Biomedical subjects

G Leder

Publications and source records attributed to G Leder.

At least 73 records · Page 4Linked to original sources

PubMed2002

Observation of the eta(c)(2S) in Exclusive B-->KK(S)K-pi(+) Decays.

We report the observation of a narrow peak in the K(S)K-pi(+) invariant mass distribution in a sample of exclusive B-->KK(S)K-pi(+) decays collected with the Belle detector at the KEKB asymmetric e(+)e(-) collider. The measured mass of the peak is M=3654+/-6(stat)+/-8(syst) MeV/c(2), and we place a 90% confidence level upper limit on the width of Gamma<55 MeV/c(2). The properties agree with heavy-quark potential model expectations for the eta(c)(2S) meson, the n=2 singlet S charmonium state.

Journal Article↗

PubMed2002

Observation of chi(c2) production in B meson decay.

We report the first observation of chi(c2) production in B meson decays. We find an inclusive B-->chi(c2)X branching fraction of (1.80(+0.23)(-0.28)+/-0.26) x 10(-3). The data set, collected with the Belle detector at the KEKB e(+)e(-) collider, consists of 31.9 x 10(6) BB events. We also present branching fractions and momentum spectra for both chi(c1) and chi(c2) production.

Journal Article↗

PubMed2002

Observation of B(+/-) --> p(-)pK(+/-).

We report the observation of the decay mode B(+/-) --> p(-)pK(+/-)based on an analysis of 29.4 fb(-1) of data collected by the Belle detector at KEKB. This is the first example of a b-->s transition with baryons in the final state. The p(-)p mass spectrum in this decay is inconsistent with phase space and is peaked at low mass. The branching fraction for this decay is measured to be B(B+/--->p(-)pK+/-) = [4.3(+1.1)(-0.9)(stat)+/-0.5(syst)]x 10(-6). We also report upper limits for the decays B(0)-->p(-)pK(S) and B(+/-)-->p(-)p pi(+/-).

Journal Article↗

PubMed2002

Measurement of the lifetime difference in D0 meson decays.

We report a measurement of the D0-D macro(0) mixing parameter y(CP) using 23.4 fb(-1) of data collected near the Upsilon(4S) resonance with the Belle detector at KEKB. y(CP) is measured from the lifetime difference of D0 mesons decaying into the K(-)pi(+) state and the CP-even eigenstate K(-)K(+). We find y(CP) = (-0.5+/-1.0(+0.7)(-0.8))x10(-2), where the first error is statistical and the second is systematic, corresponding to a 95% confidence interval -0.030<y(CP)<0.020.

Journal Article↗

PubMed2002

Production of prompt charmonia in e(+)e(-) annihilation at square root of s approximately equals 0.6 GeV.

The production of prompt J/psi, psi(2S), chi(c1), and chi(c2) is studied using a 32.4 fb(-1) data sample collected with the Belle detector at Upsilon(4S) and at 60 MeV below the resonance. The yield of prompt J/psi mesons in the Upsilon(4S) sample is compatible with that of continuum production; we set an upper limit B(Upsilon(4S)-->J/psiX) < 1.9 x 10(-4) at the 95% confidence level, and find sigma(e(+)e(-)-->J/psiX) = 1.47 plus/minus 0.10 plus/minus 0.13 pb. The cross sections for prompt psi(2S) and direct J/psi are measured. The J/psi momentum spectrum, production angle distribution, and polarization are studied.

Journal Article↗

PubMed2002

Observation of B+ --> chi(c0)K+.

Using a sample of 31.3x10(6) BB pairs collected with the Belle detector at the Upsilon(4S) resonance, we make the first observation of the charged B meson decay to chi(c0) and a charged kaon. The measured branching fraction is B(B+-->chi(c0)K+) = (6.0(+2.1)(-1.8)+/-1.1)x10(-4), where the first error is statistical, and the second is systematic.

Journal Article↗

PubMed2002

Pancreatic cancer: who benefits from curative resection?

Surgical resection is the only chance for cure of pancreatic cancer. Unfortunately, the majority of patients have grossly unresectable disease. Patients with stage I or II disease according to the criteria of the International Union Against Cancer (UICC) should be considered for potentially curative surgery. The goal of surgery is to remove the entire tumour with no residual disease (oncological R0 resection), which requires extensive resection of the surrounding tissues. Even if lymph nodes are histologically free of disease, molecular biological techniques reveal infiltration with cancer cells in 50% of cases. Therefore, extensive local resection combined with radical resection of lymphatic tissue, including lymph nodes around the head of the pancreas, retroperitoneal tissue and neural plexus around the great vessels, affords a longer median survival time than standard resection alone. Even patients with UICC stage III disease can undergo aggressive surgical treatment, but their chances for long term survival are low. Some patients develop severe diarrhea after circumferential removal of nerve tissue around the superior mesenteric artery. Adjuvant radiochemotherapy also provides a modest prolongation of survival. Despite these advances, the prognosis for pancreatic cancer is still poor, and spread of tumour within the peritoneum and to the liver is common postoperatively.

Chemotherapy, Adjuvant↗

PubMed2001

Observation of the decay B --> Kl+l-.

We report a search for the flavor-changing neutral current decay B-->K(*)l+l- using a 29.1 fb(-1) data sample accumulated at the Upsilon(4S) resonance with the Belle detector at the KEKB e+e- storage ring. We observe the decay process B-->Kl+l-(l = e, mu), for the first time, with a branching fraction of B(B-->Kl+l-) = (0.75(+0.25)(-0.21)+/-0.09)x10(-6).

Journal Article↗

PubMed2001

Regional chemotherapy of nonresectable colorectal liver metastases with mitoxantrone, 5-fluorouracil, folinic acid, and mitomycin C may prolong survival.

BACKGROUND: Regional chemotherapy of isolated, nonresectable colorectal liver metastases (CRLMs) by hepatic artery infusion (HAI) has the advantages of high response rates and the possibility of downstaging and resection of CRLMs. 5-Fluorodeoxyuridine (5-FUDR) has been the drug studied in most Phase II and III trials. The meta-analysis of the Phase III trials comparing HAI with systemic or supportive therapy confirmed an advantage for response and even survival for HAI. Hepatic artery infusion with 5-FUDR, however, is hepatotoxic, inducing sclerosing cholangitis (SC). The authors have introduced 5-fluorouracil (5-FU) with folinic acid for HAI and found equal effectivity but no SC when compared with HAI with 5-FUDR. Now, they report a new combination chemotherapy protocol based on HAI with 5-FU with FA and on in vitro Phase II studies suggesting mitoxantrone and mitomycin C as active drugs for HAI in CRLM. PATIENTS AND METHODS Between February 1993 and August 2000, 63 patients with CRLM were treated with HAI using mitoxantrone, 5-FU with FA, and mitomycin C (MFFM) via port catheters with a protocol planing up to 11 cycles of treatment. Toxicity and response were analyzed according to World Health Organization (WHO) criteria, and survival was analyzed according to Kaplan-Meier. All patients were treated with more than two HAI cycles. RESULTS: The objective response rate (complete remission and partial remission) was 54% and primary intrahepatic progression (progressive disease) occurred in 4.8%, whereas in 41.3% of the patients the intrahepatic disease was evaluated as no change. Median survival times from the first diagnosis of CRLM or start of HAI were 25.7 months and 23.7 months, respectively, and 7 patients lived longer than 40 months. Grade 3 toxicity according to WHO occurred in 34.9%, and Grade 4 occurred in 3.2%. No toxic death or SC occurred. CONCLUSIONS: Our new HAI protocol with MFFM seems to be superior to HAI with 5-FUDR, 5-FU with FA, and systemic chemotherapy with 5-FU and FA at acceptable toxicity. Currently, HAI with MFFM is compared with systemic chemotherapy using 5-FU and FA intravenously in a randomized Phase III trial.

Adult↗

PubMed2001

Reduced membranous and ectopic cytoplasmic expression of beta -catenin correlate with cyclin D1 overexpression and poor prognosis in pancreatic cancer.

Beta-catenin is a component of the E-cadherin-catenin cell adhesion complex. It plays also a role in intracellular signaling and can function as an oncogene when it binds to the T-cell factor 4 (Tcf4)-binding site in the promoter region of cyclin D1 and transactivates genes after translocation to the nucleus. We evaluated the immunohistochemical expression pattern of beta-catenin in relationship with cyclin D1 overexpression, tumor grade, clinicopathologic parameters and patients' survival in 43 ductal adenocarcinomas of the pancreas and 5 normal pancreatic tissues. We were able to show that, both reduced membranous beta-catenin expression (25 of 43, 58.1%) and accumulation of beta-catenin in the cytoplasm (28 of 43, 65.1%) correlated significantly with cyclin D1 overexpression (both p < 0.0005). Furthermore, we could show a clear correlation between reduced membranous expression and ectopic cytoplasmic expression of beta-catenin (p < 0.0005). Among patients with carcinomas showing no cytoplasmic expression, the 1-year survival was 86.6% whereas among patients with carcinomas showing cytoplasmic expression only 35.7% survived 1 year (p < 0.01). Co-precipitation experiments revealed reduced beta-catenin bound to the E-cadherin-catenin complex in pancreatic tumor tissues compared with normal pancreatic tissues. These results suggest that beta-catenin may be involved in the tumorigenesis of pancreatic cancer and exhibited its effects mainly by the transactivation of cyclin D1.

Adult↗

PubMed2001

Loss of the Y chromosome is a frequent chromosomal imbalance in pancreatic cancer and allows differentiation to chronic pancreatitis.

In a study for the identification of genomic alterations in pancreatic cancer, representational difference analysis was used and led to the isolation of 2 distinct fragments, deleted on the Y chromosome in the xenografted tumor DNA of a male patient with an adenocarcinoma of the pancreas. Loss of Y chromosomal material was further studied in 11 pancreatic cancer cell lines of male origin, using PCR amplification of 5 sequence tagged sites (STSs) distributed along the Y chromosome; 8/11 cell lines exhibited a complete loss of the Y chromosome and 3 had deletions. To examine the status of the Y chromosome in situ, interphase FISH analysis was performed on paraffin sections from pancreatic carcinoma (n=7) and chronic pancreatitis (n=7) tissues, and the loss of Y-chromosomal STS-markers was studied in 6 xenograft tumors obtained from male pancreatic cancer patients. This analysis revealed that a loss of the Y chromosome occurs in vivo in primary pancreatic tumor cells, whereas the Y chromosome was intact in chronic pancreatitis. Our data suggest that loss of Y is a frequent event occurring in male pancreatic tumors. Although there is no evidence for a functional implication of Y chromosome loss, it effectively differentiates between a malignant and a benign condition as e.g. chronic pancreatitis. Thus, this genetic alteration may be of diagnostic use.

Animals↗

PubMed2001

Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin.

BACKGROUND & AIMS: Recently, several members of the claudin family have been identified as integral constituents of tight junctions. Using expression profiling, we previously found claudin-4 to be overexpressed in pancreatic cancer. Because claudin-4 has been described as a receptor for the cytotoxic Clostridium perfringens enterotoxin (CPE), we investigated the effect of CPE on pancreatic cancer cells. METHODS: Expression of claudin-4 was analyzed by Northern blots. In vitro toxicity of CPE was determined by trypan blue exclusion and the (86)Rb-release assay. The in vivo effect of CPE was studied in claudin-4-expressing nude mouse xenografts of the Panc-1 cell line. RESULTS: Expression analyses showed that claudin-4 was overexpressed in most pancreatic cancer tissues and cell lines and several other gastrointestinal tumors. CPE led to an acute dose-dependent cytotoxic effect, restricted to claudin-4-expressing cells and dependent on claudin-4 expression levels. Furthermore, transforming growth factor beta was identified as a negative modulator of both claudin-4 expression and susceptibility to CPE. In vivo, intratumoral injections of CPE in Panc-1 xenografts led to large areas of tumor cell necrosis and significant reduction of tumor growth. CONCLUSIONS: Our findings suggest that targeting claudin-4-expressing tumors with CPE represents a promising new treatment modality for pancreatic cancer and other solid tumors.

Adenocarcinoma↗

PubMed2001

Biglycan is overexpressed in pancreatic cancer and induces G1-arrest in pancreatic cancer cell lines.

BACKGROUND & AIMS: Biglycan (PG-I), a component of the extracellular matrix (ECM), is overexpressed in pancreatic cancer. To determine possible matrix-tumor interactions, we investigated the effects of PG-I on pancreatic cancer. METHODS: PG-I expression in cell lines and tissue samples was examined by Northern blot and immunofluorescence. The effect of PG-I on proliferation was determined by measuring activity of Ras, ERK, Rb, [(3)H]-thymidine incorporation, and cell cycle analysis. Expression of cyclin A, B1, D1, E1, G1, PCNA, p21, and p27 was analyzed by Northern and Western blots. RESULTS: PG-I was overexpressed in the ECM of pancreatic cancer samples compared with normal pancreas or chronic pancreatitis tissues. Addition of transforming growth factor (TGF)-beta induced PG-I expression in HFL and HFFF2 fibroblasts as well as in the pancreatic cancer cell line PANC-1. PG-I inhibited growth of both TGF-beta-responsive and TGF-beta-unresponsive pancreatic cancer cells by inducing G1-arrest, which is accompanied by an increase of p27 and reduction of cyclin A and proliferating cell nuclear antigen. Furthermore, endogenous Ras and ERK activation was partly reduced by PG-I in vitro. CONCLUSIONS: The ECM protein PG-I inhibits growth by arresting pancreatic cancer cells in G1 and may be part of a host defense mechanism aimed at slowing down pancreatic tumor progression.

Adult↗

PubMed2000

Thymidylate synthase quantitation and in vitro chemosensitivity testing predicts responses and survival of patients with isolated nonresectable liver tumors receiving hepatic arterial infusion chemotherapy.

BACKGROUND: Patients with isolated, nonresectable liver tumors may receive regional hepatic arterial infusion (HAI) chemotherapy with response rates of about 50%. The objective of this study was to investigate the value of thymidylate synthase (TS) determination in combination with in vitro chemosensitivity testing to predict the responses and survival of patients receiving HAI. METHODS: TS mRNA expression was quantitated using a reverse transcription-polymerase chain reaction technique with beta-actin as the internal standard. In vitro chemosensitivity testing was performed with tumor cell suspensions using the human tumor colony-forming assay (HTCA). RESULTS: An analysis of the test combination in 24 consecutive patients revealed that 77% (10 of 13) of the sensitive and 9% (1 of 11) of the resistant patients had complete or partial clinical responses. Sensitive patients were 8.5-fold more likely to respond (P = 0.0036) and displayed with 32 months (range, 5-75 months) a longer median survival than resistant patients with 17 months (range, 3-28 months, P = 0.003). Analysis of the Kaplan-Meier curves revealed that sensitive patients had a higher overall survival probability, as determined by the log rank test (P = 0.044). CONCLUSIONS: These results suggest that the clinical outcomes of patients receiving HAI therapy may be predictable with TS quantitation and HTCA. It is possible, therefore, that this combination may be used in the future to select patients with liver tumors who will benefit from HAI before the start of regional chemotherapy.

Adult↗

PubMed2000

Ampullary but not periampullary duodenal diverticula are an etiologic factor for chronic pancreatitis.

BACKGROUND: Duodenal diverticula are common incidental findings. Although a definite treatment is rarely required, an association with biliary and pancreatic diseases is often suggested. Our aim was to determine the frequency of complications in relation to the location of the diverticulum. METHODS: We reviewed 64 patients with extraluminal duodenal diverticula. In 24 of these patients the diverticulum was treated surgically. The incidence of symptoms and complications is analyzed and follow-up in 88% of operated patients is presented. RESULTS: Thirty-one patients presented with ampullary, 36 patients with periampullary diverticula. Three patients had both types of diverticula. The indication for surgery in 24 patients was chronic pancreatitis (n = 12), chronic pain (n = 6), diverticular perforation (n = 3), bleeding (n = 2), or jaundice (n = 1). In 7 out of 31 patients with ampullary and none out of 36 patients with periampullary diverticula, chronic pancreatitis was considered to be induced by the diverticulum. Morbidity in 24 operated patients was 17%, no patient died. At follow-up all patients were free of symptoms. CONCLUSION: Extraluminal duodenal diverticula are frequently found. They rarely cause symptoms and need no surgical treatment. While ampullary duodenal diverticula can cause chronic pancreatitis, periampullary duodenal diverticula are no etiologic factor.

Adult↗

PubMed1999

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↗

PubMed1999

Downstaging by regional chemotherapy of non-resectable isolated colorectal liver metastases.

AIMS: To improve the course of isolated non-resectable colorectal liver metastases (CRLM) by hepatic arterial infusion treatment. Patients with CRLM have a worse prognosis than those whose liver metastases are resectable. Systemic (i.v.) chemotherapy for CRLM/colorectal metastases with 5-fluorouracil+folinic acid (5-FU+FA) i.v. may result in median survival times of 6.4-14.3 months. Hepatic artery infusion (HAI) with 5-fluorodeoxyuridine (5-FUDR) has been demonstrated in a meta-analysis of randomized trials to be superior to i.v. treatment/palliative care (median survival 15 vs. 10 months). The benefit of HAI with 5-FUDR, although recommended as treatment for CRLM, is severely compromised by the 5-FUDR induced hepatotoxicity, leading eventually to sclerosing cholangitis (SC)/liver cirrhosis. We have developed a stepwise protocol for HAI in CRLM, which is superior to HAI with 5-FUDR and to systemic chemotherapy. METHODS: Between 1982 and 1997, 168 CRLM patients were treated within the following protocols. In protocol A, 48 CRLM patients received HAI with 5-FUDR. In protocol B, 46 patients received 5-FUDR i.a. (HAI)+i.v. In protocol C 5-FU+FA were delivered via HAI in 24 patients with CRLM. In protocol D, based on in vitro phase II studies and the results of protocol C, mitoxantrone and mitomycin C were added to 5-FU+FA (MFFM). Fifty (50) CRLM patients received HAI with HFFM. RESULTS: The response rates, median survival time, systemic toxicity and SC rate were: 42%, 20.8 months, 0-19% and 38% for protocol A; 46%, 20.8 months, 0-20% and 41% for protocol B; 45%, 19.8 months, 4-25% and 0% for protocol C; and 66%, 27.4 months, 2-26% and 0% for protocol D. The surgically placed ports for HAI in protocols C and D functioned in 90%, 82% and 76% of patients, 6, 9, and 11 months after beginning HAI. Quality of life in protocol D was high. Nine patients from protocols C and D with either partial (PR, seven patients) or complete (CR, two patients) remissions received a secondary liver resection without hospital mortality, and seven of nine patients are alive 2-58 months after liver resection. The other two died 11 and 22 months after resection. CONCLUSIONS: Optimal treatment of CRLM was found to be protocol D: HAI with MFFM. The results of this protocol, including high remission rate, long median survival time, good port function, good quality of life and, interestingly, the possibility of downstaging and resecting primarily non-resectable metastases, seem to be superior to HAI with 5-FUDR or 5-FU+FA and to systemic chemotherapy with 5-FU+FA. This hypothesis is currently being examined in a phase III study (HAI with MFFM vs. 5-FU+FA i.v.).

Adult↗

PubMed1999

Basic research supported developments of chemotherapy in nonresectable isolated colorectal liver metastases to a protocol of hepatic artery infusion using mitoxantrone, 5-FU + folinic acid and mitomycin C.

OBJECTIVE: Since the developments in systemic chemotherapy of metastasized colorectal cancer have not resulted in substantial gains in survival times, we wished to improve the course of isolated nonresectable colorectal liver metastases (CPLM) by hepatic arterial infusion treatment. BACKGROUND: Patients (pts) with CRLM have a worse fate than those pts whose liver metastases could be resected. Systemic (i.v.) chemotherapy for CRLM/colorectal metastases does not improve survival to a relevant level (median survival time (med. surv.) after 5-Fluorouracil + Folinic Acid (5-FU + FA) i.v.: 6.4-14.3 months (m)). Hepatic artery infusion (HAI) with 5-Fluorode-oxyuridine (5-FUDR) has been demonstrated in a metaanalysis of randomized trials to be superior to i.v. treatment/palliative care (med. surv.: 15 vs. 10 m). The benefit of HAI with 5-FUDR, although recommended as treatment for CRLM, is severely compromised by the 5-FUDR induced hepatotoxicity, leading eventually to sclerosing cholangitis (SC)/liver scirrhosis. We have stepwise developed a protocol for HAI of CRLM, which is superior to HAI with 5-FUDR, and, most evidently, to systemic chemotherapy. PATIENTS/METHODS: Between 1982-1997, 222 CR (L) M patients were treated within subsequent protocols (Table). In protocol A, 68 CRLM pts received HAI with 5-FUDR (A1: nonrandomized pts; A2: randomized pts). In protocol B (randomized pts.), 46 pts received 5-FUDR i.a. (via HAI) + i.v. In protocol C, systemic chemotherapy with 5-FU + FA was conducted in 34 pts with metastasized colorectal cancers, including CRLM. In protocol D 5-FU + FA was delivered via HAI in 25 pts with CRLM. In protocol E, based on in vitro phase II studies and the results of protocol D, Mitoxantrone and Mitomycin C were added to 5-FU + FA (MFFM). Fifty (50) CRLM pts received HAI with MFFM. RESULTS: The response rates, med. surv. times, systemic toxicity and SC rates are shown in the table. HAI with MFFM produced objective responses in 66%, the med. surv. was 27.4 m, and no SC occurred. The ports surgically placed for HAI, e.g., in protocols D and E, functioned in 90%, 82%, and 76% 6, 9, and 11 m after start of the HAI. Quality of life in protocol E was high. Nine pts from protocols D + E with either partial (PR, 7 pts) or complete (CR, 2 pts) remissions received a secondary liver resection without hospital mortality, and 7/9 pts are living 2-58 m after liver resection, 2/9 pts died 11 and 22 m after resection. [table: see text] SUMMARY/CONCLUSIONS: Our learning curve to achieve optimal treatment of CRLM resulted in a protocol using HAI with MFFM. The results of this protocol (E) including the high remission rate, long median survival time, good port function, high quality of life, and, most interestingly, the possibility to downstage and resect primarily nonresectable metastases, seem to be superior to HAI with 5-FUDR of 5-FU + FA and to systemic chemotherapy with 5-FU + FA. This hypothesis is currently examined in a phase III study (HAI with MFFM vs. 5-FU + FA i.v.).

Antineoplastic Combined Chemotherapy Protocols↗