The combination of PAC-1 and entrectinib for the treatment of metastatic uveal melanoma.

The treatment of metastatic uveal melanoma remains a major clinical challenge. Procaspase-3, a proapoptotic protein and precursor to the key apoptotic executioner caspase-3, is overexpressed in a wide range of malignancies, and the drug PAC-1 leverages this overexpression to selectively kill cancer cells. Herein, we investigate the efficacy of PAC-1 against uveal melanoma cell lines and report the synergistic combination of PAC-1 and entrectinib. This preclinical activity, tolerability data in mice, and the known clinical effectiveness of these drugs in human cancer patients led to a small Phase 1b study in patients with metastatic uveal melanoma. The combination of PAC-1 and entrectinib was tolerated with no treatment-related grade ≥3 toxicities in these patients. The pharmacokinetics of entrectinib were not affected by PAC-1 treatment. In this small and heavily pretreated initial cohort, stable disease was observed in four out of six patients, with a median progression-free survival of 3.38 months (95% CI 1.6-6.5 months). This study is an initial demonstration that the combination of PAC-1 and entrectinib may warrant further clinical investigation. Clinical trial registration: Clinical Trials.gov: NCT04589832.

Phase I dose-escalation study of procaspase-activating compound-1 in combination with temozolomide in patients with recurrent high-grade astrocytomas.

Background: Procaspase-3 (PC-3) is overexpressed in various tumor types, including gliomas. Targeted PC-3 activation combined with chemotherapy is a novel strategy for treating patients with high-grade gliomas, with promising preclinical activity. This study aimed to define safety and tolerability of procaspase-activating compound-1 (PAC-1) in combination with temozolomide (TMZ) for patients with recurrent high-grade astrocytomas. Methods: A modified-Fibonacci dose-escalation 3 + 3 design was used. PAC-1 was administered at increasing dose levels (DL; DL1 = 375 mg) on days 1-21, in combination with TMZ 150 mg/m2/5 days, per 28-day cycle. Dose-limiting toxicity was assessed during the first 2 cycles. Neurocognitive function (NCF) testing was conducted throughout the study. Results: Eighteen patients were enrolled (13 GBM, IDH-wild type; 2 astrocytoma, IDH-mutant, grade 3; 3 astrocytoma, IDH-mutant, grade 4). Dose escalation was discontinued after DL3 (ie, PAC-1, 625 mg) due to lack of additional funding. Grade 3 toxicity was observed in 1 patient at DL1 (elevated liver transaminases) and 1 at DL 2 (headache). Two partial responses were observed at DL1 in patients with GBM, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated. Two patients had stable disease, and 11 experienced progression. NCF testing did not show a clear relationship between PAC-1 dose, treatment duration, and declines in NCF. Conclusions: Combination of PAC-1 and TMZ was well tolerated up to 625 mg orally daily and TMZ orally 150 mg/m2/5 days per 28-day cycle. The maximum tolerated dose was not reached. Further dose escalation of PAC-1 in combination with TMZ is advised before conducting a formal prospective efficacy study in this patient population.

Clinical Outcomes of Surgical Repair for Partial Distal Biceps Tendon Tears.

PURPOSE: The purpose of this study was to describe the outcomes of patients treated with surgical repair of partial tears of the distal biceps tendon. METHODS: The study was a retrospective review of repairs of partial tears of the distal biceps tendon performed by multiple surgeons from January 1, 2015 to October 15, 2020. Inclusion criteria consisted of preoperative magnetic resonance imaging indicative of distal biceps pathology without a complete tear and surgical treatment with intraoperative confirmation of a partial tear. The presence of preceding trauma, duration of symptoms, and postoperative complications were documented. Patients were contacted for outcome assessment using the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) and Patient-Reported Elbow Evaluation outcome measures. Clinical outcomes were obtained from 56 of 74 (76%) eligible patients with an average follow-up of 46 months (range: 15-85 months). RESULTS: After surgery, the median QuickDASH was 2.3 (interquartile range, 0-9.7), and the median Patient-Reported Elbow Evaluation score was 1 (interquartile range, 0-12). Postoperative QuickDASH scores were significantly lower than the preoperative scores. Known traumas preceding the symptoms and duration of symptoms before surgery were not significantly associated with the outcome. Of all eligible patients, 30 complications were reported in 25 (34%) patients and included 2 reruptures, 2 cases of heterotopic ossification, 1 deep infection, 1 case of implant irritation, 21 neuropraxias, and 3 hematomas. Five (7%) patients underwent 6 reoperations including 1 revision for a rerupture, 1 irrigation and debridement, 2 heterotopic ossification excisions, 1 hematoma evacuation, and 1 implant removal. CONCLUSIONS: The results suggest that the repair of partial distal biceps tendon tears is a viable treatment option with significant improvement in QuickDASH. There was no significant relationship between the postoperative outcome and duration of symptoms or known traumas preceding the symptoms. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Phase I study of procaspase-activating compound-1 (PAC-1) in the treatment of advanced malignancies.

BACKGROUND: Procaspase-3 (PC-3) is overexpressed in multiple tumour types and procaspase-activating compound 1 (PAC-1) directly activates PC-3 and induces apoptosis in cancer cells. This report describes the first-in-human, phase I study of PAC-1 assessing maximum tolerated dose, safety, and pharmacokinetics. METHODS: Modified-Fibonacci dose-escalation 3 + 3 design was used. PAC-1 was administered orally at 7 dose levels (DL) on days 1-21 of a 28-day cycle. Dose-limiting toxicity (DLT) was assessed during the first two cycles of therapy, and pharmacokinetics analysis was conducted on days 1 and 21 of the first cycle. Neurologic and neurocognitive function (NNCF) tests were performed throughout the study. RESULTS: Forty-eight patients were enrolled with 33 completing ≥2 cycles of therapy and evaluable for DLT. DL 7 (750 mg/day) was established as the recommended phase 2 dose, with grade 1 and 2 neurological adverse events noted, while NNCF testing showed stable neurologic and cognitive evaluations. PAC-1's t1/2 was 28.5 h after multi-dosing, and systemic drug exposures achieved predicted therapeutic concentrations. PAC-1 clinical activity was observed in patients with neuroendocrine tumour (NET) with 2/5 patients achieving durable partial response. CONCLUSIONS: PAC-1 dose at 750 mg/day was recommended for phase 2 studies. Activity of PAC-1 in treatment-refractory NET warrants further investigation. CLINICAL TRIAL REGISTRATION: Clinical Trials.gov: NCT02355535.

Internal Fixation Construct and Defect Size Affect Healing of a Translational Porcine Diaphyseal Tibial Segmental Bone Defect.

BACKGROUND AND OBJECTIVE: Porcine translational models have become the gold-standard translational tool to study the effects of major injury and hemorrhagic shock because of their similarity to the human immunologic response to trauma. Segmental bone defects (SBDs) typically occur in warfighters with associated severe limb trauma. The purpose of this study was to develop a translational porcine diaphyseal SBD model in Yucatan minipigs (YMPs), which could be used in bone healing investigations that simulate injury-relevant conditions. We were specifically working toward developing a critical sized defect (CSD). METHODS: We used an adaptive experimental design in which both 25.0 mm and 40.0 mm SBDs were created in the tibial mid-diaphysis in skeletally mature YMPs. Initially, eight YMPs were subjected to a 25.0 mm SBD and treated with intramedullary nailing (intramedullary nail [IMN] 25mm). Due to unanticipated wound problems, we subsequently treated four specimens with identical 25.0 mm defect with dual plating (open reduction with internal fixation [ORIF] 25mm). Finally, a third group of four YMPs with 40.0 mm defects were treated with dual plating (ORIF 40mm). Monthly radiographs were made until sacrifice. Modified Radiographic Union Score for Tibia fractures (mRUST) measurements were made by three trauma-trained orthopedic surgeons. CT scans of the tibias were used to verify the union results. RESULTS: At 4 months post-surgery, mean mRUST scores were 11.7 (SD ± 1.8) in the ORIF 25mm YMPs vs. 8.5 (SD ± 1.4) in the IMN 25mm YMPs (P < .0001). All four ORIF 25mm YMPs were clinically healed. In contrast, none of the IMN 25mm YMPs were clinically healed and seven of eight IMN 25mm YMPs developed delayed wound breakdown. All four of the ORIF 40mm YMPs had flail nonunions with complete hardware failure by 3 months after surgery and were sacrificed early. CT scanning confirmed that none of the IMN 25mm YMPs, none of the ORIF 40mm YMPs, and two of four ORIF 25mm YMPs were healed. A third ORIF 25mm specimen was nearly healed on CT scanning. Inter-rater and intra-rater reliability interclass coefficients using the mRUST scale were 0.81 and 0.80, respectively. CONCLUSIONS: YMPs that had a 40 mm segment of bone removed from their tibia and were treated with dual plating did not heal and could be used to investigate interventions that accelerate bone healing. In contrast, a 25 mm SBD treated with dual plating demonstrated delayed but successful healing, indicating it can potentially be used to investigate bone healing adjuncts or conversely how concomitant injuries may impair bone healing. Pigs treated with IMN failed to heal and developed consistent delayed wound breakdown presumably secondary to chronic limb instability. The porcine YMP SBD model has the potential to be an effective translational tool to investigate bone healing under physiologically relevant injury conditions.

Phase 1 study of TTC-352 in patients with metastatic breast cancer progressing on endocrine and CDK4/6 inhibitor therapy.

PURPOSE: TTC-352 is a selective human estrogen receptor (ER) partial agonist developed for treatment of hormone-refractory ER + breast cancer. METHODS: This was an accelerated dose escalation study with the primary endpoint of maximum tolerated dose that evaluated five dose levels of TTC-352 in breast cancer progressing after at least two lines of hormonal therapy including one in combination with a CDK4/6 inhibitor. The secondary objectives were to determine treatment tolerability, pharmacokinetics of TTC-352, best response, progression-free survival (PFS), and PKCα expression in tumors. RESULTS: The study enrolled 15 patients. No dose-limiting toxicity was observed. Patients experienced the following grade 3 toxicities: asymptomatic pulmonary embolism, diarrhea, aspartate transaminase elevation, and myalgia, and one grade 4 toxicity of gamma glutamyltransferase elevation. Pharmacokinetic half-life was 7.6-14.3 h. The intra- and inter-individual variability for AUC0-∞ hampered assessment of the relationship between dose and AUC0-∞. Median PFS was 58 days (95% CI = 28,112). Higher PKCα expression in tumor stroma was associated with a trend toward longer PFS. CONCLUSIONS: TTC-352 demonstrates safety and early clinical evidence of antitumor activity against heavily pretreated hormone-refractory breast cancer. Based upon TTC-352 plasma concentrations and tolerability, the 180 mg twice a day is recommended for further testing. (ClinicalTrials.gov Identifier: NCT03201913).

Phase I Study of IGF-Methotrexate Conjugate in the Treatment of Advanced Tumors Expressing IGF-1R.

OBJECTIVES: Insulin-like growth factor-methotrexate (IGF-MTX) is a conjugate of methotrexate and 765IGF, a variant of IGF-1 with high affinity for insulin-like growth factor type 1 receptor. The study aim was to determine the maximum tolerated dose of IGF-MTX in refractory solid organ and hematologic malignancies expressing insulin-like growth factor type 1 receptor. MATERIALS AND METHODS: This phase I trial used a modified toxicity probability interval design with 5 cohort dose levels, and expansion cohort at maximum tolerated dose. IGF-MTX was given intravenously over 90 minutes on days 1, 8, and 15 of a 28-day cycle. RESULTS: A total of 17 patients were enrolled. The highest tolerated dose tested was 0.80 µEq/kg with dose-limiting toxicity of grade 3 hypoglycemia. Drug-related grade 3 and 4 toxicities included abdominal pain (26%), hypoglycemia (10%), and hypotension (10%). Of the 15 evaluable for response, 3 patients (20%) had stable disease, including the patient with Hodgkin lymphoma with stable disease for 12 cycles of therapy. IGF-MTX concentrations declined rapidly, with half-lives of 5.2 to 14 minutes for the initial distribution phase and 6.5 to 7.5 hours for the terminal elimination phase. Higher IGF-R1 expression did not correlate with better outcome. CONCLUSIONS: IGF-MTX is well tolerated. IGF-MTX pharmacokinetics suggest rapid cellular uptake. The activity of IGF-MTX in Hodgkin lymphoma should be explored.

The effects of spaceflight and fracture healing on distant skeletal sites.

Spaceflight results in reduced mechanical loading of the skeleton, which leads to dramatic bone loss. Low bone mass is associated with increased fracture risk, and this combination may compromise future, long-term, spaceflight missions. Here, we examined the systemic effects of spaceflight and fracture surgery/healing on several non-injured bones within the axial and appendicular skeleton. Forty C57BL/6, male mice were randomized into the following groups: (1) Sham surgery mice housed on the earth (Ground + Sham); (2) Femoral segmental bone defect surgery mice housed on the earth (Ground + Surgery); (3) Sham surgery mice housed in spaceflight (Flight + Sham); and (4) Femoral segmental bone defect surgery mice housed in spaceflight (Flight + Surgery). Mice were 9 weeks old at the time of launch and were euthanized approximately 4 weeks after launch. Micro-computed tomography (µCT) was used to evaluate standard bone parameters in the tibia, humerus, sternebra, vertebrae, ribs, calvarium, mandible, and incisor. One intriguing finding was that both spaceflight and surgery resulted in virtually identical losses in tibial trabecular bone volume fraction, BV/TV (24-28% reduction). Another important finding was that surgery markedly changed tibial cortical bone geometry. Understanding how spaceflight, surgery, and their combination impact non-injured bones will improve treatment strategies for astronauts and terrestrial humans alike.

Phase I Study of Aurora A Kinase Inhibitor Alisertib (MLN8237) in Combination With Selective VEGFR Inhibitor Pazopanib for Therapy of Advanced Solid Tumors.

OBJECTIVES: Pazopanib is a multikinase angiogenesis inhibitor. Alisertib is a highly selective inhibitor of mitotic Aurora A kinase. There is preclinical evidence that mitosis-targeting agents exhibit antiangiogenic effects. Thus, the combination of these 2 agents may have a synergistic effect on tumor vasculature. The primary objective of this study is to determine the optimal tolerated dose (OTD) for alisertib and pazopanib. MATERIALS AND METHODS: This phase 1b study evaluated the OTD of alisertib twice a day, on days 1 to 7 with pazopanib, once a day, continuously in a 21-day cycle, both taken orally. Disease response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 every 2 cycles. OTD cohort was expanded to assure safety and perform pharmacokinetics analysis. RESULTS: A total of 27 patients received treatment. Seventy-seven percent of the patients had received at least 3 prior chemotherapy regimens. Dose-limiting toxicities occurred in dose level (DL) 2+ (grade 4 thrombocytopenia and grade 3 mucositis) and DL 3 (grade 3 liver transaminases elevation and grade 3 abdominal pain). The OTD was determined to be DL 2: alisertib 20 mg twice daily and pazopanib 600 mg daily. Pharmacokinetic analysis revealed that clearance of alisertib was reduced by ∼40% in the presence of pazopanib compared with clearance in the absence of pazopanib. Fourteen patients had stable disease and 2 patients had a partial response. CONCLUSIONS: The combination of alisertib with pazopanib demonstrates manageable safety and early clinical evidence of antitumor activity in patients with advanced malignancies (NCT01639911).

Phase I Study of Pazopanib and Ixabepilone in Patients With Solid Tumors.

OBJECTIVES: Pazopanib is a tyrosine kinase inhibitor predominantly acting on tumor endothelium, and ixabepilone is a semisynthetic analog of epothilone B that promotes microtubule stabilization inducing tumor and tumor endothelial cell apoptosis. The purpose of this study was to determine the optimal tolerated dose (OTD) of the combination of pazopanib and ixabepilone for the treatment of metastatic previously treated solid tumors. METHODS: Dose escalation started at 32 mg/m of ixabepilone and increased to 40 mg/m. Pazopanib was administered initially at 400 mg and escalated at 200 mg increments up to 800 mg. Pharmacokinetic analysis assessed effect of ixabepilone on pazopanib metabolism. Correlative studies evaluated changes in angiogenic cytokines. RESULTS: Thirty-one patients (20 male and 11 female; median age, 58 y) with ECOG PS of 0 or 1 were enrolled. Three patients had dose-limiting toxicities (fatigue and neutropenia) at dose level 2 (ixabepilone 40 mg/m and pazopanib 400 mg), and therefore the ixabepilone dose was decreased (32 mg/m) before escalating pazopanib to levels 3 and 4. One patient had a dose-limiting toxicity (thrombocytopenia) at dose level 4 (ixabepilone 32 mg/m and pazopanib 800 mg). Dose level 3 was determined to be the OTD (pazopanib 600 mg and ixabepilone 32 mg/m). The most common toxicities were cytopenias. A significant decrease in the level of sE-selectin was associated with improvement in progression free survival. CONCLUSIONS: The OTD for combination of pazopanib and ixabepilone was established. There was no impact of ixabepilone on pazopanib pharmacokinetics. The relationship between sE-selectin and progression free survival warrants further investigation.

Human placental lactogen induces CYP2E1 expression via PI 3-kinase pathway in female human hepatocytes.

The state of pregnancy is known to alter hepatic drug metabolism. Hormones that rise during pregnancy are potentially responsible for the changes. Here we report the effects of prolactin (PRL), placental lactogen (PL), and growth hormone variant (GH-v) on expression of major hepatic cytochromes P450 expression and a potential molecular mechanism underlying CYP2E1 induction by PL. In female human hepatocytes, PRL and GH-v showed either no effect or small and variable effects on mRNA expression of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5. On the other hand, PL increased expression level of CYP2E1 mRNA with corresponding increases in CYP2E1 protein and activity levels. Results from hepatocytes and HepaRG cells indicate that PL does not affect the expression or activity of HNF1α, the known transcriptional activator of basal CYP2E1 expression. Furthermore, transient transfection studies and Western blot results showed that STAT signaling, the previously known mediator of PL actions in certain tissues, does not play a role in CYP2E1 induction by PL. A chemical inhibitor of PI3-kinase signaling significantly repressed the CYP2E1 induction by PL in human hepatocytes, suggesting involvement of PI3-kinase pathway in CYP2E1 regulation by PL. CYP2E1-humanized mice did not exhibit enhanced CYP2E1 expression during pregnancy, potentially because of interspecies differences in PL physiology. Taken together, these results indicate that PL induces CYP2E1 expression via PI3-kinase pathway in human hepatocytes.

Assessing the translatability of in vivo cardiotoxicity mechanisms to in vitro models using causal reasoning.

Drug-induced cardiac toxicity has been implicated in 31% of drug withdrawals in the USA. The fact that the risk for cardiac-related adverse events goes undetected in preclinical studies for so many drugs underscores the need for better, more predictive in vitro safety screens to be deployed early in the drug discovery process. Unfortunately, many questions remain about the ability to accurately translate findings from simple cellular systems to the mechanisms that drive toxicity in the complex in vivo environment. In this study, we analyzed translatability of cardiotoxic effects for a diverse set of drugs from rodents to two different cell systems (rat heart tissue-derived cells (H9C2) and primary rat cardiomyocytes (RCM)) based on their transcriptional response. To unravel the altered pathway, we applied a novel computational systems biology approach, the Causal Reasoning Engine (CRE), to infer upstream molecular events causing the observed gene expression changes. By cross-referencing the cardiotoxicity annotations with the pathway analysis, we found evidence of mechanistic convergence towards common molecular mechanisms regardless of the cardiotoxic phenotype. We also experimentally verified two specific molecular hypotheses that translated well from in vivo to in vitro (Kruppel-like factor 4, KLF4 and Transforming growth factor beta 1, TGFB1) supporting the validity of the predictions of the computational pathway analysis. In conclusion, this work demonstrates the use of a novel systems biology approach to predict mechanisms of toxicity such as KLF4 and TGFB1 that translate from in vivo to in vitro. We also show that more complex in vitro models such as primary rat cardiomyocytes may not offer any advantage over simpler models such as immortalized H9C2 cells in terms of translatability to in vivo effects if we consider the right endpoints for the model. Further assessment and validation of the generated molecular hypotheses would greatly enhance our ability to design predictive in vitro cardiotoxicity assays.

Up-regulation of UDP-glucuronosyltransferase (UGT) 1A4 by 17beta-estradiol: a potential mechanism of increased lamotrigine elimination in pregnancy.

Oral clearance of lamotrigine, an antiepileptic drug commonly used in pregnant women, is increased in pregnancy by unknown mechanisms. In this study, we show that 17beta-estradiol (E(2)) up-regulates expression of UDP glucuronosyltransferase (UGT) 1A4, the major enzyme responsible for elimination of lamotrigine. Endogenous mRNA expression levels of UGT1A4 in estrogen receptor (ER) alpha-negative HepG2 cells were induced 2.3-fold by E(2) treatment in the presence of ER alpha expression. E(2) enhanced transcriptional activity of UGT1A4 in a concentration-dependent manner in HepG2 cells when ER alpha was cotransfected. Induction of UGT1A4 transcriptional activity by E(2) was also observed in ER alpha-positive MCF7 cells, which was abrogated by pretreatment with the antiestrogen fulvestrant (ICI 182,780). Analysis of UGT1A4 upstream regions using luciferase reporter assays identified a putative specificity protein-1 (Sp1) binding site (-1906 to -1901 base pairs) that is critical for the induction of UGT1A4 transcriptional activity by E(2). Deletion of the Sp1 binding sequence abolished the UGT1A4 up-regulation by E(2), and Sp1 bound to the putative Sp1 binding site as determined by a electrophoretic mobility shift assay. Analysis of ER alpha domains using ER alpha mutants revealed that the activation function (AF) 1 and AF2 domains but not the DNA binding domain of ER alpha are required for UGT1A4 induction by E(2) in HepG2 cells. Finally, E(2) treatment increased lamotrigine glucuronidation in ER alpha-transfected HepG2 cells. Together, our data indicate that up-regulation of UGT1A4 expression by E(2) is mediated by both ER alpha and Sp1 and is a potential mechanism contributing to the enhanced elimination of lamotrigine in pregnancy.

Postoperative concurrent chemoradiotherapy with mitomycin in advanced squamous cell carcinoma of the head and neck: results from three prospective randomized trials.

UNLABELLED: Recent prospective randomized trials have shown concurrent chemoradiotherapy improves locoregional control in postoperative patients with squamous cell carcinoma of the head and neck using cisplatin-based regimes. This report presents data pooled from three randomized trials employing mitomycin, selecting those patients treated postoperatively, to evaluate the long-term benefit of mitomycin in the postoperative setting and to compare these results with those of two other recently published randomized trials. METHODS AND MATERIALS: Between 1980 and 1999, a total of 331 patients with squamous cell carcinoma of the head and neck from the three prospective trials were enrolled. Of the 205 postoperative patients in these trials, 103 were randomized to receive mitomycin and radiation, while 102 received radiation alone or radiation with porfiromycin in the third trial. Patients were treated with standard daily radiotherapy to a total median dose of 60 Gy over 47 days. Patients who were randomized to mitomycin C received 15 mg/m2 of the drug on days 5 and 47 (or last day). RESULTS: The 5-year rate of locoregional control was higher in the mitomycin arms. There was no statistically significant difference in the rates of overall survival or distant metastasis. Patients had a lower percentage of high-risk factors in both arms of the study, compared with patients in the large prospective trials, including positive margins, two or more positive lymph nodes, or oropharynx primary tumors. The gains in locoregional control realized with mitomycin were similar to the improvements in the recently published randomized trials using platinum. CONCLUSIONS: These results confirm significant gains in locoregional control using concurrent chemoradiotherapy in the postoperative setting for patients with squamous cell carcinoma of the head and neck. The lack of consensus over a benefit in the rates of overall survival and distant metastasis emphasizes the need for further prospective trials in the postoperative management of squamous cell carcinoma of the head and neck.

Concurrent chemo-radiotherapy with mitomycin C compared with porfiromycin in squamous cell cancer of the head and neck: final results of a randomized clinical trial.

PURPOSE: Previous randomized trials have shown a benefit with concurrent use of the hypoxic cell cytotoxin mitomycin C (MC) and radiation (RT) in the management of squamous cell cancer of the head and neck (SCCHN). We conducted a randomized trial comparing MC with porfiromycin (POR) in combination with RT in the management of SCCHN. METHODS AND MATERIALS: Between 1992 and 1999, 128 patients with SCCHN were enrolled in this prospective randomized trial. Patients were stratified by management intent, and balanced with respect to stage and site of disease. They were randomized to receive MC (15 mg/M(2)) or POR (40 mg/M(2)) on Days 5 and 47 (or last day) of RT. Of 121 evaluable patients, 61 were randomized to MC and 60 to POR. Patients were treated with standard daily RT to a total median dose of 64 Gy over 47 days. Patients were well balanced with respect to management intent, stage, site, age, sex, hemoglobin levels, tumor grade, radiation dose, and days on treatment. RESULTS: There were no significant differences between the two arms with respect to acute hematologic or nonhematologic toxicities. As of January 2003 with a median follow-up of 6.3 years, there have been 19 local relapses (4 MC vs. 15 POR), 21 regional relapses (7 MC vs. 14 POR), 24 distant metastases (11 MC vs. 13 POR), and 66 deaths (33 MC vs. 33 POR). MC was superior to POR with respect to 5-year local relapse-free survival (91.6% vs. 72.7%, p = 0.01), local-regional relapse-free survival (82% vs. 65.3%, p = 0.05), and disease-free survival (72.8% vs. 52.9%, p = 0.026). There were no significant differences between the two arms with respect to overall survival (49.2% vs. 54.4%) or distant metastasis-free rate (79.9% vs. 75.9%). CONCLUSIONS: Despite promising preclinical data, and an acceptable toxicity profile, POR was inferior to MC as an adjunct to RT in the management of SCCHN. This randomized trial emphasizes the need for randomized studies to evaluate new agents in the management of SCCHN.

Is there an optimal hemoglobin level for patients with glioblastoma multiforme?

PURPOSE: The purpose of this study was to assess the relationship between hemoglobin levels and survival for patients treated with radiation therapy for glioblastoma multiforme. METHODS/MATERIALS: Between 1992 and 2001, 89 patients with newly diagnosed glioblastoma multiforme were treated with a minimum of 50 Gy of radiation therapy. The primary study endpoint was overall survival. The independent variables analyzed included peak hemoglobin level, age, sex, extent of surgery, and duration of therapy. The peak hemoglobin level was the highest hemoglobin value obtained within 1 week before the initiation of radiation therapy or at some point during radiation therapy. The peak hemoglobinlevel was stratified into values of less than or equal and values greater than for each of the following hemoglobin values: 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, and 14.0 g/dL. RESULTS: On univariate analysis, age (< or = 50 years of age) and surgical treatment (resection) were significant for increased survival at 1 year. When univariate analysis was performed on the stratification of the peak hemoglobin, levels greater than 11.0, 13.5, and 14.0 g/dL reached statistical significance for increased survival. Multivariate analysis was then performed on models composed of the hemoglobin levels that reached significance, and the other independent variables were investigated. In all models, both age and the peak hemoglobin level tested were prognostic for survival. However, for the hemoglobin level of 11.0 g/dL, an interaction was detected between hemoglobin and age. CONCLUSION: We found that increasing hemoglobin levels may have prognostic implications and could thus influence clinical outcome. We will be seeking to verify our results in larger cohorts.

Idiopathic intussusception in infancy and childhood.

OBJECTIVE: Idiopathic intussusception is an important cause of abdominal pain, bleeding per rectum and intestinal obstruction in infancy and childhood. This aim of this study was to undertake a retrospective review of all children who presented with idiopathic intussusception over a 17-year period. METHODS: The medical records of children who presented with idiopathic intussusception from January 1984 through December 2000 at King Fahad National Guard Hospital, Riyadh, Kingdom of Saudi Arabia were reviewed. The data obtained included age, sex, clinical presentation, diagnostic investigations, mode of treatment, length of hospital stay and results. RESULTS: Thirty-three children (21 male, 12 female) presented with 37 episodes of intussusception. Their mean age was 8.4 months (range 5 hours to 36 months). The clinical features included rectal bleeding (81%), vomiting (78%), abdominal colic/pain (65%) and abdominal mass (62%). All cases were ileocolic intussusception with no leading point. Barium enema was attempted in 36 cases with success in 20 (56%). Laparotomy was required in 16 cases, manual reduction being successful in 11 (30%) and 6 (16%) had bowel resection. At surgery, after attempted barium reduction, 9 (56%) cases had the intussusception already reduced to the cecum. Seventy percent of the cases presented within 24 hours of onset of symptoms. The 4 recurrences in 3 children had successful enema reduction. There was no mortality but 3 operative cases required late surgery for adhesive intestinal obstruction including one requiring bowel resection. CONCLUSION: Idiopathic intussusception commonly presents as an ileo-colic type but is uncommon in our institution. The clinical features are classical, rectal bleeding being the most common. The majority presented within 24 hours of onset of symptoms and barium enema reduction was successful in 20 out of 36 cases in which it was attempted. Since most intussusceptions were already in the cecum at surgery after failed enema reduction, a repeat or delayed enema reduction could be considered in stable cases. Recurrent intussusception occurred in 3 non-operated cases and adhesive intestinal obstruction in 3 laparotomy cases.

Papel de la mitomicina C como adyuvante a la radioterapia en el tratamiento de cáncer del cuello uterino localmente avanzado / Role of mitomycin C as adyunct in the treatment of locally advanced cancer of uterine cervix

El cáncer de cuello uterino representa un problema de grandes proporciones dentro del campo de la oncología en Venezuela, con un incremento en su incidencia desde 1985. Sigue ocupando el primer lugar en la incidencia y mortalidad por cáncer en la población femenina, con 2962 casos nuevos por año y 1214 muertes. La radioterapia constituye el tratamiento de elección en los estadios localmente avanzados de la enfermedad, del estadio IIB en adelante; sin enbargo, los resultados de control local de la enfermedad y sobrevida deben ser mejorados. En 1990 se inicia un estudio fase II en conjunto con la Universidad de Yale con objeto de estudiar el valor de un agente alquilante biorreductor, la mitomicina C, como adyuvante al tratamiento radiante en base a la toxicidad selectiva de esta droga para las células hipóxicas. Este estudio se ha venido realizando en el Hospital Universitario de Caracas, Hospital Domingo Luciani y en el Instituto Médico la Floresta