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OBJECTIVE: The cost of treating metastatic colorectal cancer places a significant economic burden on individuals, populations, and health care. However, there is a paucity of information on the costs of the contemporary management of metastatic colorectal cancer. This systematic review aims to review the literature to estimate the direct cost of treating metastatic colorectal cancer. STUDY DESIGN: Systematic review. METHODS: MEDLINE, Embase, Web of Science, Evidence-Based Medicine Reviews: National Health Service Economic Evaluation Database Guide, EconLit, and grey literature from the 1st of January 2000 to the 1st of February 2020 were all searched for studies reporting the direct costs of treating metastatic colorectal cancer. The methodological quality of the included studies was assessed using the Evers' Consensus on Health Economic Criteria checklist. RESULTS: In total, 39,489 records were retrieved, and 29 studies were included. Costs of treating metastatic colorectal cancer varied because of the heterogeneity of treatment. Studies reported average costs ranged from $12,346 to $293,461. Studies that included the cost of systemic therapy reported an estimated cost of almost $300,000. CONCLUSION: The existing evidence indicates that the cost of treating metastatic colorectal cancer places a significant economic burden on healthcare systems despite differences in methodology and treatment heterogeneity. Future research needs to define the cost components of treating metastatic colorectal cancer to improve comparability and examine the relationship between spending, overall survival, and quality of life. Identifying these costs and their impact on health care budgets can help policymakers plan health system expenditure.

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Selective estrogen receptor modulators and a combination of mechanistically distinct chemotherapeutic agents represent conventional therapeutic interventions for estrogen receptor-positive (ER+) clinical breast cancer. Long-term treatment with these agents is associated with acquired tumor resistance and other adverse side effects that impact on patient compliance. Herbal medicines are being widely used in complementary and alternative medicine. However, long-term safety and efficacy of the use of herbal medicines, as well as their interaction with conventional endocrine and chemotherapeutic drug regimens remain largely unknown. The present study utilized a human cell culture model for ER+ clinical breast cancer to examine the potential therapeutic efficacy of an aqueous extract prepared from the fruit of popular Chinese herb Cornus officinalis (CO), also known as Fructus cornii. The human mammary carcinoma-derived MCF-7 cell line represented the model. Status of anchorage-independent growth and cellular metabolism of 17ß-estradiol (E2) represented the quantitative end-point biomarkers for efficacy. MCF-7 cells adapted for growth in serum-depleted medium (0.7% serum, <1 nM E2) retained their endocrine responsiveness as evidenced by growth promotion by physiological levels of E2, and growth inhibition by the selective ER modulator tamoxifen at the clinically achievable concentrations. Treatment of MCF-7 cells with CO resulted in inhibition of E2-stimulated growth in a dose-dependent manner. Similarly, CO treatment also produced a dose-dependent progressive reduction in the number of anchorage-independent colonies, indicating effective reduction of the carcinogenic risk. Treatment of MCF-7 cells with CO at a maximally effective cytostatic concentration resulted in a 5.1-fold increase in the formation of the anti-prolifertive E2 metabolite 2-hydoxyestrone (2-OHE1), a 63.6% decrease in the formation of the pro-mitogenic metabolite 16α-hydroxestrone (16-αOHE1) and a 9.1% decrease in the formation of mitogenically inert metabolite estrone (E3). These alterations led to a 14.5-fold increase in the 2-OHE1:16α-OHE1, and a 3.3-fold increase in the E3:16α-OHE1 ratios. These data validate a rapid cell culture-based mechanistic approach to prioritize efficacious herbal medicinal products for long-term animal studies and future clinical trials on ER+ clinical breast cancer.

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Selective estrogen receptor (ER) modulators are used as a therapy for ER+ clinical breast cancer, but they exhibit adverse effects. Herbal medicines may provide an alternative or complementary approach. Taheebo, extracted from the inner bark of the Tabebuia avellandae tree found in the Brazilian Amazon, exhibits selective anti-proliferative effects in carcinoma cell lines. The present study identifies the mechanistic leads for the inhibitory effects of Taheebo. Human breast carcinoma derived ER+MCF-7 cells were used as the model. Aqueous extract of Taheebo was the test compound. Cell cycle analysis, clonogenic assay, and global gene expression profiles were the quantitative parameters. Taheebo treatment resulted in a dose/time-dependent growth inhibition (S phase arrest, reduced clonogeneticity) and initiation of apoptosis (chromatin condensation). A 6-h treatment with 1.5 mg/ml Taheebo modulated the gene expression of G2 specific cyclin B1 (-2.0-fold); S phase specific PCNA (-2.0-fold) and OKL38 (+11.0-fold); apoptosis specific GADD-45 family (+1.9-5.4-fold), Caspases (+1.6-1.7-fold), BCL-2 family (-1.5-2.5-fold), estrogen responsive ESR1 (-1.5-fold), and xeno-biotic metabolism specific CYP 1A1 (+19.8 fold) and CYP 1B1 (+7.9-fold). The anti-proliferative effects of Taheebo correlate with down-regulated cell cycle regulatory and estrogen responsive genes, and up-regulated apoptosis specific and xeno-biotic metabolism specific genes. These data validate a rapid mechanistic approach to prioritize efficacious herbal medicines, thereby complementing the existing endocrine therapy for breast cancer.

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Kappa-opioid receptors are located on visceral pain fibres. JNJ-38488502 is a highly selective tetrapeptide kappa-opioid agonist with little access to the central nervous system and low risk of central nervous system side effects. The aim of the study was to evaluate the effects of i.v. JNJ-38488502 on sensations, including pain, during colonic distension. In a single-centre study, 23 healthy adult males underwent a single-dose, randomized, double-blind crossover study of JNJ-38488502 (0.42 mg kg(-1) i.v. infusion) vs placebo on left colon compliance, sensory thresholds and ratings during standard distensions. One participant could not undergo sensation studies. In the other 22, JNJ-38488502 increased colonic compliance (pressure at half-maximum volume 17.9 +/- 0.8 mmHg) compared to placebo (21.6 +/- 0.9 mmHg, P = 0.007). There was no significant effect on sensory thresholds which, however, were not reached by 44 mmHg in >50% of participants in both treatment phases. There were no significant treatment effects on sensory ratings to distensions at 8, 16, 24, 32 and 36 mmHg above baseline operating pressure. JNJ-38488502 was associated with increased urine output and plasma prolactin, consistent with kappa-opioid receptor activation. This study concluded that i.v. JNJ-38488502 induced kappa-opioid effects, but did not attenuate colonic sensations following random order colonic distension. Further studies of effects on pain sensations in health and disease are required.

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OBJECTIVE: To investigate whether the accuracy of vacuum cup placement can be improved by intrapartum ultrasound assessment of the fetal head position during the second stage of labor prior to vacuum extraction for prolonged second stage. METHODS: 50 women undergoing vacuum extraction for prolonged second stage were randomly allocated to either digital examination (n=25) or digital examination together with transabdominal intrapartum ultrasound (n=25) prior to vacuum extraction by the attending obstetrician. The distance between the centre of the chignon and the flexion point was then measured by a midwife immediately after delivery. The flexion point was defined as 6 cm posterior to the anterior fontanelle or 3 cm anterior to the posterior fontanelle. RESULTS: There were no statistically significant differences in the demographic data, duration of labor, incidence of induction/augmentation, and intrapartum complications between the two groups. The mean distance between the centre of the chignon and the flexion point was 2.1+/-1.3 cm in the group with digital examination and ultrasound assessment and 2.8+/-1.0 cm in the group with digital examination alone. The difference in the mean distance between the two groups was statistically significant (p=0.039). CONCLUSION: Intrapartum transabdominal ultrasound assessment of the fetal head position during the second stage of labor improves the accuracy of vacuum cup placement during vacuum extraction for prolonged second stage.

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Spondylocostal dysostosis (SCD) is a rare congenital disorder that is characterized by vertebral segmentation and formation defects, and asymmetrical rib anomalies. We describe a case diagnosed during the second trimester of pregnancy with the sonographic features of abnormal alignment of the spine, hemivertebrae in the thoracic spine and kyphoscoliosis. Three-dimensional ultrasound demonstrated a 'fan-like' rib cage with fusion of the ribs. The postmortem findings confirmed the ultrasound findings and were consistent with SCD.

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Pain from pancreatitis or pancreatic cancer can be both chronic and severe although little is known about the mechanisms that generate and maintain this pain. To define the peripheral sensory and sympathetic fibers involved in transmitting and modulating pancreatic pain, immunohistochemistry and confocal microscopy were used to examine the sensory and sympathetic innervation of the head, body and tail of the normal mouse pancreas. Myelinated sensory fibers were labeled with an antibody raised against 200 kD neurofilament H (clone RT97), thinly myelinated and unmyelinated peptidergic sensory fibers were labeled with antibodies raised against calcitonin gene-related peptide (CGRP) and post-ganglionic sympathetic fibers were labeled with an antibody raised against tyrosine hydroxylase (TH). RT97, CGRP, and TH immunoreactive fibers were present in parenchyma of the head, body and tail of the pancreas with the relative density of both RT97 and CGRP expressing fibers being head>body>tail, whereas for TH, a relatively even distribution was observed. In all three regions of the pancreas, RT97 fibers were associated mainly with large blood vessels, the CGRP fibers were associated with the large- and medium-sized blood vessels and the TH were associated with the large- and medium-sized blood vessels as well as capillaries. In addition to this extensive set of sensory and sympathetic nerve fibers that terminate in the pancreas, there were large bundles of en passant nerve fibers in the dorsal region of the pancreas that expressed RT97 or CGRP and were associated with the superior mesenteric plexus. These data suggest the pancreas receives a significant sensory and sympathetic innervation. Understanding the factors and disease states that sensitize and/or directly excite the nerve fibers that terminate in the pancreas as well as those that are en passant may aid in the development of therapies that more effectively modulate the pain that frequently accompanies diseases of the pancreas, such as pancreatitis and pancreatic cancer.

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OBJECTIVE: To examine the potential contribution of neurologic influences on hamstring length during passive range of motion. DESIGN: Prospective study. SETTINGS: Academic sports medicine center. PATIENTS: 15 subjects undergoing arthroscopic surgery for unilateral knee injuries without previous injury to the contralateral knee. INTERVENTIONS: Subjects received: 1) spinal anesthesia with bupivacaine, 2) epidural anesthesia with lidocaine, 3) general anesthesia, or 4) femoral nerve block of injured leg only. MAIN OUTCOME MEASURES: Noninjured leg popliteal angle preoperatively, intraoperatively under anesthesia, and postoperatively after recovery from anesthesia. RESULTS: The overall mean popliteal angle was 132.5 +/- 3.1 degrees preoperatively, 134.31 +/- 11.6 degrees intraoperatively, and 130.7 +/- 10.2 degrees postoperatively. Overall, the intraoperative angle was significantly greater than the postoperative angle (p = 0.02). The mean change in popliteal angle was 8.1 +/- 2.2 degrees (Group 1), -0.4 +/- 1.9 degrees (Group 2), 0.9 +/- 1.4 degrees (Group 3), and -2.4 +/- 3.8 degrees (Group 4). There was no significant change in pre- to postoperative popliteal angle in relation to postoperative pain. Females had a greater mean popliteal angle (139.84 degrees ) compared with males (128.84 degrees ) (p = 0.04). CLINICAL RELEVANCE: Understanding the neuromuscular influences on muscle flexibility will assist in the development of new rehabilitative and injury preventative techniques. CONCLUSION: The present pilot study implicates neural contributions to muscle flexibility. Further studies are needed to delineate the relative contributions of neural and muscular components and to facilitate new techniques in the rehabilitation and prevention of injury.

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BACKGROUND: The goal of this study was to determine if the combination of surgery and anesthesia is an independent risk factor for the development of incident (first-time) ischemic stroke. METHODS: All residents of Rochester, MN, with incident ischemic stroke from 1960 through 1984 (1,455 cases and 1,455 age- and gender-matched controls) were used to identify risk factors associated with ischemic stroke. Cases and controls undergoing surgery involving general anesthesia or central neuroaxis blockade before their stroke/index date of diagnosis were identified. A conditional logistic regression model was used to estimate the odds ratio of surgery and anesthesia for ischemic stroke while adjusting for other known risk factors. RESULTS: There were 59 cases and 17 controls having surgery within 30 days before their stroke/index date. After adjusting for previously identified risk factors, surgery within 30 days before the stroke/index date (perioperative period) was found to be an independent risk factor for stroke (P<0.001; odds ratio, 3.9; 95% confidence interval, 2.1-7.4). In an analysis that excluded matched pairs where the case and/or control underwent surgery considered "high risk" for stroke (cardiac, neurologic, or vascular procedures), "non-high-risk surgery" was also found to be an independent risk factor for perioperative stroke (P = 0.002; odds ratio, 2.9; 95% confidence interval, 1.5-5.7). CONCLUSION: Our results suggest that there is an increased risk of ischemic stroke in the 30 days after surgery and anesthesia. This risk remains elevated even after excluding surgeries (cardiac, neurologic, and vascular surgeries) considered to be high risk for ischemic stroke.

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Effective management of the pain of chronic pancreatitis may require a multidisciplinary approach involving gastroenterologists, anesthesiologists, psychologists or counselors for chemical addiction (alcohol, narcotics), and surgeons. Viable approaches use pharmacologic analgesics with selected psychotropic medications, celiac plexus blocks, and possibly thoracoscopic splanchnic nerve transections. If these management techniques that preserve pancreatic parenchyma and function, fail, resective surgical therapy may be indicated. For most of these patients, all attempts at nonresective therapy should be exhausted before operative intervention.

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A beta-escin-permeabilized canine tracheal smooth muscle preparation was used to test the hypothesis that cGMP decreases Ca2+ sensitivity in airway smooth muscle primarily by inhibiting the membrane receptor-coupled mechanisms that regulate Ca2+ sensitivity and not by inhibiting Ca2+/calmodulin activation of the contractile proteins. 8-Bromo-cGMP (100 microM) had no effect on the free Ca2+ concentration-response curves generated in the absence of muscarinic receptor stimulation. In the presence of 100 microM ACh plus 10 microM GTP, 8-bromo-cGMP (100 microM) caused a rightward shift of the free Ca2+ concentration-response curve, significantly increasing the EC50 for free Ca2+ from 0.35 +/- 0.03 to 0.75 +/- 0.06 microM; this effect of 8-bromo-cGMP was concentration dependent from 1 to 100 microM. 8-Bromo-cGMP (100 microM) decreased the level of regulatory myosin light chain (rMLC) phosphorylation for a given cytosolic Ca2+ concentration but had no effect on the amount of isometric force produced for a given level of rMLC phosphorylation. These findings suggest that cGMP decreases Ca2+ sensitivity in canine tracheal smooth muscle primarily by inhibiting the membrane receptor-coupled mechanisms that modulate the relationship between cytosolic Ca2+ concentration and rMLC phosphorylation.

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AIMS: To evaluate the efficacy and safety of orally administered naltrexone, alone or in combination with nicotine patches, as a treatment for cigarette smoking. DESIGN: Randomized, partially-blinded, 2 x 2 factorial trial using naltrexone (active vs. placebo) and nicotine patches (active vs. none). PARTICIPANTS: One hundred cigarette smokers. INTERVENTION: Twelve weeks of either placebo-only, naltrexone-only, placebo with nicotine patches or naltrexone with nicotine patches. The naltrexone dose was 50 mg taken once daily, and the nicotine patch dose was 21 mg/24-hour for the first 8 weeks and 14 mg/24-hour for the remaining 4 weeks. Brief behavioral intervention was provided at each visit. MEASUREMENTS: One-week point-prevalence smoking abstinence rates confirmed by an expired air carbon monoxide level of 8 parts per million (ppm) or less, daily cigarette smoking and cigarette craving. FINDINGS: At the end of treatment, there was no effect of naltrexone on smoking abstinence. The smoking abstinence rates were 19% and 22% for the placebo only and naltrexone only treatment groups, respectively, and 48% and 46% for the placebo with nicotine patch and naltrexone with nicotine patch groups, respectively. However, the effect of the nicotine patch at this time was significant (p = 0.006), but not at the 6-month follow-up. No significant effect of naltrexone was observed on daily cigarette smoking on cigarette craving during the study. CONCLUSIONS: The opioid antagonist naltrexone was not found to be effective for smoking cessation and had no significant effect on daily cigarette consumption or craving. The results of the present study provide no support for the use of naltrexone, alone or in combination with nicotine patches, as a therapeutic treatment for smoking cessation.

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UNLABELLED: Infraclavicular brachial plexus block is a technique well suited to prolonged continuous catheter use. We used a coracoid approach to this block to create an easily understood technique. We reviewed the magnetic resonance images of the brachial plexus from 20 male and 20 female patients. Using scout films, the parasagittal section 2 cm medial to the coracoid process was identified. Along this oblique section, we located a point approximately 2 cm caudad to the coracoid process on the skin of the anterior chest wall. From this point, we determined simulated needle direction to contact the neurovascular bundle and measured depth. At the skin entry site, the direct posterior insertion of a needle will make contact with the cords of the brachial plexus where they surround the second part of the axillary artery in all images. The mean (range) distance (depth along the needle shaft) from the skin to the anterior wall of the axillary artery was 4.24 +/- 1.49 cm (2.25-7.75 cm) in men and 4.01 +/- 1.29 cm (2.25-6.5 cm) in women. Hopefully, this study will facilitate the use of this block. IMPLICATIONS: We sought a consistent, palpable landmark for facilitation of the infraclavicular brachial plexus block. We used magnetic resonance images of the brachial plexus to determine the depth and needle orientation needed to contact the brachial plexus. Hopefully, this study will facilitate the use of this block.

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BACKGROUND AND OBJECTIVES: Interscalene brachial plexus block is a useful technique to provide anesthesia and analgesia for the shoulder and proximal upper extremity. The initial needle direction at the interscalene groove has been described as being "perpendicular to the skin in every plane" (1). A cross-sectional (axial) approach may offer a more easily conceptualized directed needle placement. The purpose of this study is to define the cross-sectional anatomy and idealized needle angles important to interscalene brachial plexus block. METHODS: Following IRB approval, 50 patients were studied. Cross-sectional volume coil T1-weighted magnetic resonance images (MRI) were obtained from 50 patients undergoing cervical region imaging for other reasons. At the interscalene groove, a simulated needle path to contact the ventral rami or trunks of the brachial plexus was approximated at the level of C6 or C6-C7 interspace. The angle of this needle path intersecting the sagittal plane was recorded for each patient. RESULTS: The mean angle of the simulated needle path relative to sagittal plane was determined to be 61.1 +/- 6.1 degrees (range, 50-78 degrees). In 13 of 50 (26%) MRI scans, the cervical nerve roots were not visualized at the level of C6 and were measured at the C6-C7 level. CONCLUSIONS: These findings suggest initial needle placement at the interscalene groove should be angled less perpendicularly relative to the sagittal plane than is often observed. A cross-sectional approach enables more practical visualization of initial needle placement. A more accurate initial needle placement may minimize the number of needle passes necessary to contact the nerve roots, thereby more efficiently obtaining a successful block.

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OBJECTIVE: To assess whether patients with pancreatic cancer-associated pain living near a pain control center were more likely to undergo neurolytic celiac plexus block (NCPB) than those living at a distance and to determine the rationale of physicians at our institution for referring patients for NCPB. DESIGN: We retrospectively reviewed the frequency of use of NCPB in patients with pancreatic cancer and conducted an anonymous physician survey of referral patterns for NCPB for such patients. MATERIAL AND METHODS: A prospective database of medical diagnoses and a clinical database at our institution were used to identify patients with pancreatic cancer within three geographic regions who were assessed during the inclusive years 1980 through 1989: group I ("local") = all patient with pancreatic cancer in Olmsted County, Minnesota; group II ("surrounding") and group III ("distant") = patients referred for pancreatic cancer evaluation who lived within 100 miles of our institution (excluding Olmsted County) or more than 100 miles from our institution, respectively. Medical records were retrospectively reviewed to assess the use of NCPB at any time during the course of pancreatic cancer. For the physician survey component, all medical oncologists, gastroenterologists, and general surgeons at our institution who might be responsible for the care of patients with pancreatic cancer were sent a questionnaire about their referral patterns for NCPB among patients with pancreatic cancer. RESULTS: Overall, approximately 15% of the 292 patients with pancreatic cancer studied underwent NCPB. Distance from our pain control center was not found to be associated with frequency of use of NCPB. Of the 78 physicians surveyed, 59 (76%) responded, and 35 of the responders (59%) had encountered at least 1 patient with pancreatic cancer during the preceding 12 months. In that subset of physicians, perceived barriers for referral for NCPB were limited appointment availability and need for repeating the procedure. CONCLUSION: On the basis of this study, referral patterns for NCPB in patients with pancreatic cancer do not seem to be associated with the geographic distance of a patient's residence from a pain control center. Improving appointment availability for NCPB might increase the number of patients offered this technique for control of pain.

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A new classification system, termed complex regional pain syndromes types I and II, has been devised to replace the nomenclature of pain disorders previously termed reflex sympathetic dystrophy and causalgia. CRPS type I does not have identifiable major nerve injury, whereas CRPS type II has an identifiable major nerve injury. The classification is based on clinical symptoms and signs without incorporating any mechanistic connotations. These CRPS disorders may have SMP, SIP, or both.

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