Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE).

Pexastimogene devacirepvec (Pexa-Vec) is a vaccinia virus-based oncolytic immunotherapy designed to preferentially replicate in and destroy tumor cells while stimulating anti-tumor immunity by expressing GM-CSF. An earlier randomized Phase IIa trial in predominantly sorafenib-naïve hepatocellular carcinoma (HCC) demonstrated an overall survival (OS) benefit. This randomized, open-label Phase IIb trial investigated whether Pexa-Vec plus Best Supportive Care (BSC) improved OS over BSC alone in HCC patients who failed sorafenib therapy (TRAVERSE). 129 patients were randomly assigned 2:1 to Pexa-Vec plus BSC vs. BSC alone. Pexa-Vec was given as a single intravenous (IV) infusion followed by up to 5 IT injections. The primary endpoint was OS. Secondary endpoints included overall response rate (RR), time to progression (TTP) and safety. A high drop-out rate in the control arm (63%) confounded assessment of response-based endpoints. Median OS (ITT) for Pexa-Vec plus BSC vs. BSC alone was 4.2 and 4.4 months, respectively (HR, 1.19, 95% CI: 0.78-1.80; p = .428). There was no difference between the two treatment arms in RR or TTP. Pexa-Vec was generally well-tolerated. The most frequent Grade 3 included pyrexia (8%) and hypotension (8%). Induction of immune responses to vaccinia antigens and HCC associated antigens were observed. Despite a tolerable safety profile and induction of T cell responses, Pexa-Vec did not improve OS as second-line therapy after sorafenib failure. The true potential of oncolytic viruses may lie in the treatment of patients with earlier disease stages which should be addressed in future studies. ClinicalTrials.gov: NCT01387555.

Alkaline pulping of some eucalypts from Sudan.

Four eucalypts (Eucalyptus camaldulensis, Eucalyptus microtheca, Eucalyptus tereticornis and Eucalyptus citriodora) grown in Sudan were examined for their suitability for pulping and papermaking with different alkaline methods. Their physical, morphological and chemical characteristics are reported. The pulping trials with E. citriodora and E. tereticornis were carried out using the kraft-AQ, soda-AQ, modified AS/AQ (ASA), ASAM and kraft methods. For the other two species, only the ASAM and the kraft process were applied. ASAM pulping gave the best results in terms of yield, degree of delignification, mechanical and optical pulp properties. The best pulps, obtained in kraft and ASAM cooking of E. citriodora, were bleached to 88% ISO brightness in a totally chlorine free bleaching sequence (OQ1O/PQ2P). The bleached pulps, especially the ASAM pulp, showed good papermaking properties and would be suitable for manufacture of writing and printing grades of paper.

International investigation of breast MRI: results of a multicentre study (11 sites) concerning diagnostic parameters for contrast-enhanced MRI based on 519 histopathologically correlated lesions.

A multicentre study was undertaken to provide fundamentals for improved standardization and optimized interpretation guidelines of dynamic contrast-enhanced MRI. Only patients scheduled for biopsy of a clinical or imaging abnormality were included. They underwent standardized dynamic MRI on Siemens 1.0 (163 valid lesions > or = 5 mm) or 1.5 T (395 valid lesions > or = 5 mm) using 3D fast low-angle shot (FLASH; 87 s) before and five times after standardized bolus of 0.2 mmol Gd-DTPA/kg. One-Tesla and 1.5 T data were analysed separately using a discriminant analysis. Only histologically correlated lesions entered the statistical evaluation. Histopathology and imaging were correlated in retrospect and in open. The best results were achieved by combining up to five wash-in or wash-out parameters. Different weighting of false-negative vs false-positive calls allowed formulation of a statistically based interpretation scheme yielding optimized rules for the highest possible sensitivity (specificity 30%), for moderate (50%) or high (64-71%) specificity. The sensitivities obtained at the above specificity levels were better at 1.0 T (98, 97, or 96%) than at 1.5 T (96, 93, 86%). Using a widely available standardized MR technique definition of statistically founded interpretation rules is possible. Choice of an optimum interpretation rule may vary with the clinical question. Prospective testing remains necessary. Differences of 1.0 and 1.5 T are not statistically significant but may be due to pulse sequences.

Pain and loss of function in head and neck cancer survivors.

Head and neck cancers are relatively uncommon malignancies and the characteristics of pain and functional impairments in survivors are not well studied. To characterize the incidence, location, severity, types and causes of pain; associated functional impairments, and pain management methods, the medical charts of 40 consecutive outpatients with biopsy-proven head and neck cancers were reviewed. Pain was severe in 52% (N = 21), and was located near sites of tumor origin. Pain was caused by tumor recurrence in 35% (N = 14), treatment sequelae in 30% (N = 12), multiple etiologies in 25% (N = 10), and unrelated causes in 10% (N = 4). Pains were mixed nociceptive and neuropathic pain in 37.5% (N = 15), nociceptive pain in 32.5% (N = 13), myofascial in 13.0% (N = 6), neuropathic in 7.5% (N = 3); and other mixed types in 7.5% (N = 3). Despite the high prevalence of dysphagia (82%), 60% used orally administered opioid-nonopioid analgesics. Physical disfigurement (87.5%; N = 35), dysphagia (62.5%, N = 25), and jaw dysfunction (40.0%; N = 16) were the most frequent physical impairments. Multiple regression analysis showed that the presence of skull base or mandibular bone involvement had significant influence on the severity of pain (P = 0.03, adjusted R2 0.25) We conclude that pain in head and neck cancer can be chronic, severe, and persistent despite completion of oncologic treatment.

Complex renal cysts: findings on MR imaging.

OBJECTIVE: We retrospectively evaluated our experience with complex cystic renal masses on MR imaging, using T1-weighted, T2-weighted, and gadolinium-enhanced images, to determine whether imaging features could permit distinction between benign and malignant lesions. MATERIALS AND METHODS: Thirty-seven patients with complex cystic renal lesions were included in this retrospective study. The patients selected had undergone T1-weighted, T2-weighted, and gadolinium-enhanced MR imaging examinations using 1.5-T scanners, with at least one of the following findings: cyst fluid of heterogeneous signal intensity, mural irregularity, septa, mural masses or nodules, increased mural thickness, or intense mural enhancement. The diagnosis was established by histology in 19 patients and by follow-up studies in the remaining 18 patients. RESULTS: Fifty-five complex renal cystic lesions were present in the 37 patients. Among the 55 lesions, of 37 that contained fluid of a heterogeneous signal intensity, eight were malignant (22%); of 16 with irregular walls, 10 were malignant (63%); of four with septa, two were malignant (50%); of four with mural masses or nodules, three were malignant (75%); of 14 with a thick wall (>2 mm), 10 were malignant (71%); and of 32 with intense mural enhancement, 14 were malignant (44%). As independent variables, mural irregularity, mural masses or nodules, increased mural thickness, and intense mural enhancement each were highly associated with malignancy (p = .0003-.0022). The combination of mural irregularity and intense mural enhancement had the highest correlation with malignancy (p = .0002). CONCLUSION: The combination of mural irregularity and intense mural enhancement is a strong predictor of malignancy in renal cystic lesions. However, the appearance of benign and malignant lesions may overlap, suggesting that distinct separation of these entities is not currently possible in all cases with MR imaging.

T2-weighted MRI of the uterus: fast spin echo vs. breath-hold fast spin echo.

This study compared one routine T2-weighted fast spin echo (T2FSE) sequence with a breath-hold T2FSE (BH T2FSE) sequence of the female pelvis for image quality, uterine anatomy, lesion detection, and signal intensity measurements. Thirty-two consecutive women (mean age 41.7 years) were imaged at 1.5 T with one high-resolution routine T2FSE sequence and one BH T2FSE sequence in the sagittal plane as part of comprehensive pelvic magnetic resonance imaging. The different image sets were rated separately for imaging characteristics (overall image quality, uterine anatomy definition, lesion detection, and free fluid conspicuity) and then compared side by side. The image sets were also compared for artifacts (ghosting, blurring, pulsatility, and chemical shift misregistration). Signal-to-noise (S/N) and signal difference-to-noise (SD/N) ratios were calculated for the different uterine zones, uterine abnormalities, free fluid, rectus abdominis muscle, and bladder. Contrast-to-noise ratios (CNRs) were calculated for uterine abnormalities. Twenty-eight uterine abnormalities were detected in 20 patients and included leiomyomata (13 patients), adenomyosis (7 patients), benign endometrial polyps (6 patients), endometrial carcinoma (1 patient), and pregnancy (1 patient). BH T2FSE was superior or equivalent to T2FSE for overall image quality in 23/32 patients (71.8%), uterine anatomy definition in 19/32 patients (59.3%), and lesion detection in 13/20 patients (65%). BH T2FSE performed less well than T2FSE for free fluid conspicuity in 5/5 (100%) patients. BH T2FSE was equivalent to or less affected than T2FSE for ghosting artifact in 24/32 patients (75%) and blurring artifact in 29/32 patients (90.6%). Pulsatility and chemical shift artifacts were not problematic for either image set. S/N and SD/N were higher for all BH T2FSE determinations compared with T2FSE. For the endometrium, junctional zone, myometrium, and bladder, these differences were statistically significant. There were no statistically significant differences for CNR between the two image sets, although BH T2FSE values for leiomyomata, adenomyosis, and abnormal endometria were higher than those calculated for T2FSE. All pathology detected with T2FSE was detected on BH T2FSE despite the breath-hold sequence's inherently poorer spatial resolution compared with the non-breath-hold sequence. BH T2FSE may be able to replace T2FSE for some uterine applications with a substantial time savings.

Dose-titration, multicenter study of oral transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain.

PURPOSE: Supplemental, "as-needed," administration of an opioid is a common approach to the problem of breakthrough pain in cancer patients. Oral transmucosal fentanyl citrate (OTFC) is undergoing investigation as a new treatment for breakthrough pain. The primary purpose of the study was to demonstrate that a single-unit dose of OTFC can safely and effectively treat breakthrough pain. A secondary goal was to determine appropriate dosing guidelines. PATIENTS AND METHODS: This was a multicenter, randomized, double-blind, dose-titration study in 62 adult cancer patients using transdermal fentanyl for persistent pain. Consenting patients provided 2 days of baseline data to evaluate the performance of their usual breakthrough pain medication. Patients then randomly received 200 microg or 400 microg OTFC in double-blind fashion. (Patients were always assigned, rather than randomized, to 200 microg if 400 microg represented > 20% of around-the-clock medication.) Pain intensity (PI), pain relief (PR), and global satisfaction scores were recorded. OTFC was then titrated until the patient received adequate PR for each episode using one OTFC unit. Orders to titrate up were ignored one third of the time to improve the blind. Two days of baseline data were compared with 2 days of OTFC data after titration identified an effective dose of OTFC. RESULTS: Most patients (76%) found a safe and effective dose of OTFC. There was no meaningful relationship between the around-the-clock opioid regimen and the effective dose of OTFC. In open-label comparisons, OTFC produced a faster onset of relief and a greater degree of PR than patients' usual breakthrough medication. Somnolence, nausea, and dizziness were the most common side effects associated with OTFC. CONCLUSION: Most patients find a single OTFC dosage that adequately treats breakthrough pain. The optimal dose is found by titration and is not predicted by around-the-clock dose of opioids.

Breakthrough pain in cancer patients: characteristics, prevalence, and treatment.

"Breakthrough pain" is a common clinical term that has not been conclusively defined or described. Breakthrough pain is a transitory flare of pain experienced when baseline pain has been reduced to a mild or moderate level. Breakthrough pain may be characterized by its relationship to a fixed around-the-clock (ATC) opioid dose, rapid onset and short duration, precipitating events, predictability, pathophysiology (with nociceptive pain being most easily controlled), and etiology. The only prospective study of breakthrough pain conducted to date found a 63% prevalence of breakthrough pain in cancer patients referred to a pain service. Although prevalence figures from other studies vary widely, partly due to the populations chosen, all of the studies verify that breakthrough pain is a serious problem in cancer patients. In fact, several studies have listed incident pain, a subset of breakthrough pain, as a predictor of poor response to analgesic therapy. Breakthrough pain is currently managed with oral or parenteral breakthrough pain medications given in addition to the ATC analgesic regimen. The ATC dosage may also be increased until limited by side effects. Newer agents with a more rapid onset of analgesia and shorter duration of effect may help in the management of breakthrough pain.

Sequential use of ferumoxide particles and gadolinium chelate for the evaluation of focal liver lesions on MRI.

This study describes the sequential use of ferumoxide (superparamagnetic iron oxide) particles and nonspecific extracellular gadolinium chelate (Gd) for evaluation of focal liver lesions on MRI to evaluate order of contrast administration and imaging effect of the first contrast agent on sequences acquired after the second contrast agent. Thirteen patients underwent MR examinations that included ferumoxide and Gd. The order and timing of administration were as follows: separate sessions (three patients; Gd study 4-19 days before ferumoxide study), same session, Gd first (seven patients; Gd study 1-2 hours before ferumoxide study), and same session, ferumoxide first (three patients; ferumoxide administered less than 1 hour before Gd study). Postcontrast sequences were reviewed in a randomized, blinded fashion by two separate investigators. Determination was made regarding whether (a) the presence of the first agent administered could be detected on sequences obtained after the second agent and (b) the presence of the first agent interfered with the image quality of those sequences. No evidence for the presence of Gd was appreciated by either observer on postferumoxide sequences acquired in separate session studies. In same session, Gd first studies, the presence of Gd was observed in six of seven patients on T1-weighted spoiled gradient-echo (SGE) images obtained after ferumoxide administration. The presence of Gd was not apparent in seven of seven patients on T2-weighted fat-suppressed images obtained after ferumoxide. In same session, ferumoxide first studies, the presence of ferumoxide was appreciated on post-Gd sequences in two of three patients. The presence of ferumoxide did not appreciably diminish image quality on those sequences. Exact agreement was achieved by the independent investigators. Our results suggest that Gd and ferumoxide can be administered sequentially within one study session without substantial loss of diagnostic information obtained on sequences performed after administration of the second contrast agent. Administrating Gd first resulted in less of an effect of the visualization of the first agent on sequences acquired after the second agent.

Neural blockade for abdominopelvic pain of oncologic origin.

Neural blockade, like other accepted treatments for persistent pain, is not a panacea. Careful assessment is required to elicit the need for complementary interventions, including pharmacological management and psychobehavioral and rehabilitative approaches, combined with attention to the palliation of other symptoms. Celiac and superior hypogastric plexus blocks are well-accepted, effective, and minimally hazardous means for providing palliation of visceral abdominopelvic pain. Although they require radiological imaging, they are relatively undemanding of the experienced anesthesiologist pain specialist and do not deplete patients' limited resources and energy. Because of their uniquely favorable risk:benefit ratio, these procedures should be considered early in the course of treating patients with abdominopelvic pain that is expected to persist.

Palliation of intractable cancer pain by MRI-guided cingulotomy.

CASE REPORT: Three cases of intractable pain arising from widespread metastatic cancer with poor response to opioids were treated with MRI-guided cingulotomy. RESULTS AND CONCLUSIONS: In most cases, MRI-guided cingulotomy was associated with significant pain relief and reduced opioid use. To provide insight into the role of MRI-guided cingulotomy in oncologic pain refractory to more conservative measures, the relative risks and benefits of cingulotomy are discussed, along with the course of one patient who experienced postoperative cognitive impairment. This report also describes the relevant neurosurgical and pharmacotherapeutic issues associated with management of pain in patients with widespread metastatic disease.

Clinical realities and economic considerations: economics of intrathecal therapy.

The estimated annual cost of medical management of chronic back pain is $25 billion. Such management is often ineffective and overly costly. Most physicians who have employed intrathecal pain therapy attest to its efficacy in the management of intractable chronic pain. However, few economic analyses are available to evaluate the cost effectiveness of different modalities and to aid in clinical decision making and third-party reimbursement policies. Current analyses tend to focus on short-term cost-benefit measurements and to ignore variables such as quality of life and patient functioning. This bias has impaired the ability of payers to make appropriate decisions regarding the safety, cost effectiveness, and efficacy of intrathecal pain therapy in noncancer patients. Clinical data demonstrate that for cancer patients whose expectancies exceed 3 months, the overall costs of intrathecal pain therapy may be less than those of tunneled epidural catheters or external infusion devices. In nonmalignant pain, intrathecal therapy appears to be cost effective compared to conventional medical management at 22 months. Further debate and fine tuning of these economic models from all perspectives are required.

High-dose epidural infusion of opioids for cancer pain: cost issues.

The safety and efficacy of intraspinal opioids as therapy for selected patients with cancer pain are well-established. The choice of the appropriate drug is influenced by many variables that are to date incompletely elucidated. The cost of therapy is an increasingly important component of decision-making. This report describes the management of a patient who achieved excellent pain control with the administration of epidural sufentanil and bupivacaine. Daily Average Wholesale Price for sufentanil was, however, $698. Until the data comparing the efficacy of different epidurally administered opioids in the treatment of cancer pain are available, we suggest that treatment with more costly opioids be reserved for patients for whom analgesia cannot be achieved after maximizing epidural morphine analgesia with aggressive side-effect management.

Effective but near disastrous subarachnoid neurolysis for mechanical root pain in a paraplegic cancer patient.

CASE REPORT: A 43-year-old white man with advanced renal cell carcinoma and consequent paraplegia complained of the new onset of lancinating pain involving the right upper chest wall. This pain, which was superimposed on well-controlled chronic back pain and was intermittent and related to activity, failed to respond to conventional pharmacologic management. METHODS AND RESULTS: A cisternal myelogram suggested an absence of gross rostral extension of spinal metastases, and subarachnoid neurolysis was performed with hyperbaric phenol. Unexpected contralateral brachial weakness developed towards the conclusion of the procedure, but resolved spontaneously. The target pain had not recurred at follow-up 8 months later.

MR imaging appearance of the uterus in postmenopausal women receiving tamoxifen therapy for breast cancer: histopathologic correlation.

PURPOSE: To describe the spin-echo and dynamic gadolinium-enhanced magnetic resonance (MR) imaging appearance of the uterus in women receiving tamoxifen. MATERIALS AND METHODS: Thirty-five postmenopausal women with breast carcinoma receiving tamoxifen therapy underwent pelvic MR imaging. T1-weighted, T2-weighted, and dynamic gradient-echo T1-weighted sequences were used. Twenty-seven patients underwent uterine sampling within 3 months of MR imaging. RESULTS: Endometrial width on T2-weighted images ranged from 0.1 to 7.5 cm (mean thickness, 1.1 cm). Two uterine imaging patterns were noted. Patients with pattern 1 findings had homogeneous high signal intensity of the endometrium on T2-weighted images (mean, 0.5 cm) and enhancement of the endometrial-myometrial interface and a signal void in the lumen on gadolinium-enhanced images (18 patients). Patients with pattern 2 findings had heterogeneous endometrial signal intensity on T2-weighted images (mean, 1.8 cm) with enhancement of the endometrial-myometrial interface and latticelike enhancement traversing the endometrial canal on gadolinium-enhanced images (17 patients). Other imaging findings included subendometrial cysts, nabothian cysts, leiomyoma, and adenomyosis. Ten patients with pattern 1 findings had atrophic or proliferative endometria at histopathologic analysis; 12 of the 17 patients with pattern 2 findings had polyps, one of which had a focus of endometrial carcinoma. CONCLUSION: MR imaging of the uterus showed two distinct patterns in women receiving tamoxifen therapy.

Psoas sheath chemical neurolysis for management of intractable leg pain from metastatic liposarcoma.

CASE REPORT: A 56-year-old man with widely metastatic liposarcoma, after left Tower extremity amputation, complained of severe right lower extremity pain. Trials of systemic opioids had resulted in poor pain control while introducing intolerable dose-limiting side effects. METHODS AND RESULTS: Initial inpatient management consisted of a lumbar epidural infusion of a dilute local anesthetic and preservative-free morphine. This provided satisfactory relief but was discontinued because of recrudescence of phantom limb pain. A lumbar epidural infusion of preservative-free morphine sulfate was associated with poor pain relief, central nervous system (CNS) side effects, and severe urinary retention resulting in acute renal failure. A repeated trial of parental opioids provided marginal pain relief with persistent CNS side effects. Chemical neurolysis of the lumbar plexus was performed with 10 ml of 10% aqueous phenol injected into the psoas muscle sheath. The pain gradually resolved over a 2-day period without apparent side effects. Motor function was preserved, pain was resolved, and as systemic opioids were reduced, cognitive function and overall well-being were improved.