Pulmonary blood flow is inhomogeneously reduced after Euro Collins-preservation and lung transplantation

BACKGROUND: Vasoconstriction after lung transplantation is a well-known phenomenon, but only limited information is available on blood flow distribution after ischemia and reperfusion. The aim of our study was to determine the regional flow characteristics in transplanted and native dog lungs after 24 hours of cold storage and preservation with Euro Collins-solution. METHODS: Six pairs of weight-matched Foxhounds (25 to 30 kg) were used. In donors and recipients, aortic and pulmonary artery catheters were inserted percutaneously and a reference withdrawal catheter was placed into the main pulmonary artery. For preservation, the lungs were perfused with modified Euro Collins-solution and stored at 4 degrees C. After 24 hours, the left lung was transplanted. Regional pulmonary blood flow was assessed by injection of colored microspheres into the right atrium using the reference withdrawal technique. Measurements of regional pulmonary blood flow were conducted twice in donors and recipients (baseline and 3 hours after reperfusion). Tissue samples from five distinct regions (apical, medial, dorsal, ventral, and lateral) were taken to assess regional pulmonary blood flow and wet-dry ratios. RESULTS: The relative (per thousand Confidence Intervals/100 mg dry weight) regional pulmonary blood flow was significantly reduced in the transplanted lung but not in the native organ. This reduction was most pronounced in apical regions and smallest in regions close to the hilum. Edema formation occurred in both lungs, as judged from wet-to-dry ratios of lung tissue specimen. CONCLUSIONS: Two separate processes can be observed after single lung transplantation: (1) reduced regional pulmonary blood flow, which is a regional phenomenon restricted to the transplanted organ, and (2) extensive edema affecting both the transplanted and the native lung.     

Incidental granulomatous inflammation of the uterus

BACKGROUND: Granulomas of the uterine corpus have been reported in a variety of pathologic conditions but are relatively rare findings in routine histopathologic material. METHODS: This retrospective clinicopathologic study reviewed patients diagnosed with uterine granulomas between 1980 and 1999 in a tertiary referral center. RESULTS: The study group was comprised of 11 women, ranging in age from 37 to 90 years. All patients had histologically confirmed, non-necrotizing granulomas. The most common symptom prompting biopsy or hysterectomy was abnormal bleeding. Several concomittant histopathologies were noted. Eight of 11 patients had a known history of uterine instrumentation. None of the patients had clinical evidence of sarcoidosis or systemic infection, and stains for microorganisms were negative in all cases. Polarizable or foreign materials were not seen. CONCLUSIONS: Well-formed, non-necrotizing granulomas are an infrequent finding in the uterus. A history of instrumentation may explain the presence of granulomas in a subset of patients.     

Phase II trial of docetaxel for cholangiocarcinoma

The authors evaluated the activity and toxicity of docetaxel given as a 1-hour infusion every 21 days in patients with unresectable cholangiocarcinoma. Seventeen patients with cytologically or histologically confirmed cholangiocarcinoma received intravenous docetaxel over 1 hour, repeated every 21 days. The initial dose of docetaxel was 100 mg/m2, with a subsequent 25% dose reduction for patients experiencing grade 3 or 4 toxicities. Treatment was continued until disease progression or occurrence of intolerable side effects. All patients received premedication with dexamethasone 8 mg by mouth twice daily for 5 days, starting 1 day before docetaxel infusion. Sixteen of the 17 patients were assessable for response and toxicity; one patient was removed from the trial for intercurrent illness. Thirty-eight cycles of docetaxel were delivered (median, two cycles). No complete or partial responses were noted. Fourteen patients had progressive disease, one patient had stable disease, and one patient died of septic shock shortly after starting treatment. Granulocytopenia was the dose-limiting toxicity. Thirteen patients had grade 4 granulocytopenia, 11 of whom required antibiotics for neutropenic fever. Granulocytopenia was the only grade 4 toxicity observed. Grade 3 toxicities included stomatitis, anemia, fatigue, vomiting, and hypotension. Grade 1 or 2 toxicities included alopecia, diarrhea, peripheral edema, myalgias, and anorexia. Administered on this dose and schedule, docetaxel lacked activity in patients with cholangiocarcinoma. The toxicity profile, including dose-limiting granulocytopenia, has been previously described in patients receiving docetaxel.     

Activity of the multitargeted antifolate LY231514 in the human tumor cloning assay

Purpose: This study was performed to evaluate the activity of the multitargeted antifolate (MTA or LY231514) against a broad range of human tumors taken directly from patients. Materials and methods: Human tumor colony-forming units were treated with MTA at concentrations of 0.1, 1.0, and 10 μg/ml in 1-h exposure studies. The responses of a limited number of specimens were also evaluated concurrently in 1-h exposures to cisplatin, fluorouracil, irinotecan, and/or paclitaxel. Results: Of 358 specimens plated in the 1-h exposure studies, 148 (41%) were evaluable. Overall, responses were observed in 3% of specimens (4/144) at 0.1 μg/ml, 11% (17/148) at 1.0 μg/ml, and 23% (33/141) at 10 μg/ml. In this range of concentrations achievable clinically, there was a significant concentration-response relationship. At 10 μg/ml in the 1-h exposure studies, the response rate in colorectal cancer specimens was 32% (9/28), and the response rate in non-small-cell lung cancer was 25% (6/24). Responses were also observed in several chemoresistant tumors, including renal cell carcinoma, hepatocellular carcinoma, mesothelioma, and pancreatic carcinoma. The activity of MTA was not completely cross-resistant with that of cisplatin, fluorouracil, irinotecan, and paclitaxel. Conclusions: MTA demonstrated in vitro activity against a spectrum of tumors, including several tumors generally considered chemoresistant. Received: 18 September 1998 / Accepted: 21 December 1998     

Phase I and pharmacokinetic study of the oral fluoropyrimidine capecitabine in combination with paclitaxel in patients with advanced solid malignancies.

PURPOSE: To evaluate the feasibility of administering the oral fluoropyrimidine capecitabine in combination with paclitaxel, to characterize the principal toxicities of the combination, to recommend doses for subsequent disease-directed studies, and to determine whether significant pharmacokinetic interactions occur between these agents when combined. PATIENTS AND METHODS: Sixty-six courses of capecitabine and paclitaxel were administered to 17 patients in a two-stage dose-escalation study. Paclitaxel was administered as a 3-hour intravenous (IV) infusion every 3 weeks, and capecitabine was administered continuously as two divided daily doses. During stage I, capecitabine was escalated to a target dose of 1,657 mg/m(2)/d, whereas the paclitaxel dose was fixed at 135 mg/m(2). In stage II, paclitaxel was increased to a target dose of 175 mg/m(2), and the capecitabine dose was the maximum established in stage I. Pharmacokinetics were characterized for each drug when given alone and concurrently. RESULTS: Myelosuppression, predominately neutropenia, was the principal dose-limiting toxicity (DLT). Other toxicities included hand-foot syndrome, diarrhea, hyperbilirubinemia, skin rash, myalgia, and arthralgia. Two patients treated with capecitabine 1,657 mg/m(2)/d and paclitaxel 175 mg/m(2) developed DLTs, whereas none of six patients treated with capecitabine 1,331 mg/m(2)/d and paclitaxel 175 mg/m(2) developed DLTs during course 1. Pharmacokinetic studies indicated that capecitabine and paclitaxel did not affect the pharmacokinetic behavior of each other. No major antitumor responses were noted. CONCLUSION: Recommended combination doses of continuous capecitabine and paclitaxel are capecitabine 1,331 mg/m(2)/d and paclitaxel 175 mg/m(2)/d IV every 3 weeks. Favorable preclinical mechanistic interactions between capecitabine and paclitaxel, as well as an acceptable toxicity profile without clinically relevant pharmacokinetic interactions, support the performance of disease-directed evaluations of this combination.     

Novel chemotherapy agents for colorectal cancer: Oral fluoropyrimidines, oxaliplatin, and raltitrexed

Agents now under investigation for treatment of advanced colorectal cancer (CRC) include the oral fluoropyrimidines, oxaliplatin, and raltitrexed. Research efforts directed at finding agents that conveniently and effectively deliver 5-fluorouracil (5-FU) in a protracted fashion have led to the development of several oral fluoropyrimidines. These agents, which include capecitabine; tegafur and uracil plus leucovorin (UFT/LV); eniluracil plus oral 5-FU; and S-1, are convenient and less toxic than intravenous bolus 5-FU. Oxaliplatin has a uniquely different mechanism of action compared with that of 5-FU and has demonstrated activity not only in the first-line treatment setting but also in patients whose disease has progressed during or following 5-FU treatment. In the first-line setting, when oxaliplatin is combined with 5-FU plus LV, response rates and time to disease progression are remarkably improved compared with 5-FU/LV alone. Raltitrexed, a unique thymidylate synthase inhibitor, has undergone extensive phase III evaluation in CRC. The advent of these novel agents has led to development of combined chemotherapy regimens now being introduced into the adjuvant setting.     

Biochemical and growth-modulatory effects of the new S-adenosylmethionine decarboxylase inhibitor CGP 48664 in malignant and immortalized normal human breast epithelial cells in culture

We have examined the relations between the incidence of cancer of the corpus uteri and pregnancies in a cohort of 765,756 Norwegian women, contributing a total of 9,307,118 person–years in the age interval 30–56 years. Incidence rate ratios (IRR) were calculated by Poisson regression analyses of person–years at risk. Separate analyses were carried out for the 2 main histological subtypes, endometrial carcinomas (554 cases) and sarcomas (112 cases). We observed a decrease in risk of endometrial carcinoma with an increasing number of fullterm pregnancies (p < 0.001). The reduction in risk associated with the first pregnancy was more pronounced than that observed for any subsequent pregnancy. The risk of endometrial carcinoma increased with increasing time since last birth (IRR = 1.20, 95% CI = 1.08–1.34 per 5-year time interval). The reduction in risk among parous women compared to nulliparous women diminished with increasing time since last birth. For endometrial carcinoma, the decrease in risk with increasing age at first and last birth disappeared after adjustment for time since last birth. For sarcomas, however, the relation with age at births remained in analyses adjusted for time since birth, and time since birth seemed to be of minor importance as an independent risk factor. Our results support the hypothesis that the reduction in risk of endometrial carcinoma associated with a pregnancy is related to a mechanical shed of malignant or pre-malignant cells at each delivery. © 1995 Wiley-Liss, Inc.