Pazopanib and Fosbretabulin in recurrent ovarian cancer (PAZOFOS): A multi-centre, phase 1b and open-label, randomised phase 2 trial.

OBJECTIVE: Vascular co-option is a resistance mechanism to anti-angiogenic agents, but combinations of anti-vascular agents may overcome this resistance. We report a phase 1b and randomised phase 2 trial to determine the safety and efficacy of pazopanib with fosbretabulin. METHODS: Eligible patients had recurrent, epithelial ovarian cancer with a platinum-free interval (PFI) of 3 to 12 months. Patients were stratified according to PFI (>6 versus ≤6 months) and prior bevacizumab use. RESULTS: Twelve patients were treated in the phase 1b. Commonest grade ≥ 2 adverse events (AEs) were hypertension (100%), neutropenia (50%), fatigue (50%), vomiting (50%). There was one DLT (grade 3 fatigue). The recommended phase 2 dose level was fosbretabulin 54 mg/m2 on days 1, 8 and 15 and pazopanib 600 mg once daily (od), every 28 days, which was then compared to pazopanib 800 mg od in a randomised phase 2 trial. Twenty-one patients were randomised (1:1) in the phase 2 trial. In phase 1b and phase 2, four patients treated with pazopanib and fosbretabulin developed reversible, treatment-related cardiac AEs, leading to premature discontinuation of the study. In the phase 2 trial, the median PFS was 7.6 months (95% CI 4.1-not estimated) versus 3.7 months (95% CI 1.0-8.1) in favour of the experimental arm (HR 0.30, 95% CI 0.09-1.03, P = .06). CONCLUSIONS: It remains unclear whether pazopanib with with fosbretabulin is an efficacious regimen to treat epithelial ovarian cancer. Effective cardiac risk mitigation is needed to increase the tolerability and maximize patient safety in future trials.

Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Angiogenesis is a validated clinical target in advanced epithelial ovarian cancer. Cediranib is an oral antiangiogenic vascular endothelial growth factor receptor 1-3 inhibitor that has shown antitumour activity in recurrent ovarian cancer. We assessed efficacy and safety of cediranib in combination with platinum-based chemotherapy and as continued maintenance treatment in patients with first relapse of platinum-sensitive ovarian cancer. METHODS: In this randomised, three-arm, double-blind, placebo-controlled phase 3 trial, we randomly assigned patients aged 18 years or older with relapsed platinum-sensitive ovarian cancer at 63 centres in Australia, Canada, New Zealand, Spain, and the UK. Participants received up to six cycles of platinum-based chemotherapy (once every 3 weeks) then entered a maintenance phase. Participants were randomly allocated (2:3:3), with five stratification factors and in alternating blocks, to receive placebo alongside chemotherapy and then placebo only maintenance (arm A; reference), cediranib 20 mg once-daily alongside chemotherapy then placebo only maintenance (arm B; concurrent), or cediranib 20 mg once-daily alongside chemotherapy then cediranib 20 mg once-daily maintenance (arm C; maintenance). Patients continued treatment to progression or excessive toxic effects. The primary efficacy endpoint was progression-free survival between arms A and C. Efficacy analysis was by intention to treat. Safety was assessed in all patients who received the allocated study drug. This trial is registered with ClinicalTrials.gov, number NCT00532194; the ISRCTN registry, number ISRCTN68510403; and ANZ Clinical Trials Registry, number ACTRN1261000016003. FINDINGS: We randomly assigned 486 [corrected] women between Nov 13, 2007, and Dec 23, 2011; results presented are for 456 patients randomly assigned subsequent to the 30mg safety phase. During a median of 19·5 months (IQR 14-26) follow-up, 113 (96%) of 118 women assigned to arm A and 141 (86%) of 164 assigned to arm C had disease progression. Median progression-free survival was 11·0 months (95% CI 10·4-11·7) in arm C and 8·7 months (7·7-9·4) in arm A (hazard ratio 0·56, 0·44-0·72, p<0·0001). 156 (90%) of 174 patients in arm B had disease progression, and median progression-free survival was 9·9 months (95% CI 9·4-10·5). Diarrhoea, neutropenia, hypertension, and voice changes were significantly more common, during chemotherapy with cediranib, and diarrhoea, hypothyroidism and voice changes were more common during maintenance. Poor compliance with cediranib was noted during maintenance treatment with toxic effects being the most common cause for discontinuation. INTERPRETATION: Cediranib, when given orally with chemotherapy and continued as maintenance, yielded a meaningful improvement [corrected] in progression-free survival in women with recurrent platinum-sensitive ovarian cancer, albeit with added toxic effects. The positive results in ICON6 could provide women with a new therapeutic option for recurrent ovarian cancer. Assessment of the secondary endpoint of overall survival will need longer follow-up. FUNDING: Medical Research Council, Cancer Research UK, Canadian Cancer Society Research Institute, Cancer Australia, National Gynecological Cancer Centre, and AstraZeneca.

Audit of CA125 Follow-Up After First-Line Therapy for Ovarian Cancer.

AIMS: The Medical Research Council OVO5/EORTC 55955 trial showed that patients in remission after first-line therapy for ovarian cancer did not benefit from routine measurement of CA125 during follow-up. Since the presentation of these results, we have counseled patients about the options for follow-up and provided them with an information leaflet about the trial results and the symptoms that should prompt an early appointment and CA125 measurement. We present an audit of practice after the presentation of those results. METHODS: The medical records of 143 consecutive patients completing first-line therapy for epithelial ovarian, fallopian tube, or primary peritoneal cancer in our unit between July 2009 and December 2013 were analyzed. RESULTS: An agreed plan of CA125 follow-up was recorded in 69 (79%) of 87 eligible patients on completion of first-line therapy. No routine CA125 follow-up was selected by 55 (80%) patients, and routine CA125 follow-up was selected by 14 (20%), of whom 3 wished not to be informed of the results. CA125 levels were checked in 28 (51%) patients in the no routine CA125 follow-up group, in 26 cases because of the development of symptoms. Relapse was confirmed in 22. Median follow-up was 360 days (range, 100-836). CA125 levels were checked in all 14 patients who had requested routine CA125 follow-up. Relapse has been confirmed in 2 patients. Median follow-up was 560 days (range, 500-620). CONCLUSIONS: If patients are given sufficient information about the role of routine CA125 measurements during follow-up, the majority decide against CA125 monitoring and hence, avoid these blood tests.

Anti-inflammatory and anti-bacterial properties of tetramethylhexadecenyl succinyl cysteine (TSC): a skin-protecting cosmetic functional ingredient.

BACKGROUND: The skin is the first line of defence against exposure to microbial, physical, environmental and chemical insults. In mobilizing a protective response, several different cell types located in our skin release and respond to pro-inflammatory cytokines ensuring skin homeostasis and health. However, chronic activation of this response eventually causes damage resulting in premature ageing. Diosodium tetramethylhexadecenyl succinyl cysteine (TSC or SIG1273), an isoprenylcysteine small molecule, down modulates these inflammatory signalling pathways in various cell types (keratinocytes, peripheral blood mononuclear cells (PBMCs) and endothelial cells) and possesses anti-bacterial properties. Thus, TSC represents a novel cosmetic functional ingredient that provides a broad spectrum of benefits for the skin. OBJECTIVE: To assess the anti-inflammatory properties of TSC in several cutaneous cell types and further investigate its anti-microbial activity. METHODS: Cultured normal human epidermal keratinocytes were exposed to chemical irritant phorbol 12-myrisate 13-acetate (TPA) or ultraviolet-B light (UVB) to induce pro-inflammatory cytokine (IL-6, IL-8 and TNF-α) production. T-cell receptor (TCR) activation of PBMCs and nickel (Ni(2+) ) treatments of human dermal microvascular endothelial cells (HDMECs) were performed resulting in IL-4, IL-6, IL-8 and IL-17 production. Streptococcus pyogenes were cultured to determine minimal inhibitory concentration values. RESULTS: In vitro studies demonstrate TSC blocks TPA and UVB-induced cytokine production in cultured keratinocytes. Similarly, TSC inhibits overproduction of IL-4 and IL-17 in T-cell receptor (TCR)-activated PBMCs as well as nickel induction of IL-6 and IL-8 in HDMECs. Lastly, TSC demonstrated anti-microbial properties, inhibiting cell growth of S. pyogenes. CONCLUSIONS: Tetramethylhexadecenyl succinyl cysteine represents a novel cosmetic functional ingredient that provides a dual modulating benefit of skin protection to individuals by reducing inflammation in keratinocytes, endothelial and mononuclear cell types and S. pyogenes counts.

Current controversies in the management of germ cell ovarian tumours.

PURPOSE OF REVIEW: Fewer than 70 new cases of malignant ovarian germ cell tumours (MOGCTs) are seen each year in the UK. Because of their rarity, no randomized trials have been reported and many of the advances in management have arisen from adopting practices developed for managing male germ cell tumours (GCTs). Not surprisingly, there have been few important publications related to ovarian germ cell tumuors over the past 2 years. We have therefore included some relevant male germ cell publications. The area in which there is greatest variability in practice globally is in the proportion of patients with stage 1a disease who go on surveillance rather than receiving adjuvant chemotherapy. Although there is increasing agreement about the best management of ovarian GCTs amongst those who treat more than five per year, many patients are still treated by doctors who usually manage epithelial ovarian cancer but rarely see these patients. RECENT FINDINGS: Novel biomarkers including microRNA profiles and DICER1 mutations, identify potential diagnostic and therapeutic targets in this group of tumours. The role of KIT mutation and amplification in the development of ovarian dysgerminoma and the use of Sunitinib, a receptor tyrosine kinase inhibitor with an effect on vascular endothelial growth factor, platelet-derived growth factor and KIT receptors in patients with platinum-resistant GCT, are novel promising approaches. SUMMARY: We will therefore highlight some key differences in management of epithelial and germ cell ovarian tumours.

Pathological findings after primary chemotherapy in patients undergoing simultaneous orchidectomy and retroperitoneal lymph node dissection for advanced germ cell tumours.

OBJECTIVE: To determine the differential response to systemic chemotherapy in patients undergoing simultaneous orchidectomy and retroperitoneal lymph node dissection (RPLND) after chemotherapy for metastatic testicular cancer. PATIENTS AND METHODS: Patients who underwent simultaneous RPLND and orchidectomy after chemotherapy were identified from our clinical databases. Postoperative pathological findings and patient characteristics were reviewed. RESULTS: In all, 42 patients were identified. After chemotherapy, necrosis, teratoma and cancer were identified in 25 (59.5%), 14 (33.3%) and three (7.1%) RPLN specimens and 15 (35.7%), 15 (35.7%) and 12 (28.6%) orchidectomy specimens respectively. Of the 25 patients with necrotic RPLN specimens 12 (48.0%) had active disease within the orchidectomy specimen (eight invasive cancer and four mature teratoma). The overall histological discordance rate was 38.1%. Findings in the orchidectomy specimens were more aggressive than those in the RPLN specimens (i.e. cancer worse than teratoma, which is worse than necrosis) in 33.3%. CONCLUSIONS: There is significant disparity between orchidectomy and RPLND findings with viable tumour appearing frequently in the testis despite tumour-free RPLNs. These findings support completion orchidectomy as part of advanced testicular germ cell treatment.

Imaging Modality and Frequency in Surveillance of Stage I Seminoma Testicular Cancer: Results From a Randomized, Phase III, Noninferiority Trial (TRISST).

PURPOSE: Survival in stage I seminoma is almost 100%. Computed tomography (CT) surveillance is an international standard of care, avoiding adjuvant therapy. In this young population, minimizing irradiation is vital. The Trial of Imaging and Surveillance in Seminoma Testis (TRISST) assessed whether magnetic resonance images (MRIs) or a reduced scan schedule could be used without an unacceptable increase in advanced relapses. METHODS: A phase III, noninferiority, factorial trial. Eligible participants had undergone orchiectomy for stage I seminoma with no adjuvant therapy planned. Random assignment was to seven CTs (6, 12, 18, 24, 36, 48, and 60 months); seven MRIs (same schedule); three CTs (6, 18, and 36 months); or three MRIs. The primary outcome was 6-year incidence of Royal Marsden Hospital stage ≥ IIC relapse (> 5 cm), aiming to exclude increases ≥ 5.7% (from 5.7% to 11.4%) with MRI (v CT) or three scans (v 7); target N = 660, all contributing to both comparisons. Secondary outcomes include relapse ≥ 3 cm, disease-free survival, and overall survival. Intention-to-treat and per-protocol analyses were performed. RESULTS: Six hundred sixty-nine patients enrolled (35 UK centers, 2008-2014); mean tumor size was 2.9 cm, and 358 (54%) were low risk (< 4 cm, no rete testis invasion). With a median follow-up of 72 months, 82 (12%) relapsed. Stage ≥ IIC relapse was rare (10 events). Although statistically noninferior, more events occurred with three scans (nine, 2.8%) versus seven scans (one, 0.3%): 2.5% absolute increase, 90% CI (1.0 to 4.1). Only 4/9 could have potentially been detected earlier with seven scans. Noninferiority of MRI versus CT was also shown; fewer events occurred with MRI (two [0.6%] v eight [2.6%]), 1.9% decrease (-3.5 to -0.3). Per-protocol analyses confirmed noninferiority. Five-year survival was 99%, with no tumor-related deaths. CONCLUSION: Surveillance is a safe management approach-advanced relapse is rare, salvage treatment successful, and outcomes excellent, regardless of imaging frequency or modality. MRI can be recommended to reduce irradiation; and no adverse impact on long-term outcomes was seen with a reduced schedule.

Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial.

BACKGROUND: Serum CA125 concentration often rises several months before clinical or symptomatic relapse in women with ovarian cancer. In the MRC OV05/EORTC 55955 collaborative trial, we aimed to establish the benefits of early treatment on the basis of increased CA125 concentrations compared with delayed treatment on the basis of clinical recurrence. METHODS: Women with ovarian cancer in complete remission after first-line platinum-based chemotherapy and a normal CA125 concentration were registered for this randomised controlled trial. Clinical examination and CA125 measurement were done every 3 months. Patients and investigators were masked to CA125 results, which were monitored by coordinating centres. If CA125 concentration exceeded twice the upper limit of normal, patients were randomly assigned (1:1) by minimisation to early or delayed chemotherapy. Patients and clinical sites were informed of allocation to early treatment, and treatment was started as soon as possible within 28 days of the increased CA125 measurement. Patients assigned to delayed treatment continued masked CA125 measurements, with treatment commencing at clinical or symptomatic relapse. All patients were treated according to standard local practice. The primary outcome was overall survival. Analysis was by intention to treat. This study is registered, ISRCTN87786644. FINDINGS: 1442 patients were registered for the trial, of whom 529 were randomly assigned to treatment groups and were included in our analysis (265 early, 264 delayed). With a median follow-up of 56·9 months (IQR 37·4-81·8) from randomisation and 370 deaths (186 early, 184 delayed), there was no evidence of a difference in overall survival between early and delayed treatment (HR 0·98, 95% CI 0·80-1·20, p=0·85). Median survival from randomisation was 25·7 months (95% CI 23·0-27·9) for patients on early treatment and 27·1 months (22·8-30·9) for those on delayed treatment. INTERPRETATION: Our findings showed no evidence of a survival benefit with early treatment of relapse on the basis of a raised CA125 concentration alone, and therefore the value of routine measurement of CA125 in the follow-up of patients with ovarian cancer who attain a complete response after first-line treatment is not proven. FUNDING: UK Medical Research Council and the European Organisation for Research and Treatment of Cancer.

How to follow-up patients with epithelial ovarian cancer.

PURPOSE OF REVIEW: Despite optimal primary treatment most patients with advanced epithelial ovarian cancer will relapse. This review discusses the controversy regarding surveillance and the timing of treatment for recurrent disease. RECENT FINDINGS: Routine physical examination has a limited role in the detection of recurrent ovarian cancer. PET/computed tomography (CT) has been shown to be useful in detecting small volume disease not apparent on traditional imaging in patients with suspected recurrence based on symptoms and/or rising CA125. The results of PET/CT can alter treatment plans and have particular use in guiding site-directed therapy. The benefits of early detection and systemic treatment of recurrence are now in doubt following the presentation of the MRC/EORTC CA125 surveillance trial. The impact on survival of secondary cytoreductive surgery requires more investigation. SUMMARY: Uncertainties remain in the surveillance and timing of treatment for relapsed disease. Patients should be informed of these uncertainties and become involved in decisions regarding their follow-up.

What surveillance plan should be advised for patients in remission after completion of first-line therapy for advanced ovarian cancer?

Based on the results of the Medical Research Council OVO5/European Organisation for Research and Treatment of Cancer 55955 trial, the follow-up plan I recommend for patients in remission after completion of first-line therapy for advanced ovarian cancer is appointments: every 3 months for 2 years, every 4 months on the third year, then every 6 months thereafter, and discharge if no relapse by 10 years. History and examination (not internal) should be performed at each appointment. CA-125 should only be measured if there is a suspicion of relapse or at patient's request. No scans should be performed unless clinical indication or rising CA-125.

Heterogeneous binding of high mobility group chromosomal proteins to nuclei.

A dramatic difference is observed in the intracellular distribution of the high mobility group (HMG) proteins when chicken embryo fibroblasts are fractionated into nucleus and cytoplasm by either mass enucleation of cytochalasin-B-treated cells or by differential centrifugation of mechanically disrupted cells. Nuclei (karyoplasts) obtained by cytochalasin B treatment of cells contain more than 90 percent of the HMG 1, while enucleated cytoplasts contain the remainder. A similar distribution between karyoplasts and cytoplasts is observed for the H1 histones and the nucleosomal core histones as anticipated. The presence of these proteins, in low amounts, in the cytoplast preparation can be accounted for by the small percentage of unenucleated cells present. In contrast, the nuclei isolated from mechanically disrupted cells contain only 30-40 percent of the total HMGs 1 and 2, the remainder being recovered in the cytosol fraction. No histone is observed in the cytosol fraction. Unike the higher molecular weight HMGs, most of the HMGs 14 and 17 sediment with the nuclei after cell lysis by mechanical disruption. The distribution of HMGs is unaffected by incubating cells with cytochalasin B and mechanically fractionating rather than enucleating them. Therefore, the dramatic difference in HMG 1 distribution observed using the two fractionation techniques cannot be explained by a cytochalasin-B-induced redistribution. On reextraction and sedimentation of isolated nuclei obtained by mechanical cell disruption, only 8 percent of the HMG 1 is released to the supernate. Thus, the majority of the HMG 1 originally isolated with these nuclei, representing 35 percent of the total HMG 1, is stably bound, as is all the HMGs 14 and 17. The remaining 65 percent of the HMGs 1 and 2 is unstably bound and leaks to the cytosol fraction under the conditions of mechanical disruption. It is suggested that the unstably bound HMGs form a protein pool capable of equilibrating between cytoplasm and stably bound HMGs.

Changes in the H-1 histone complement during myogenesis. I. Establishment by differential coupling of H-1 species synthesis to DNA replication.

Proportions of the four major chicken H-1 histones (referred to as H-1's a-d) change during in vitro skeletal myogenesis. As myoblasts fuse and differentiate into myotubes, the relative amount of H-1c increases dramatically. The change occurs primarily because synthesis of the H-1 species is coupled to DNA synthesis to different extents. H-1c synthesis is least tightly coupled to DNA replication in precursor myoblasts and in differentiated myotubes. Thus H-1c synthesis predominates after dividing myoblasts fuse into postmitotic myotubes. This results in the replacement of pre-existing H-1 and therefore increases the relative amount of H-1c. Differences in the stability of the H-1's are also involved in changing H-1 proportions. The results show that changes in H-1 proportions during myogenesis are a consequence of withdrawal from the cell cycle. The data provides a general mechanistic explanation of how tissue-specific H-1 proportions are established.

Changes in the H-1 histone complement during myogenesis. II. Regulation by differential coupling of H-1 variant mRNA accumulation to DNA replication.

We have shown that changes in proportions of the four chicken H-1's during in vitro myogenesis are primarily the result of differential coupling of their synthesis to DNA replication (see the previous paper). We show here that the four major chicken H-1's are encoded by distinct mRNAs which specify primary amino acid sequence variants. Accumulation of the H-1-variant mRNAs is coupled to DNA replication to different extents. The level of mRNA encoding H-1c (the H-1 variant that increases relative to the other H-1's in nondividing muscle cells) is completely uncoupled. In contrast, the level of mRNAs encoding H-1's a, b, and d (which have levels that decrease in nondividing muscle cells) are more tightly coupled. Polyadenylation is not involved in uncoupling H-1c mRNA accumulation from DNA replication.

Wanna Get Away? Maintenance Treatments and Chemotherapy Holidays in Gynecologic Cancers.

Epithelial ovarian cancer has a very high rate of relapse after primary therapy; historically approximately 70% of patients with a complete clinical response to surgery and adjuvant chemotherapy will relapse and die of the disease. Although this number has slowly improved, cure rates remain less than 50%. As such, maintenance therapy with the aim of preventing or delaying disease relapse and the goal of improving overall survival has been the subject of intense study. Numerous earlier studies with agents ranging from radioactive phosphorus to extended frontline therapy or to monthly taxol administration demonstrated encouraging improvements in progression-free survival (PFS) only to find, disappointingly, no benefit in overall survival. In addition, the PFS advantage of maintenance therapy was associated with disconcerting side effects such that maintenance therapy was not adapted as standard of care. Studies with bevacizumab and PARP inhibitors have demonstrated a PFS advantage with a manageable side-effect profile. However, an overall survival advantage remains unclear, and the use of these approaches thus remains controversial. Furthermore, in recurrent disease, the length of chemotherapy and benefits of extended chemotherapy is unclear. Thus, additional trials assessing maintenance strategies in ovarian and other gynecologic malignancies are needed.

Salvage Chemotherapy With Gemcitabine, Paclitaxel, Ifosfamide, and Cisplatin for Relapsed Germ Cell Cancer.

BACKGROUND: Metastatic germ cell tumors remain potentially curable when treated with salvage chemotherapy at first relapse. In the present phase I/II study, we sought to improve on the response rate and duration of the TIP (paclitaxel, ifosfamide, cisplatin) regimen by adding gemcitabine (Gem-TIP). MATERIALS AND METHODS: Twenty patients were recruited after failure of first-line cisplatin-containing chemotherapy. The primary objectives were to determine the maximum tolerated dose of gemcitabine when combined with TIP and to establish the dose intensity of the TIP drugs in this combination. The secondary objectives were the response rates, failure-free survival, and overall survival. RESULTS: The maximum tolerated dose of gemcitabine was 1200 mg/m2. The mean relative dose intensity was 95% (95% confidence interval [CI], 90.2%-99.2%) for gemcitabine, 96% (95% CI, 92.9%-98.7%) for paclitaxel, 92% (95% CI, 84.5%-98.8%) for ifosfamide, and 94% (95% CI, 89.3%-99.0%) for cisplatin. The overall complete response rate was 50%; another 30% of the patients achieved a partial response. The 1-year failure-free survival and overall survival rates were 68% (95% CI, 43%-84%) and 89.5% (95% CI, 64%-97%), respectively. CONCLUSION: Gemcitabine can be added to TIP chemotherapy at the full dose, with manageable toxicity and no detrimental effect on the dose intensity of the TIP drugs. The response rate and duration were improved compared with those reported from the Medical Research Council TIP trial; further evaluation is warranted.

Audiologic characteristics in a sample of recently-separated military Veterans: The Noise Outcomes in Servicemembers Epidemiology Study (NOISE Study).

Military Service Members are often exposed to high levels of occupational noise, solvents, and other exposures that can be damaging to the auditory system. Little is known about hearing loss and how it progresses in Veterans following military service. This epidemiology study is designed to evaluate and monitor a cohort of Veterans for 20 years or more to determine how hearing loss changes over time and how those changes are related to noise exposure and other ototoxic exposures encountered during military service. Data reported here are from baseline assessments of the first 100 study participants (84 males; 16 females; mean age 33.5 years; SD 8.8; range 21-58). Each participant was asked to complete a comprehensive audiologic examination and self-report questionnaires regarding sociodemographic characteristics, noise and solvent exposures, health conditions common among post-deployment Veterans, and the social and emotional consequences of hearing loss. For this relatively young cohort, 29% exhibited hearing loss, defined as average hearing threshold >20 dB HL in the conventional audiometric range. Forty-two percent exhibited hearing loss in the extended-high-frequency audiometric range using the same criterion (average hearing threshold >20 dB HL). Certain factors were found to be associated with poorer hearing in both conventional and extended-high-frequency ranges, including age, type of military branch, years of military service, number of military deployments, noise exposure, tinnitus, and a positive screen for post-traumatic stress disorder. Although the majority of participants had hearing within normal limits, 27% reported a self-perceived mild/moderate hearing handicap and 14% reported a significant handicap. Further research is needed to identify a cause for this discrepancy in audiologic results versus self-report. The information obtained from this longitudinal study could be used in future resource planning with the goal of preventing, as much as possible, the development of hearing loss during military service, and the exacerbation of prevalent hearing loss after military service and over Veterans' lifetimes.

Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging.

PURPOSE: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) causes vascular shutdown in preclinical models. Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) studies were performed in the phase I trials to examine changes related to blood flow and permeability in tumor and muscle. PATIENTS AND METHODS: Sixteen patients treated with DMXAA from 500 to 4,900 mg/m(2) had DCE-MRI examinations before and after treatment. The maximum gradient, the maximum enhancement, and the area under the signal-intensity-time curve (AUC) over the first 90 seconds were calculated for each pixel in regions of interest (ROIs) in muscle and tumor, and the median value for each ROI was obtained. Changes after treatment were compared with 95% limits of agreement for an individual and for groups using data from our reproducibility study. RESULTS: Nine of 16 patients had significant reductions in AUC 24 hours after the first dose of DMXAA, and eight of 11 patients had reductions of up to 66% in AUC 24 hours after the last dose. Mean reductions in gradient, enhancement, and AUC were 25%, 18%, and 31%, respectively, 24 hours after the last dose, significantly greater than the 95% limits of change for a group of 11 patients. Enhancement and AUC in muscle 24 hours after the first dose were significantly reduced, but no significant changes were seen 24 hours after the last dose. CONCLUSION: DMXAA significantly reduces DCE-MRI parameters related to tumor blood flow, over a wide dose range, consistent with the reported tumor vascular targeting activity. Further clinical evaluation of DMXAA is warranted.

Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results.

PURPOSE: A phase I trial was performed with combretastatin A4 phosphate (CA4P), a novel tubulin-binding agent that has been shown to rapidly reduce blood flow in animal tumors. PATIENTS AND METHODS: The drug was delivered by a 10-minute weekly infusion for 3 weeks followed by a week gap, with intrapatient dose escalation. Dose escalation was accomplished by doubling until grade 2 toxicity was seen. The starting dose was 5 mg/m2. RESULTS: Thirty-four patients received 167 infusions. CA4P was rapidly converted to the active combretastatin A4 (CA4), which was further metabolized to the glucuronide. CA4 area under the curve (AUC) increased from 0.169 at 5 mg/m2 to 3.29 micromol * h/L at 114 mg/m2. The mean CA4 AUC in eight patients at 68 mg/m2 was 2.33 micromol * h/L compared with 5.8 micromol * h/L at 25 mg/kg (the lowest effective dose) in the mouse. The only toxicity that possibly was related to the drug dose up to 40 mg/m2 was tumor pain. Dose-limiting toxicity was reversible ataxia at 114 mg/m2, vasovagal syncope and motor neuropathy at 88 mg/m2, and fatal ischemia in previously irradiated bowel at 52 mg/m2. Other drug-related grade 2 or higher toxicities seen in more than one patient were pain, lymphopenia, fatigue, anemia, diarrhea, hypertension, hypotension, vomiting, visual disturbance, and dyspnea. One patient at 68 mg/m2 had improvement in liver metastases of adrenocortical carcinoma. CONCLUSION: CA4P was well tolerated in 14 of 16 patients at 52 or 68 mg/m2; these are doses at which tumor blood flow reduction has been recorded.

Combretastatin A4 phosphate has tumor antivascular activity in rat and man as demonstrated by dynamic magnetic resonance imaging.

PURPOSE: Combretastatin A4 phosphate (CA4P) is a novel vascular targeting agent. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) studies were performed to examine changes in parameters related to blood flow and vascular permeability in tumor and normal tissue after CA4P treatment. MATERIALS AND METHODS: Changes in kinetic DCE-MRI parameters (transfer constant [Ktrans] and area under contrast medium-time curve [AUC]) over 24 hours after treatment with CA4P were measured in 18 patients in a phase I trial and compared with those obtained in the rat P22 carcinosarcoma model, using the same imaging technique. Rats were treated with 30 mg/kg of CA4P; patients received escalating doses from 5 to 114 mg/m2. RESULTS: A similar pattern and time course of change in tumor and normal tissue parameters was seen in rats and humans. Rat tumor Ktrans was reduced by 64% 6 hours after treatment with CA4P (30 mg/kg). No significant reductions in kidney or muscle parameters were seen. Significant reductions were seen in tumor Ktrans in six of 16 patients treated at >or= 52 mg/m2, with a significant group mean reduction of 37% and 29% at 4 and 24 hours, respectively, after treatment. The mean reduction in tumor initial area under the gadolinium-diethylenetriamine pentaacetic acid concentration-time curve (AUC) was 33% and 18%, respectively, at these times. No reduction was seen in muscle Ktrans or in kidney AUC in group analysis of the clinical data. CONCLUSION: CA4P acutely reduces Ktrans in human as well as rat tumors at well-tolerated doses, with no significant changes in kidney or muscle, providing proof of principle that this drug has tumor antivascular activity in rats and humans.