, 2005 Feb 20.
Article in English | MEDLINE | ID: mdl-15718321

ABSTRACT

PURPOSE: Preoperative chemoradiotherapy may increase the R0 (curative) resection rate, overall survival (OS) duration, and disease-free survival (DFS) duration. We evaluated paclitaxel-based induction chemotherapy and chemoradiotherapy in patients with localized gastric or gastroesophageal adenocarcinoma to determine its feasibility, impact on the R0 resection rate, type of pathologic response, OS, and DFS. PATIENTS AND METHODS: Patients with operable, localized gastric, or gastroesophageal adenocarcinoma were eligible. Staging included endoscopic ultrasonography (EUS) and laparoscopy. Patients received two 28-day cycles of induction chemotherapy of fluorouracil, paclitaxel, and cisplatin followed by 45 Gy of radiation and concurrent fluorouracil plus paclitaxel. The cancer was restaged and surgery was attempted. Postsurgery pathologic findings and R0 resection were correlated with OS and DFS. RESULTS: Forty-one patients were enrolled. Most carcinomas were proximal (83%) and pretreatment stage EUST3 (85%). Forty patients (98%) underwent surgery, and 78% had an R0 resection. We observed a pathologic complete response (pathCR) rate of 20% and a pathologic partial response (pathPR) rate of 15% (< 10% residual cancer cells in the resected specimen). No pretreatment parameter (sex, cancer location, baseline T stage, or baseline N stage) predicted the type of postsurgery pathologic response, OS, or DFS. However, pathCR (P = .02), pathCR + pathPR (P = .006), R0 resection (P < .001), and postsurgery T and N stages (P = .01 and P < .001, respectively) were associated with OS. Same parameters were significantly correlated with DFS. Toxicity was manageable. CONCLUSION: The type of pathologic response but not pretreatment parameters was associated with OS and DFS. Efforts to increase the rate of pathologic response and better systemic cancer control are warranted.


Subject(s)
Adenocarcinoma/therapy , Chemotherapy, Adjuvant , Paclitaxel/administration & dosage , Radiotherapy, Adjuvant , Stomach Neoplasms/therapy , Adenocarcinoma/mortality , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Combined Modality Therapy , Drug Administration Schedule , Esophageal Neoplasms/mortality , Esophageal Neoplasms/pathology , Esophageal Neoplasms/therapy , Female , Humans , Male , Neoadjuvant Therapy , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Survival Analysis
11.
J Clin Oncol ; 22(14): 2774-80, 2004 Jul 15.
Article in English | MEDLINE | ID: mdl-15254045

ABSTRACT

PURPOSE: In the West, curative (R0) resection is achieved in approximately 50% of patients with localized gastric carcinoma, and more than 60% die of cancer following an R0 resection. A multi-institutional study of preoperative chemoradiotherapy was done to assess the R0 resection rate, pathologic complete response (pathCR) rate, safety, and survival in patients with resectable gastric carcinoma. PATIENTS AND METHODS: Operable patients with localized gastric adenocarcinoma were eligible. Staging also included a laparoscopy and endoscopic ultrasonography (EUS). Patients received up to two 28-day cycles of induction chemotherapy of fluorouracil, leucovorin, and cisplatin, followed by 45 Gy of radiation plus concurrent fluorouracil. Patients were then staged and surgery was attempted. RESULTS: Thirty-four patients were registered at three institutions. One ineligible patient was excluded. Most patients had a promixal cancer and EUST3N1 designation. Twenty-eight (85%) of 33 patients underwent surgery. The R0 resection rate was 70% and pathCR rate was 30%. A pathologic partial response (< 10% residual carcinoma in the primary) occurred in eight patients (24%). EUS T plus N and postsurgery T plus N correlation showed significant downstaging (P = <.01). The median survival time for 33 patients was 33.7 months. Patients achieving a pathCR or pathPR had a significantly longer median survival time (63.9 months) than those achieving less than pathPR (12.6 months; P =.03). There were two treatment-related deaths. CONCLUSION: Our data suggest that the three-step strategy of preoperative induction chemotherapy followed by chemoradiotherapy resulted in substantial pathologic response that resulted in durable survival time. This strategy is worthy of a direct comparison with postoperative adjuvant chemoradiotherapy.


Subject(s)
Adenocarcinoma/therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Stomach Neoplasms/therapy , Adenocarcinoma/pathology , Adult , Aged , Cisplatin/administration & dosage , Combined Modality Therapy , Female , Fluorouracil/administration & dosage , Folic Acid/administration & dosage , Gastrectomy/methods , Humans , Leucovorin/administration & dosage , Male , Middle Aged , Neoplasm Staging , Radiotherapy/methods , Stomach Neoplasms/pathology , Survival Analysis , Treatment Outcome
12.
Br J Cancer ; 90(3): 705-11, 2004 Feb 09.
Article in English | MEDLINE | ID: mdl-14760388

ABSTRACT

The purpose of this study was to examine the effects of ZD6126, a novel vascular-targeting agent, on tumour growth and angiogenesis in an orthotopic model of gastric cancer. TMK-1 human gastric adenocarcinoma cells were injected into the gastric wall of nude mice. After the tumours were established (day 14), therapy was initiated. Mice (n=11-12/group) received (a). vehicle, (b). ZD6126 at 100 mg x kg day(-1) i.p. one time per week or (c) ZD6126 at 100 mg x kg day(-1) i.p. five times per week. Tumour mass, volume and the presence or absence of peritoneal carcinomatosis were determined at sacrifice on day 38. Tumours from each group were stained for markers of blood vessels, proliferation and apoptosis. To further define the time frame of the vascular-targeting effects of chronic therapy with ZD6126, TMK-1 cells were again injected into the gastric wall of mice in a second experiment. On day 14, a single i.p. injection of ZD6126 100 mg x kg(-1) mouse(-1) or vehicle was delivered. Groups of three mice each were killed and the tumours harvested at days 1, 3 and 5 post-ZD6126 injection. Tumours were processed and stained for endothelial and tumour cell apoptosis and proliferation. No overt toxicity was observed with ZD6126 therapy. ZD6126 led to a marked inhibition of tumour growth (82% decrease vs control (P<0.001)). ZD6126 also led to a significant decrease in the incidence of peritoneal carcinomatosis (10 out of 12 controls, vs one out of 12 ZD6126) (P<0.01). Histological analysis of tumours revealed large regions of central necrosis in the treated group, as well as a dramatic increase in tumour cell apoptosis (7.4-fold increase (P<0.001)), consistent with the vascular-targeting activity of ZD6126. Mice treated with ZD6126 demonstrated a 59% decrease in PCNA-positive cells (P< 0.02), indicating reduced tumour cell proliferation. In addition, tumours treated with ZD6126 exhibited a 40% decrease in microvessel density (P<0.05). Results from mice treated with a single injection of ZD6126 demonstrated the acute effects this agent has on the tumour vasculature. The ratio of endothelial cell apoptosis to endothelial cell proliferation was increased within 24 h of a single injection. In conclusion, ZD6126 significantly inhibited tumour growth and metastasis in an orthotopic model of human gastric adenocarcinoma, without detectable problematic adverse effects. These data suggest that ZD6126 may be worthy of investigation in the treatment of primary gastric adenocarcinoma.


Subject(s)
Adenocarcinoma/pathology , Neoplasm Metastasis/physiopathology , Neovascularization, Pathologic , Organophosphorus Compounds/pharmacology , Peritoneal Neoplasms/secondary , Stomach Neoplasms/physiopathology , Animals , Apoptosis , Cell Division , Disease Models, Animal , Disease Progression , Endothelial Cells , Humans , Mice , Mice, Nude , Tumor Cells, Cultured
13.
MAGMA ; 16(3): 113-20, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14593514

ABSTRACT

Peripheral neural stimulation is a major problem in current gradient coil designs. Induced current problems in patients relate directly to gradient strength and modulation frequency. Current designs of gradient coil tend to limit ultra-high-speed imaging methods such as echo-planar imaging through the effect of induced currents which produce tingling sensations and involuntary muscle twitch. Neural stimulation could also trigger epileptic fits and/or cardiac fibrillation. For reduction of induced currents, an important aspect is the coil geometry. It is desirable to design the gradient coil in such a way as to prevent closed loop circulating currents within the body. Preliminary results using a four-sector gradient coil with rectangular geometry, operating in a low mutual coupling mode, indicate significant reduction in the E-field within the subject volume of the coil. Reduction in induced currents in the patient allows safer operation at higher magnetic field strengths together with faster scans currently prohibited through neural stimulation effects in standard coil geometries.


Subject(s)
Equipment Safety/instrumentation , Evoked Potentials/radiation effects , Magnetic Resonance Imaging/adverse effects , Magnetic Resonance Imaging/instrumentation , Magnetics/adverse effects , Magnetics/instrumentation , Models, Biological , Neurons/radiation effects , Computer Simulation , Computer-Aided Design , Equipment Design , Equipment Failure Analysis , Equipment Safety/methods , Humans , Magnetic Resonance Imaging/methods , Radiation Dosage , Radiometry/methods
14.
Magn Reson Med ; 50(5): 931-5, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14587003

ABSTRACT

The concept of active acoustic control was recently introduced by Mansfield and Haywood (MAGMA 2000:10:147-151) to ameliorate the problem of acoustic noise from MRI, particularly that from high-speed EPI. A 30 dB reduction in noise was previously achieved with the use of acoustic control operating at spot frequencies within a narrow band. In this work, a new acoustic gradient pulse is introduced that comprises an oscillating gradient of finite duration, incorporating a combination of frequencies within this band designed for use as the switched read gradient in echo-planar imaging (EPI). Employing this pulse with active acoustic control results in a reduction of acoustic noise by 50 dB.


Subject(s)
Acoustics , Echo-Planar Imaging/methods , Electricity , Humans
15.
J Cancer Res Clin Oncol ; 129(10): 549-55, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14513369

ABSTRACT

PURPOSE: To perform a phase I study of intraperitoneal cis-bis-neodecanoato ( trans- R, R-1, 2-diaminocyclohexane)-platinum II entrapped in multilamellar vesicles (L-NDDP) for peritoneal carcinomatosis or sarcomatosis. METHODS: Eligible patients had normal renal, hematologic, and liver functions. Laparoscopy was performed on the first two courses for evaluation, adhesiolysis, and chemotherapy administration. Afterwards, chemotherapy was administered through a peritoneal catheter. Up to six courses were allowed. Peritoneal imaging with technetium-labeled sulfur colloid was used to determine adequate distribution prior to each course. Volunteering patients underwent pharmacokinetics studies during the second course. RESULTS: Fifteen of 16 registered patients, seven women and eight men (median age 53 years (range 26-76) and median performance status of 1) were assessable. Diagnoses were: malignant mesothelioma (six patients), signet ring cell (three), colon adenocarcinoma, pseudomyxoma peritonei, gastrointestinal stromal tumor (two each), and ovarian carcinoma (one). Median number of courses was two (range, one to six) Dose-limiting toxicity symptoms were fatigue and abdominal pain. Hematologic toxicities were minimal. Peri-operative complications included one colonic perforation requiring primary closure, a peritoneal catheter malfunction, a port site hematoma, and an ascites leak requiring re-suture. Five patients survived at least 3 years. Pharmacokinetics studies indicated a rapid but low absorption of drug into the systemic circulation, with a prolonged retention of platinum in the plasma compartment. Peritoneal L-NDDP exposure was 17 to 49-times greater than in the plasma compartment. CONCLUSIONS: Peritoneal cavity exposure to L-NDDP is prolonged, and systemic absorption is limited, yielding a high peritoneal/plasmatic ratio. The recommended dose for phase II studies is 400 mg/m2 every 28 days.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Organoplatinum Compounds/pharmacokinetics , Peritoneal Neoplasms/metabolism , Adenocarcinoma/drug therapy , Adenocarcinoma/metabolism , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/blood , Area Under Curve , Ascites/metabolism , Carcinoma, Signet Ring Cell/drug therapy , Carcinoma, Signet Ring Cell/metabolism , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Endometrial Stromal Tumors/drug therapy , Endometrial Stromal Tumors/metabolism , Female , Humans , Injections, Intraperitoneal , Liposomes , Male , Mesothelioma/drug therapy , Mesothelioma/metabolism , Middle Aged , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/blood , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Peritoneal Neoplasms/drug therapy , Peritoneum/diagnostic imaging , Peritoneum/metabolism , Radionuclide Imaging , Technetium , Tissue Distribution
17.
Br J Cancer ; 88(5): 796-802, 2003 Mar 10.
Article in English | MEDLINE | ID: mdl-12618892

ABSTRACT

The epidermal growth factor receptor (EGF-R) pathway plays a pivotal role in the progression of human gastric cancer. The angiogenic factor vascular endothelial growth factor (VEGF) has been shown to be induced by EGF in various cancer cell lines. Neuropilin-1 (NRP-1) acts as a coreceptor for VEGF-165 and increases its affinity for VEGF receptor 2 (VEGFR-2) in endothelial cells. Furthermore, NRP-1 has been found to be expressed by tumour cells and has been shown to enhance tumour angiogenesis and growth in preclinical models. We examined the expression of NRP-1 mRNA and EGF-R protein in seven human gastric cancer cell lines. NRP-1 expression was expressed in five of seven cell lines, and EGF-R expression closely mirrored NRP-1 expression. Moreover, in EGF-R-positive NCI-N87 and ST-2 cells, EGF induced both NRP-1 and VEGF mRNA expression. C225, a monoclonal antibody to EGF-R, blocked EGF-induced NRP-1 and VEGF expression in NCI-N87 cells in a dose-dependent manner. The treatment of NCI-N87 cells with EGF resulted in increases in phosphorylation of Erk1/2, Akt, and P38. Blockade of the Erk, phosphatidylinositol-3 kinase/Akt, or P38 pathways in this cell line prevented EGF induction of NRP-1 and VEGF. These results suggest that regulation of NRP-1 expression in human gastric cancer is intimately associated with the EGF/EGF-R system. Activation of EGF-R might contribute to gastric cancer angiogenesis by a mechanism that involves upregulation of VEGF and NRP-1 expression via multiple signalling pathways.


Subject(s)
Endothelial Growth Factors/genetics , Epidermal Growth Factor/physiology , Gene Expression Regulation, Neoplastic/physiology , Intercellular Signaling Peptides and Proteins/genetics , Lymphokines/genetics , Neuropilin-1/genetics , Stomach Neoplasms/metabolism , Base Sequence , Blotting, Northern , Blotting, Western , DNA Primers , Humans , Immunohistochemistry , Phosphorylation , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/physiology , Stomach Neoplasms/pathology , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
18.
Radiat Prot Dosimetry ; 98(3): 313-28, 2002.
Article in English | MEDLINE | ID: mdl-12018748

ABSTRACT

Models are routinely used to calculate doses following routine releases and potential accidental releases of radionuclides. These models contain a number of parameters. Values for many of these are not accurately known. The primary aim of this study was to determine the level of uncertainty on predicted concentrations of radionuclides in foods, and doses to individuals consuming those foods, arising from uncertainties on the model input parameter values. A secondary objective was to identify those input parameters whose uncertainty makes a major contribution to the overall uncertainty on the predicted endpoints. The methodology adopted and results obtained are presented for the following radionuclides: 90Sr, 131I, 137Cs and 239Pu. The estimated uncertainty ratios (the ratio of the 95th to the 5th percentile) are frequently very large, often two to three orders of magnitude. The results of this study may be used to identify areas where further research could improve assessment capabilities.


Subject(s)
Computer Simulation , Food Contamination, Radioactive , Nuclear Reactors , Accidents , Adult , Cesium Radioisotopes/metabolism , Europe , Humans , Iodine Radioisotopes/metabolism , Plutonium/metabolism , Strontium Radioisotopes/metabolism
19.
Eur J Cancer ; 38(8): 1133-40, 2002 May.
Article in English | MEDLINE | ID: mdl-12008203

ABSTRACT

We hypothesised that the combination of anti-angiogenic and anti-epidermal growth factor (EFG)-receptor (R) therapies would more effectively inhibit gastric cancer growth than single-agent therapy. TMK-1 gastric cancer cells were injected into the gastric wall of nude mice to generate tumours. After 4 days, mice were randomly assigned to the following groups: control, DC101 ([vascular endothelial growth factor (VEGF)-receptor (R)-2 antibody], C225 (EGF-R antibody), or a combination of DC101 and C225. The combination therapy significantly inhibited gastric tumour growth compared with the control group, whereas the decrease in tumour growth in mice treated with DC101 or C225 alone did not reach statistical significance. All mice administered DC101 demonstrated decreased tumour vascularity and increased endothelial cell apoptosis. C225 alone did not affect angiogenesis, but inhibited tumour cell proliferation. The combination therapy led to a further decrease in tumour cell proliferation. The combination of anti-VEGF-R and anti-EGF-R therapies was effective in inhibiting gastric cancer growth. These findings support the hypothesis that inhibiting multiple biological pathways that mediate tumour growth may be an effective therapeutic strategy.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , ErbB Receptors/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptors, Growth Factor/antagonists & inhibitors , Stomach Neoplasms/drug therapy , Animals , Apoptosis , Cell Division , ErbB Receptors/immunology , Immunohistochemistry , Mice , Mice, Nude , Neovascularization, Pathologic/prevention & control , Random Allocation , Receptor Protein-Tyrosine Kinases/immunology , Receptors, Growth Factor/immunology , Receptors, Vascular Endothelial Growth Factor , Stomach Neoplasms/blood supply , Tumor Cells, Cultured
20.
Mar Pollut Bull ; 42(10): 927-34, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11693647

ABSTRACT

Estimates have been made of the reduction in dissolved oxygen levels in coastal waters that would result from the disposal of contaminated milk following a radiological accident. Two contrasting sites were chosen: the Bristol Channel near Hinkley Point and the coast of Cumbria near Sellafield. The results suggest that the dilution would be sufficiently strong near Hinkley Point, due to vigorous tidal mixing, that the impact on the DO levels of the coastal waters would be negligible. However, at both Sellafield and Heysham the disposal of milk could result in a reduction of the DO by 1-2 mg l(-1). In contrast to shallow estuarine waters, the recovery of oxygen levels due to the effects of re-aeration through surface gas exchange is unlikely to be significant due to the depth of the coastal waters. However, the recovery of the dissolved oxygen levels to ambient conditions following the completion of the discharge would occur on a time scale of about 17 days due to mixing of the DO deficit plume into the surrounding waters.


Subject(s)
Food Contamination, Radioactive/analysis , Milk/metabolism , Oxygen/metabolism , Seawater/analysis , Water Pollutants, Radioactive/analysis , Animals , Milk/radiation effects , Radioactive Hazard Release , Radioactive Waste/analysis , Radioactive Waste/prevention & control , United Kingdom
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