Continuous 28-day iododeoxyuridine infusion and hyperfractionated accelerated radiotherapy for malignant glioma: a phase I clinical study.

PURPOSE: To investigate the maximal tolerated dose of a continuous 28-day iododeoxyuridine (IUdr) infusion combined with hyperfractionated accelerated radiotherapy (HART); to analyze the percentage of IUdr-thymidine replacement in peripheral granulocytes as a surrogate marker for IUdr incorporation into tumor cells; to measure the steady-state serum IUdr levels; and to assess the feasibility of continuous IUdr infusion and HART in the management of malignant glioma. METHODS AND MATERIALS: Patients were required to have biopsy-proven malignant glioma. Patients received 100 (n = 4), 200 (n = 3), 300 (n = 3), 400 (n = 6), 500 (n = 4), 625 (n = 5), or 781 (n = 6) mg/m(2)/d of IUdr by continuous infusion for 28 days. HART was started 7 days after IUdr initiation. The total dose was 70 Gy (1.2 Gy b.i.d. for 25 days with a 10-Gy boost [2.0 Gy for 5 Saturdays]). Weekly assays were performed to determine the percentage of IUdr-DNA replacement in granulocytes and serum IUdr levels using standard high performance liquid chromatography methods. Standard Phase I toxicity methods were used. RESULTS: Between June 1994 and August 1999, 31 patients were enrolled. No patient had Grade 3 or worse HART toxicity. Grade 3 or greater IUdr toxicity predominantly included neutropenia (n = 3), thrombocytopenia (n = 3), and elevated liver function studies (n = 3). The maximal tolerated dose was 625 mg/m(2)/d. Thymidine replacement in the peripheral granulocytes peaked at 3 weeks and increased with the dose (maximal thymidine replacement 4.9%). The steady-state plasma IUdr level increased with the dose (maximum, 1.5 microM). CONCLUSION: In our study, continuous long-term IUdr i.v. infusion had a maximal tolerated dose of 625 mg/m(2)/d. Granulocyte incorporation data verified the concept that prolonged IUdr infusion results in IUdr-DNA replacement that corresponds to a high degree of cell labeling. IUdr steady-state plasma levels increased with increasing dose and attained levels needed for clinical radiosensitization. Continuous IUdr infusion and HART were both feasible and well tolerated.

Activation of diverse pathways to apoptosis by (125)IdUrd and gamma-photon exposure.

PURPOSE: To delineate the mechanisms underlying induction of apoptosis in malignant cells irradiated by DNA-incorporated iodine-125 or gamma-photons. MATERIALS AND METHODS: Human tumor cells (RKO, LS174T, TE671, and MCF7) were irradiated by DNA-incorporated 5-[125I]iodo-2'-deoxyuridine (125IdUrd) or by gamma-photons. Clonogenic survival was determined by the colony-forming assay. Caspase-3 induction was measured with a fluorogenic substrate assay, and DNA fragmentation was determined by ligation-mediated polymerase chain reaction. DNA arrays were used to assess the expression of the B-cell lymphoma/leukaemia-2 (Bcl-2) family and related genes in RKO cells and in caspase-3-gene-defective MCF7 cells. RESULTS: After 125IdUrd or y-photon exposure, the highest induction of caspase-3 was observed in the radiation-sensitive cell lines (RKO and LS174T). DNA fragmentation was prominent in the radiosensitive cells and undetectable in TE671 (125IdUrd and gamma-photons) and MCF7 (125IdUrd only) cells. Exposure of RKO and MCF7 cells to 125I decay led to up-regulation of several pro-apoptotic and antiapoptotic Bcl-2 family genes whereas y-irradiation produced minimal activation. CONCLUSIONS: Apoptosis generated by a DNA-incorporated Auger electron emitter is induced through the mitochondrial/caspase-3-mediated pathway and correlates with cellular radiosensitivity. Apoptosis caused by y-radiation can be signaled without activation of Bcl-2 family genes, and DNA fragmentation occurs with or without caspase-3 activation.

GammaH2AX foci induced by gamma rays and 125idU decay.

PURPOSE: GammaH2AX foci formation was investigated after gamma irradiation and after accumulating 125IdU decays to study the DNA double strand break (dsb) damage repair response in human breast cancer cells, MCF-7. MATERIALS AND METHODS: Confocal laser scanning microscopy (CLSM) was used to detect yH2AX foci formed in response to DNA dsbs induced by 0, 0.5, 1, 2 and 5 Gy gamma irradiation and 125IdU decays accumulated at -90 degrees C in human breast cancer cells, MCF-7. 125IdU treated cells were labeled with 4 different concentrations of 125IdU and then accumulated decays for 6, 19 or 35 days. gammaH2AX foci formation time for all experiments was 1 hour at 37 degrees C. Visual confirmation of gammaH2AX foci was achieved by digital imaging (histogram analysis or profile analysis) and by standardizing the scored number of foci. The average numbers of gammaH2AX foci formed per cell after gamma irradiation or accumulated (125)IdU decays were determined by counting red voxels or counting gammaH2AX foci in propidium iodide (PI) counterstained nuclei by eye in optically sectioned cells. RESULTS: Control, unirradiated MCF-7 cells had an average of 1.7 gammaH2AX foci per cell and an average of 32 yH2AX foci were scored for cells irradiated with 1 Gy gamma rays. The data for doses up to approximately 1 Gy was a good linear fit (r2 =0.97) indicating that the assay is sensitive to low doses of gamma rays. The average number of gammaH2AX foci scored in control cells that were frozen and thawed but not irradiated (=2.3) was not statistically significantly different from controls that were not frozen and thawed. The average number of yH2AX foci was linearly related (r2 = 0.98) to low numbers (< 200 decays/cell) of 125IdU decays indicating that the assay is also sensitive to low numbers of accumulated 125IdU decays. At 125I decays greater than 200 decays/cell, the average number of yH2AX foci plateaued. Regression analysis of the data for 0-140 125IdU decays per cell was used to calculate the rate of yH2AX foci formation (=0.26 foci per 125I decay). CONCLUSIONS: The gammaH2AX foci formation assay is sensitive to low doses of gamma rays and accumulated 125I decays. When 125IdU decays were accumulated at -90 degrees C (to overcome confounding DNA damage repair processes that occur during simultaneous 125IdU incorporation and decay accumulation at 37 degrees C), 0.26 gammaH2AX foci were formed per 125IdU decay. Methods used to incorporate 125I decay may modulate the number of gammaH2AX foci scored in cells.

Phase I trial of sequential administration of raltitrexed (Tomudex) and 5-iodo-2'-deoxyuridine (IdUrd).

Raltitrexed (Tomudex) is a specific inhibitor of thymidylate synthase with clinical activity in colorectal cancer. The combination of raltitrexed and 5-iodo-2'-deoxyuridine (IdUrd, a cytotoxic pyrimidine analog) resulted in increased IdUrd incorporation into DNA and exhibited in vitro synergism against colon and bladder human carcinoma cell lines. We designed a phase I trial to determine the MTD, pharmacokinetics, and biologic effects of escalating doses of the combination of IdUrd given as a 24-hour infusion after a raltitrexed 15-minute infusion every three weeks. Thirty-four patients received 95 courses of raltitrexed and IdUrd at doses ranging from raltitrexed 1 mg/m2 and IdUrd 750 mg/m2 to raltitrexed 2.5 mg/m2 and IdUrd 10,400 mg/m2. The median number of cycles administered was 2 (range 1-10). Dose limiting hematologic toxicity occurred at doses of raltitrexed 2.5 mg/m2 and IdUrd 10,400 mg/m2. In addition, we determined the mean plasma concentrations C(SS) of IdUrd, the iodouracil level at 22 hours and the IdUrd clearance. Raltitrexed did not appear to affect the pharmacokinetics of IdUrd in the dose range tested. The recommended phase II dose is raltitrexed 2 mg/m2 and IdUrd 10,400 mg/m2 repeated every three weeks. Evidence of potential antitumor activity was observed: 1 patient (with colon cancer) had a partial response while 15 others had stable disease.

Phase I trial of intraperitoneal iododeoxyuridine with and without intravenous high-dose folinic acid in the treatment of advanced malignancies primarily confined to the peritoneal cavity: flow cytometric and pharmacokinetic analysis.

In this Phase I study, the maximally tolerated doses (MTDs) of i.p. iododeoxyuridine (IdUrd) alone and in combination with i.v. calcium leucovorin (LV) were determined. The pharmacokinetics and pharmacological advantage of IdUrd were evaluated, and flow cytometric analysis allowed examination of the extent of incorporation of IdUrd into tumor cells with and without the addition of i.v. LV. Thirty-nine patients with advanced neoplasms primarily confined to the peritoneal space were enrolled in a dose-escalation trial using 4-h dwells of IdUrd administered i.p. daily for 4 days with and without an i.v. infusion of LV 500 mg/m2/day for 4.5 days. Twenty-three patients received single-agent therapy, and 13 patients received i.p. IdUrd in combination with i.v. LV. The MTD of single-agent IdUrd administered on this schedule was 4125 mg/m2/day for 4 days; and that of the IdUrd in combination was 3438 mg/m2/day. Dose-limiting toxicities were myelosuppression and stomatitis. During the period of the dwell, the peritoneal AUC (area under the curve) of IdUrd exceeded the plasma AUC of IdUrd by one or two orders of magnitude in all patients at all doses tested; there was a possible effect of LV on peritoneal AUC. The geometric mean pharmacological advantage (AUCperitoneal/ AUCplasma) was 181 at 625 mg/m2/day and 90 at 4538 mg/m2/day. Flow cytometric analysis suggests saturation of IdUrd measured in DNA at the 2500-3125 mg/m2 dose level, without an increase after the addition of LV. Twelve patients received 4-12 courses of therapy. One patient with recurrent ovarian cancer who received 16 courses of therapy experienced complete resolution of her ascites, near normalization of CA-125 levels, and improved quality of life; two patients with high-risk tumors receiving "adjuvant" therapy are disease-free at 3 and 6 years after treatment; other patients experienced transient clearing of ascites. The recommended Phase II dose of i.p. IdUrd using a 4-h dwell daily for 4 days is 3750 mg/m2/day alone or 3125 mg/m2/day in combination with continuous i.v. LV at 500 mg/m2/day for 4.5 days. Although flow cytometric data suggest that DNA incorporation of IdUrd is not affected by the addition of LV, the cytotoxicity of the combination regimen may be increased due to LV-enhanced, IdUrd-related inhibition of thymidylate synthase. For this reason, we recommend that efficacy studies of the combination continue in parallel with studies of IdUrd alone.

Preoperative idoxuridine and radiation for large soft tissue sarcomas: clinical results with five-year follow-up.

BACKGROUND: Local control remains an important issue in the management of large soft tissue sarcomas. Radiation is the main adjuvant to surgery for local therapy of sarcomas, but it requires relatively high doses, hitherto considered prohibitive in areas such as the retroperitoneum. We developed a preoperative treatment approach to large soft tissue sarcomas that would deliver a high total dose of radiation administered in conjunction with the halogenated pyrimidine radiosensitizer idoxuridine (IdUrd). METHODS: Thirty-seven patients with large sarcomas of the head and neck, mediastinum, retroperitoneum, or extremity received three or five cycles of sequential IdUrd infusion (1000-1600 mg/m2/d x 5 d) alternating weekly with twice daily radiation (125-150 cGy per dose) and were then evaluated for resection. The delivered preoperative radiation dose was up to 6250 to 7500 cGy. RESULTS: Five patients (14%) had a partial response to preoperative therapy, and 28 of 37 patients underwent successful resection. There were no intra- or postoperative deaths. Local control was achieved in 19 of 28 resected patients, but in only 1 of 6 patients who remained unresectable despite therapy. With a median follow-up of 5.8 years, 28% of patients are alive with no evidence of disease, 17% are alive with disease, and 53% have died of their disease. CONCLUSIONS: Using the dose and schedule we employed, resection of large soft tissue sarcomas was possible after high-dose radiation delivered in conjunction with IdUrd. Although local control was acceptable, the high rate of distant failure represents a limitation of any local approach to the treatment of large soft tissue sarcomas and suggests the need for integration of this approach with an effective systemic therapy.

Biochemical modulation in the treatment of advanced cancer: a study of combined leucovorin, fluorouracil, and iododeoxyuridine.

Multiple studies have shown that leucovorin-fluorouracil regimens are modestly superior to fluorouracil alone in the treatment of advanced colorectal cancer. Laboratory data suggest that iododeoxyuridine could further enhance the efficacy of leucovorin-fluorouracil regimens. This report describes the Phase I clinical evaluation of a leucovorin-fluorouracil-iododeoxyuridine chemotherapy regimen. Twenty-four patients received treatment with leucovorin (500 mg/m2), fluorouracil (500 mg/m2), and iododeoxyuridine (escalating doses) on days 1 and 8 of a 21-day cycle. The maximum tolerated dose of iododeoxyuridine was 1200 mg/m2, with a recommended Phase II dose of 1000 mg/m2. Myelosuppression (leukopenia) was dose limiting; other commonly observed treatment toxicities were nausea/vomiting, mucositis, and hyperlacrimation. Although the 1200 mg/m2 dose was tolerated during the initial few cycles of therapy, chronic administration could not be maintained secondary to dose-limiting neutropenia. Since neutropenia was dose limiting, in a follow-up study, 10 patients received a modified regimen (treatment on days 1 and 6 instead of days 1 and 8) with the addition of granulocyte colony-stimulating factor (days 8-19). The addition of granulocyte colony-stimulating factor, however, did not permit further escalation of the iododeoxyuridine dose. Three partial responses and six minor responses were observed. Phase II studies of this regimen are ongoing in advanced colorectal and advanced pancreatic cancer to determine response rates in these diseases.

Iododeoxyuridine (IUdR) combined with radiation in the treatment of malignant glioma: a comparison of short versus long intravenous dose schedules (RTOG 86-12).

PURPOSE: To evaluate the toxicity and tumor efficacy of the halopyrimidine IUdR (NSC #39661, IND 22475) as a chemical modifier of radiation response when used in a high dose short time infusion versus the acceptable 4 day infusion. METHODS AND MATERIALS: In August 1987 we initiated a prospective study in patients with newly diagnosed anaplastic astrocytoma and glioblastoma. The study was designed to have a fixed dose of radiation (60.16 Gy = 1.88 Gy in 32 fractions in 6.5 weeks) but varying the dose schedule of IUdR, keeping the total dose between 21 and 24 g/m2. IUdR was delivered in a 96, 48, or 24 hr continuous intravenous infusion per week for 6.5 weeks during radiation treatment. RESULTS: The study was closed for patient accrual on October 1, 1991. Twenty-two patients were treated on the 96 hrs, 32 on the 48 hr and 25 on the 24 hr schedules. The incidence of glioblastoma ranged between 68 and 75% in the three arms. Seventy percent of the patients had a Karnofsky of 80-90% at the onset of treatment. Over 50% of the patient population were under age 55. Drug tolerance was related to the duration of the IUdR infusion. Toxicities were most pronounced in the 96 hr IUdR infusion schedule where 27.4% of the patients reported a grade 3 drug toxicity. No fatal or grade 4 toxicities were observed. More patients on the 24 and 48 hr schedule received at least 80% of the IUdR dose specified per protocol. We did not observe a trend in acute normal tissue radiation reactions in any of the three arms. The median survivals calculated from the Kaplan-Meier plot are 13.4, 10.5, and 11 months, respectively, for the 96, 48, and 24 hr infusions. The Cox Proportional Hazards model showed that any difference in survival can be attributed to histological grade, type of previous surgery and, to some extent, age of the patient. Dose schedule was not a significant predictor of survival, although statistically nonsignificant trend toward longer survival is seen in those patients with glioblastoma treated in the "long" 4 day schedule. CONCLUSION: Overall, our treatment combination, particularly for patients with glioblastoma, has not shown convincing evidence of an improvement in survival. Of interest, however, it is the 2 year survival rate of 68% for patients with anaplastic astrocytoma. In our experience, the administration of IUdR is laborious, time consuming and with bothersome acute gastrointestinal and hematological toxicities.

Phase I clinical and pharmacological study of iododeoxyuridine and bleomycin in patients with advanced cancer.

Studies previously performed in our laboratory demonstrated synergistic cytotoxicity and DNA strand break formation in human tumor cells following exposure to a combination of bromodeoxyuridine and bleomycin. Synergy was evident when bromodeoxyuridine was administered prior to or simultaneously with bleomycin and occurred over a wide range of concentration ratios. We therefore undertook a phase I clinical trial of the combination of iododeoxyuridine (IdUrd) and bleomycin to determine the maximally tolerated dose of IdUrd that could be administered with a standard dose of bleomycin and to determine the toxicities of the combination. Eligible patients were those with advanced cancer refractory to standard therapy who had a performance status of 0-2, measurable or evaluable disease, and adequate organ function. IdUrd was administered as a 5-day continuous i.v. infusion beginning at a dose of 250 mg/m2/day with escalation in cohorts of 3-6 patients according to a modified Fibonacci scheme. Bleomycin was administered at a dose of 15 mg/m2/day as a continuous i.v. infusion during the last 3 days of the IdUrd infusion. Cycles of therapy were repeated every 28 days. Plasma levels of IdUrd and iodouracil were determined by high performance liquid chromatography. Thirty patients received a total of 79 cycles of IdUrd/bleomycin. Dose-limiting toxicity was bone marrow suppression. At the maximally tolerated IdUrd dose of 2780 mg/m2/day, the median neutrophil nadir after the first cycle of therapy was 805/microliters and the median platelet nadir was 48,000/microliters. Other toxic effects included mucositis, fatigue, nausea, diarrhea, fever, and skin toxicity. Plasma steady-state concentrations of IdUrd increased proportionally to administered IdUrd dose. IdUrd clearance varied from 0.253 liters/min/m2 to 0.503 liters/min/m2 and did not correlate with IdUrd dose. IdUrd dose and concentration correlated significantly with granulocyte and platelet nadirs, and a pharmacodynamic model for white blood cell count nadir could be defined by pretreatment white blood cell count, IdUrd dose, and gender. The recommended IdUrd dose for phase II testing of this combination is 2140 mg/m2/day. Phase II studies will be of particular interest in those diseases, such as carcinomas of the head, neck, and esophagus, where bleomycin has documented activity as a single agent.

[A topical solution of 40% idoxuridine in dimethyl sulfoxide compared to oral acyclovir in the treatment of herpes zoster. A double-blind multicenter clinical trial]. / Solución tópica de idoxuridina al 40% en dimetilsulfóxido frente a aciclovir oral en el tratamiento del herpes zoster. Ensayo clínico multicéntrico a doble ciego.

BACKGROUND: Both topical 40% idoxuridine in dimethylsulfoxide (IDU) and oral acyclovir (ACV) are useful in herpes zoster (HZ). This is the first clinical trial which compares the efficacy of both drugs in the course of the disease and in the prevention of post-herpetic neuralgia (PHN). METHODS: Patients of both sexes older than 18 years, with a HZ of less than 4 days were selected. Patients with otic or ophthalmic zoster, serious concomitant illness or pregnant or breast-feeding women were excluded. Following a double dummy design, the patients received at random topical IDU and oral placebo, or oral ACV and topical placebo. Topical treatment was applied during 4 days and oral treatment during 7 days. The evolution of the disease (number of individual lesions, evolution of symptoms, use of analgesic drugs and eventual appearance of complications) was controlled on days 0, 2, 4, 6, 8, and weekly until its resolution. RESULTS: The group of patients treated with IDU (85) showed a better evolution of the disease than those treated with ACV (86) in some of the parameters controlled: day of first and all vesicles drying (p less than 0.05), last day of moderate-intense pain (p less than 0.05), hyperaesthesia (p less than 0.05) and itching (p less than 0.05) and last day of analgesic use (p less than 0.01). The appearance of new vesicles during treatment was lower in the IDU treated group (p less than 0.01). A tendency favouring IDU can be observed in the appearance of PHN. CONCLUSIONS: In our study topical 40% idoxuridine in DMSO was better than oral acyclovir in 7 of the 14 clinical parameters studied.

Primary treatment of large and massive adult sarcomas with iododeoxyuridine and aggressive hyperfractionated irradiation.

For a decade, the authors have experimented with treatment for unresectable adult soft tissue and bony sarcomas. Over the last 6 years, they have combined hyperfractionated radiation therapy and intravenous iododeoxyuridine as a radiosensitizer, in regimens designed to minimize toxicity and permit delivery of aggressive radiation therapy. Patients with solitary lesions and those with metastasis (38%) were treated in the hope of both potential cure in some and durable palliation in others. The most formidable of these cancers have been those that are large or massive, often requiring five or more fields and extensive treatment planning. The authors report results from 36 patients with large unresectable sarcomas (tumors ranging from 5 to 35 cm; average 14 cm) treated with hyperfractionated radiation therapy, with a minimum follow-up of 1 year, follow-up of 4 or more years (in 50%), or follow-up until death. Overall local control has been 60%, with control of 66% of lesions from 5 to 9 cm, 63% of those from 10 to 14 cm, 63% of those from 15 to 19 cm, and 57% of those greater than 20 to 40 cm. Morbidity has been modest. This experience compares favorably with the authors' earlier trials with misonidazole, and toxicity has been reduced considerably.

Early application of topical 15% idoxuridine in dimethyl sulfoxide shortens the course of herpes simplex labialis: a multicenter placebo-controlled trial.

In a double-blind, randomized, patient-initiated treatment study at five medical centers, 301 immunocompetent patients experiencing a recurrence of herpes labialis were treated with topical 15% idoxuridine (IDU) in dimethyl sulfoxide (DMSO), 80% DMSO control solution, or 2% DMSO control solution. IDU did not prevent the development of lesions but significantly accelerated lesion resolution in comparison with the combined control groups. For the total population, the mean duration of pain was reduced by 1.3 days (35%, P = .01) and the mean healing time to loss of crust by 1.7 days (21%, P = .004). Analysis of subpopulations revealed that the beneficial activity of the treatment was concentrated among the patients who began treatment in the prodrome or erythema lesion stage. For these patients, the mean duration of pain was reduced by 1.8 days (42%, P = .08) and the mean healing time to loss of crust by 3.3 days (38%, P less than .001). If only patients with classic herpes lesions (vesicle, ulcer, or crust formation) were considered, there was a greater drug effect on the duration of pain (reduction by 2.6 days, 49%; P = .03) and the mean healing time to normal skin was significantly shortened (reduction by 2.3 days, 23%; P = .004). Adverse reactions to the medication were minimal.

Phase I trial of hepatic artery infusion of 5-iodo-2'-deoxyuridine and 5-fluorouracil in patients with advanced hepatic malignancy: biochemically based combination chemotherapy.

Eighteen patients with hepatic metastases primarily from colorectal carcinoma were treated on a phase I protocol employing hepatic artery infusion (HAI) of 5-fluorouracil (FUra) and 5-iodo-2'-deoxyuridine (IdUrd) via implantable infusion pump. Patients received a 14-day continuous HAI of 300 mg/day FUra. During days 8-14 of therapy, patients received IdUrd as a separate 3-h HAI daily x 7. Treatment cycles were repeated every 28 days. IdUrd was escalated from 0.1 to 2.86 mg/kg/day x 7. Myelosuppression and stomatitis were mild and not dose limiting. Hepatotoxicity was dose limiting and similar to that reported for 5-fluoro-2'deoxyuridine alone administered as a 14-day infusion every month. One patient developed a clinical picture consistent with sclerosing cholangitis and another had biopsy-proven cholestasis and triaditis. Catheter complications occurred in 7 of 18 patients. Plasma concentrations of FUra during the 7-day continuous HAI of FUra alone were consistently either undetectable or very low (less than or equal to 0.1 microM). At level 3 (1.0 mg/kg/day IdUrd) and beyond, measurable plasma concentrations of FUra, iodouracil, and IdUrd were found at the end of the daily 3-h infusion of IdUrd. The maximum tolerated dose of IdUrd as administered in this trial is 2.2 mg/kg/day x 7 and the recommended starting dose for further clinical investigation is 1.7 mg/kg/day x 7.

[Adverse side effects caused by topically applied antiviral agents in herpetic keratitis].

The present paper reviews the adverse side effects caused by topically applied antiviral agents in herpetic keratitis. The effective treatment of herpetic keratitis with IDU, a chemotherapeutic agent, was first reported in 1962. After its introduction into ophthalmic therapy for herpetic keratitis, drops of IDU were administered every hour by day combined with ointment every two hours by night. The therapy often continued for months or in some cases, even more than one year. Numerous reports on its side effects have appeared. The side effects can be classified into two categories. The first category is allergic contact blepharodermatitis, a type IV delayed hypersensitivity reaction. Its occurrence is difficult to foresee. This category I side effect rarely results in the destruction of the ocular tissues. The second category of side effects is a drug-induced toxic side effect resulting in punctate epithelial keratitis, papillary conjunctivitis or follicular hypertrophy and lacrimal punctal obstruction. After withdrawal of IDU, these ill effects usually subside soon. When IDU is further continued, the destructive change of the tissues will ensue. Conjunctival cicatrization, symblepharon, corneal neovascularization, cicatrization and irreversible punctal occlusion have been reported in cases with prolonged IDU treatment. In addition to IDU for therapy of herpetic keratitis, we are fortunate to have F3T, Ara-A and acyclovir. They show no cross sensitivity reaction nor any cross toxic reaction to each other. However, if administered more than several times daily and continued for a prolonged period of time, these antiviral agents, like IDU, can also result in reversible side effects and, further, irreversible tissue destruction. Conjunctival cicatrization and permanent punctal occlusion caused by prolonged administration of F3T have been reported. Prompt recognition of the untoward reactions and withdrawal of the antiviral agent will result in the subsidence of the toxic reaction changes and prevent the eye from irreversible destruction. The recognition, prevention and management of the untoward side effects also are discussed.

A phase I study of intraarterial iododeoxyuridine in patients with colorectal liver metastases.

Regional delivery of iododeoxyuridine (IdUrd) to patients with colorectal liver metastases was examined in a phase I study. The maximum-tolerated intraarterial (IA) dose (MTD) was 1,333 mg/m2/d administered continuously for 14 days. The dose-limiting toxicity was thrombocytopenia. Thrombocytopenia and leukopenia were correlated with the amount of IdUrd incorporated into DNA of peripheral granulocytes. In contrast to our experience with 5-fluorodeoxyuridine, there was no evidence of hepatobiliary toxicity. In 11 patients who received IA IdUrd alone, seven had a greater than or equal to 50% decrease in carcinoembryonic antigen (CEA) levels, with five having tumor volume reductions of 65%, 48%, 46%, 44%, and 27%. Thus, IA IdUrd alone has antitumor efficacy. Patients subsequently received IdUrd in combination with external beam radiation to a total dose of 2,400 cGy without acute local toxicity. In addition to these favorable clinical findings, we have previously shown that IdUrd is selectively incorporated into tumor DNA compared with normal liver in these patients. Further phase II evaluations of this approach are warranted.

Dispositivo intrauterino intramioma / Intramyoma intrauterine device

"Señuelos extraviados" de un DIU no significan necesariamente perforación uterina. Este artículo decribe un caso de un anillo de Zipper incrustado en un mioma. El diagnóstico fue hecho después de una histeroscopía complicada. Es razonable tener presente esta posibilidad cuando se investiga un caso de "señuelos extraviados". Tal como ha sido publicado, es muy difícil asegurar si el mioma creció alrededor del DIU o el mioma fue perforado al momento de la inserción. Las evidencias histológicas conducen hacia la primera opción